IAP

Textbook
of Pediatrics
4th Edition
 IAP
Textbook
of Pediatrics
4th Edition
Editor-in-Chief
A Parthasarathy
Professor of Pediatrics, Madras Medical College, and
Deputy Superintendent, Institute of Child Health and Hospital for Children, Chennai (Retired)
National President, IAP 1997, Regional Advisor, APPA, 1997–99
Founding Editor-in-Chief, Indian Journal of Practical Pediatrics
Contributory Editor, ColorAtlas of Tropical Pediatrics, American Academy of Pediatrics 2009

Executive Academic Editor

PSN Menon
Sub-Dean, Professor of Pediatrics, Division of Pediatric Endocrinology and
Officer in-Charge Genetic Unit, All India Institute of Medical Sciences, New Delhi (Retired)
Consultant and Head, Department of Pediatrics
Jaber Al-Ahmed Armed Forces Hospital, Kuwait

Senior Editors
RK Agarwal Panna Choudhury
President, IAP 2008 President, IAP 2009
Senior Consultant Pediatrician and Director Editor-in-Chief, Indian Pediatrics 2005-7
RK Hospital Consultant Pediatrician
Udaipur, Rajasthan, India Lok Nayak Hospital, New Delhi, India

Naveen C Thacker Deepak Ugra

President, IAP 2006 President Elect, IAP 2010
Senior Consultant Pediatrician and Director Consultant Pediatrician
Deep Children Hospital and Research Centre Lilawati Hospital and Research Centre, Mumbai
Gandhidham (Kutch), Gujarat, India Guru Nanak Hospital and Research Centre, Mumbai

Senior Academic Editors

Piyush Gupta MKC Nair
Professor of Pediatrics Professor of Pediatrics and Clinical Epidemiology
University College of Medical Sciences Director, Child Development Centre
New Delhi, India Medical College, Thiruvananthapuram, Kerala, India
Editor-in-Chief, Indian Pediatrics 2008-10 President IAP 2004, President INDIACLEN 2005-7
Executive Editors
Rohit C Agrawal Tanmay Amladi
Honorary Secretary General, IAP 2007-08 Treasurer, IAP 2007-8, Honorary Neonatologist
Director, Chandra-Jyoti Children Hospital Nowrosjee Wadia Maternity Hospital and NICU
Mumbai, Maharashtra, India Parel, Mumbai, Maharashtra, India
Academic Editor
K Nedunchelian
Editor-in-Chief, Indian Journal of Practical Pediatrics
Assistant Professor of Pediatrics, Madras Medical College
Institute of Child Health and Hospital for Children, Chennai, Tamil Nadu, India
®

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IAP Textbook of Pediatrics , 4th edition

© 2009, Indian Academy of Pediatrics, Kailas Darshan, 1st Floor, Kennedy Bridge, Nana Chowk, Mumbai 400 007, India
Tel: (022) 23887906/23887922/23889565 Fax: (022) 23851713
E-mail: iapcoff@bom5.vsnl.net.in; centraloffice@iapindia.org
Websites: www.iapindia.org/www.ijpp.org/www.indianpediatrics.net/www.iapdrugformulary.com
All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means:
electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the Indian Academy of Pediatrics and
the publisher.

This book has been published in good faith that the material provided by editors is original. Every effort is made to ensure accuracy of
material, but the publisher, printer and Indian Academy of Pediatrics will not be held responsible for any inadvertent error(s). In case of
any dispute, all legal matters are to be settled under Delhi jurisdiction only.

First Edition: 1999, 2000

Second Edition: 2002, 2003
Third Edition: 2006
Revised Reprint 2007
Fourth Edition: 2009
ISBN 978-81-8448-580-6
Typeset at JPBMP typesetting unit
Printed at Ajanta
 To
The Children of India
Whose Care, Survival and
Development are Our Concern
IAP Textbook of Pediatrics
“… This textbook has covered all aspects of child health contributed by reputed authors, in addition to
National Health Programs. Thus, it has fulfilled all the criteria of a ‘reader friendly’ treatise…”

Dr Uday Bodhankar
President, IAP 1995
President, ISTP 1999-2001
Nagpur

“… Several luminaries who are past and present teachers have contributed their might which has made the
present textbook a novel production in many aspects…”

Prof YC Mathur
President, IAP 2001
Hyderabad

“… Indeed it is a millennium gift to students and practitioners in a well written and well presented
comprehensive format covering A to Z in Pediatric care…”

Dr Swati Y Bhave
President, IAP 2000
New Delhi

“… Teachers of Pediatrics will find in this book guidelines for the course contents in undergraduate and
postgraduate medical education. Medical students will find readable and reasonably detailed, yet concise
information in this book, not only to complete the course and pass the final examination, but also to guide
them during their clinical career as intern, house surgeon and medical practitioner…”

Prof T Jacob John

President, IAP 1999
Vellore

“… I hope this textbook finds an appropriate place in the students' and practitioners' bookshelf. I sincerely
wish that this book is also suitable for undergraduates and postgraduates…”

Prof MR Lokeshwar
President, IAP 1998
Mumbai
Contributors
Aditi Sinha Agarwal RK Anand N Pandit
Senior Research Associate Consultant Child Specialist British Council Building
Department of Pediatrics RK Hospital 917/1 Fergusson College Road
All India Institute of Medical 5A Madhuban Pune 411 004, Maharashtra
Sciences, New Delhi 110 029 Opposite RSEB Window Email: kemhrc@vsnl.com
Residence Udaipur 313 001, Rajasthan
5B Srijan Apartments Email: rk_hospital@hotmail.com; Anand RK
B 9/8 Sector 62 presidentiap2008@gmail.com 55 Kavi Apartments, Worli
Noida Mumbai 400 018, Maharashtra
Uttar Pradesh Ajit Kumar
Email: ishanand@rediffmail.com
Email: aditisinha4@rediffmail.com 3/6/69/B/20/4/A
Avanti Colony
Near Skyline Theatre Anandam R
Advani SH
KB Lal Road, Bashirbag Professor of Pediatric Neurology (Retd)
Director
Hyderabad 500 029 Consultant Neurologist
Department of Medical Oncology
Jaslok Hospital, Peddar Road Andhra Pradesh PRS Hospital, Killippalam
Mumbai Thiruvananthapuram, Kerala
Maharashtra Amdekar YK Residence
Residence 151 ‘Tushar’ 1st Floor ”RAJCOT”
201 Satyam Shivam Sunderam 14th Road Chembur Thycaud
Ghatkopar Mumbai 400 071, Maharashtra Thiruvananthapuram 695 014
Mumbai 400 077 Email: ykasya@gmail.com Kerala
Maharashtra Email: anandam45@yahoo.com
Email: shadvani2000@rediffmail.com Amit Upadhyaya
Consultant Hematologist Anil Mokashi
Agarwal DK Sunflag-Pahuja Center for Ramabai Maternity General
D-115 Sector 36, Noida Blood Disorders and Children’s Hospital
Gautam Budh Nagar 201 301 Sunflag Hospital, Faridabad Baramati, Pune 413 102
Uttar Pradesh Haryana Maharashtra
Email: dramit.upadhyay@yahoo.co.in
Agarwal KN Anil Sachdev
D-115 Sector 36, Noida Amrish Vaidya
63/12
Gautam Budh Nagar 201 301 Consultant Pediatric Surgeon
Old Rajinder Nagar
Uttar Pradesh Kokilaben Dhirubhai Ambani
New Delhi 110 060, Delhi
Email: kna_noida@hotmail.com; Hospital, Andheri West
Email: anilcriticare@hotmail.com
adolcare@hotmail.com Mumbai 400 053
Maharashtra
Agarwal R Residence Anita Khalil
Department of Pediatrics 5E Sundatta Apartments The Heart Centre
BJ Wadia Hospital for Children and 10A Mount Pleasant Road 2 Ring Road
Institute of Child Health Mumbai 400 006 Lajpat Nagar IV
Parel, Mumbai 400 012 Maharashtra New Delhi 110 024, Delhi
Maharashtra Email: amrishvaidya@yahoo.com Email: anitakhalil@yahoo.com
X IAP Textbook of Pediatrics

Anju Aggarwal Archana Sathe Ashish R Bavdekar

Reader in Pediatrics ’Om Padmalaya’ 11 Yeshwant Nagar
University College of Medical 1123/A Shukrawar Peth Ganeshkhind Road
Sciences and Guru Tegh Bahadur Opposite Hirabag Pune 411 007
Hospital Pune 411 002 Maharashtra
Delhi Maharashtra Email: bavdekar@vsnl.com
Residence
Flat # 3C Block C2B, Janakpuri Armida Fernandez Ashok Gupta
New Delhi 110 058, Delhi 53 Sea Springs 25 Chetak Marg
Email: aggar_anju@yahoo.com; BJ Road, Band Stand Near JK LON Hospital
aanju67@gmail.com Bandra (West) Jaipur 302 004, Rajasthan
Mumbai 400 050 Email: dr_ashok_05@hotmail.com
Anju Virmani Maharashtra
C 6/6477 Email: drfernandez@snehamumbai.org Ashok K Deorari
Vasant Kanj Professor of Pediatrics
New Delhi 110 070 Arun Gupta Division of Neonatology
Email: virmani.anju@gmail.com BP 33, Pitampura All India Institute of
New Delhi 110 034, Delhi Medical Sciences
Anupam Sachdeva Email: ritarun@vsnl.com New Delhi 110 029
C-107 Neelambar Apartment Residence
Near Sainik Vihar Arun Kumar Gupta D-II/22, Ansari Nagar
Shakurbasti Professor and Head New Delhi 110 029, Delhi
New Delhi 110 034 Department of Radiodiagnosis Email: sdeorari@yahoo.com;
Email: anupamace@yahoo.co.in All India Institute of ashokdeorari_56@hotmail.com
Medical Sciences, New Delhi 110 029
Anupama Borker Email: arun676@hotmail.com; Ashok K Gupta
Consultant Pediatric arunk676@yahoo.com 50 B/D, Gandhinagar
Hemato-Oncologist Jammu 180 004
SL Raheja Hospital Arun Phatak Jammu and Kashmir
Mahim, Mumbai 102 Ambica Apartments Email: doc_ashokg@yahoo.com
Maharashtra Shanker Tekri
Residence Dandia Bazaar Ashok K Patwari
22 Kaustubh Plot # 8 Vadodara 390 001 Reader’s Flat # 4
Bandra Reclamation Gujarat LHMC Campus
Bandra (West) Email: atphatak@satyam.net.in Bangla Sahib Road
Mumbai 400 050 New Delhi 110 001
Maharashtra Arunmozhi T Email: akpatwari@hotmail.com;
Email: anupamasb@hotmail.com Assistant Professor of akpatwari@gmail.com
Community Medicine
Anurag Tomar Madras Medical College Ashok S Kapse
4 Govind Marg Residence Kapse Children Hospital
Jaipur 302 004 8I Block, 2nd Main Road 1st Floor, Akshar Complex
Rajasthan Chennai 600 102 B/H Rang Upvan, Makkaipool
Email: anurag@nimsr.com Tamil Nadu Surat 395 001, Gujarat
Email: ashokkapse@hotmail.com
Archana S Kher Arvind Bagga
6/A Anand Bhavan Professor of Pediatrics Babu George
36th Road, TPS III Division of Nephrology Medical Superintendent
Bandra (West) All India Institute of Medical Child Development Centre
Mumbai 400 050 Sciences, Ansari Nagar Medical College Campus
Maharashtra New Delhi 110 029 Thiruvananthapuram,
Email: kheras@bom8.vsnl.net Email: arvindbagga@hotmail.com Kerala
 Contributors XI

Balachandran A Bharat Agarwal Brijesh Arora

F/177 Plot # 235 A1101 Jagat Vidya CHS Associate Professor
Anna Nagar, Chennai 600 102 Behind Guru Nanak Hospital Pediatric Oncology
Tamil Nadu Bandra-Kurla Complex Tata Memorial Hospital
Email:dr_abalachandran@hotmail.com; Bandra (East) Ernest Borges Marg
drabalachandran@yahoo.com Mumbai 400 051 Parel, Mumbai 400 012
Maharashtra Maharashtra
Baldev S Prajapati Email: parul@bom5.vsnl.net.in Residence
Aakanksha Children Hospital House No 7 Anand Bhavan
Opposite Tulsishyam Flats Bhula Bhai Desai Road
Bharat Dalvi
Nava Vadaj Road Near Breech Candy Hospital
Division of Pediatric Cardiology
Ahmedabad 380 013 Mumbai 400 026
Gujarat Department of Cardiology Email: brijesharora@rediffmail.com
Email: drbprajapati@yahoo.co.in King Edward VII Memorial Hospital
Mumbai, Maharashtra Chandan J Das
Balvir S Tomar Senior Research Associate
4 Govind Marg Bhaskar Raju B Department of Radiodiagnosis
Jaipur 302 004 # 11 Sringeri Mutt Road All India Institute of Medical
Rajasthan Ramkrishna Nagar Sciences
Chennai 600 028 New Delhi 110 029
Banapurmath CR Tamil Nadu Email: chandanjd@yahoo.com
DOOR # 176 3rd Main Road Email: drbhaskarraju@yahoo.com
PJ Extension Choudhry VP
Devangere 577 002, Karnataka A-26 Shivalik
Bhavuk Garg
Email: crbanapurmath@hotmail. com Malviya Nagar
Senior Research Associate
New Delhi 110 017, Delhi
Banerjee SR Department of Orthopedics Email: vedpchoudhry@yahoo.co.in
8 Jessore Road, Dum Dum All India Institute of
Kolkata 700 028, West Bengal Medical Sciences Dadhich JP
Email: purnima@cal.bsnl.net.in; New Delhi 110 029 23 Canara Apartments
srbanerjee@vsnl.net Residence Sector 13, Rohini
525 Masjid Moth Doctor’s Hostel New Delhi 110 085, Delhi
Baskar PK Masjid Moth
Director Email: jpdadhich@gmail.com
New Delhi 110 049
Sri Viveka Institute of Dental
Email: drbhavukgarg@gmail.com Dagar KS
Sciences
54, GN Chetty Road, T Nagar Consultant
Bina Ahuja Department of Pediatrics and
Chennai 600 017, Tamil Nadu
Clinical Specialist Congenital Heart Surgery
Bhandari B National Polio Surveillance Project Escorts Heart Institute and
90/L Road, Bhupalpura India-WHO Research Centre, Okhla Road
Udaipur 313 001, Rajasthan RK Khanna Tennis Stadium New Delhi
Bhandari NR Africa Avenue
C-32 Koh-e-Fiza New Delhi 110 029 Dani VS
BDA Colony Residence Gandhi Sagar (East)
Bhopal 462 001 E 285 Narain Vihar Mahal
Madhya Pradesh New Delhi 110 028, Nagpur 440 002
Email: bhandari33@rediffmail.com; Email: ahujabina@rediffmail.com; Maharashtra
nr_bhandari@yahoo.com ahujabi@npsuindia.org Email: visadani@nagpur.dot.net.in
XII IAP Textbook of Pediatrics

Deepak Bansal Dutta AK Guruprasad G

House # 1334, Sector 19 Flat # 8 2164 ‘Veda’ IV Main X Cross
Faridabad, Haryana Lady Hardinge Medical College MCC A Block
Email: deepakkritu@yahoo.com Campus, New Delhi 110 001, Delhi Devangere 577 004
Email: drdutta@gmail.com Karnataka
Deepak Seth Email: gurug61@hot.com;
Department of Pediatrics Gadadhar Sarangi dr_g_gp@yahoo.com
Himalayan Institute of Professor
Harish Kumar
Medical Sciences Department of Pediatrics
12/406 Sunder Vihar
Post Doiwala, Dehradun 248 140 Hitech Medical College, Pandara, New Delhi 110 041
Uttarakhand Bhubaneswar, Orissa Email: harishalwadhi@hotmail.com;
Email: drdeepakseth@rediffmail.com Residence hkumar@unicef.org
C/o Dr Laxmi Kanta Mohapatro
Indra Shekhar Rao M
Deepak Ugra At Telisahi (Parijat Lane)
Former Medical Superintendent
A-402/403 Sausalito Ranihat, Cuttack 753 001, Orissa Institute of Child Health and
Kia Park Prathamesh Complex Email: gdsarangi@sify.com; Niloufer Hospital, Hyderabad
Veera Desai Road, Andheri (West) gdsarangi@hotmail.com Andhra Pradesh
Mumbai 400 053 Residence
Email: deepakugra@hotmail.com Ganessan KM Indra Prastha
13 Chinna Mudali Street Plot # 106
Desai AB Gudiyattam Abhinav Nagar
1004 Panchtirth Gudiyattam 632 602, Tamil Nadu Secunderabad 500 025
Jodhpur Char Rasta, Satellite Email: dr_kmganessan@ rediffmail. com Andhra Pradesh
Ahmedabad 380 015, Gujarat Email: indramummulla@yahoo.co.in
Email: drabdesai@hotmail.com George Moses L
Iyer KS
Prof of Microbiology (Retd)
Senior Consultant and Head
Digant D Shastri Director
Department of Pediatrics and
Killol Children Hospital Kilpauk Laboratory Services Congenital Heart Surgery
303-304 Takshashila Apartments 27(12) Vasy Street Escorts Heart Institute and
Majuragate, Surat 395 002 Near Ega Theatre Research Centre, Okhla Road
Gujarat Kilpauk, Chennai - 600 010 New Delhi
Email: drdigant@hotmail.com
Jacob John T
Gowrishankar NC
Thekkekara 439 Civil Supplies
Dilip Mukherjee Assistant Professor Godown Lane
9/1 Ramnath Pal Road Department of Pulmonology Kamalakshipuram, Vellore
Kolkata 700 023 Institute of Child Health and North Arcot 632 002
West Bengal Hospital for Children Tamil Nadu
Email: dilipmukherjee@rediffmail.com Chennai 600 008 Email: vlr_tjjohn@sancharnet.in
Residence Jain MK
Divya Prabhat 12/A Balasubramaniam Street Quarters # 2
Ear Nose Throat Specialist and Mylapore Opposite District Hospital
Head and Neck Surgeon Chennai 600 004 Vidisha, Madhya Pradesh
Jeevak Hospital Tamilnadu
Opposite Asiad Bus Stand Jayakar Thomas
Senior Consultant Dermatologist
Dadar (East) Mumbai (East) Gupta BD Kanchi Kamakoti Childs TRUST
Vrandwan 120 Hospital and Mehta’s Hospital
Dubey AP Bhagat Ki Kothi Extension Chennai, Tamil Nadu
6E MS Flats Near Asha Hospital Residence
Mint Road Complex Opposite New Campus 2 West Mada Church Road
New Delhi 110 002 Pali Road, Jodhpur 342 001 Royapuram
Email: apdubey52@rediffmail.com; Rajasthan Chennai 600 013, Tamil Nadu
anand_dubey52@hotmail.com Email: Brahmadgupta@Hotmail.com Email: jayakarthomas@gmail.com
 Contributors XIII

Jayashree A Mondkar Kalpana D Kochupillai N

22/24 Vaibhav Apartments Assistant Professor
SK Bole Road, Dadar Department of Pediatric Neurology
Mumbai 400 028 SAT Hospital
Maharashtra Medical College
Email: jamond@vsnl.com; Thiruvananthapuram 695 004,
jayashreemondkar@hotmail.com Kerala
Residence
Jayashree Muralidharan ‘KALPANA’
127 Type V PGI Flats NSP Nagar
Sector 24-A Kesavadasapuram
Chandigarh 160 023 Thiruvananthapuram 695 004,
Email: mjshree@hotmail.com Kerala
Email: vijaykal@hotmail.com
Jaydeep Choudhury
Assistant Professor Kamath SS
Department of Pediatrics XL/5152 TD Road (North End)
Institute of Child Health Kochi, Ernakulam 682 035
Kolkata, West Bengal Kerala
Residence Email: sskamath@vsnl.net
95/2 Ballygunge Place
Karmarkar DP
Kolkata 700 019
1165 Harbhat Road
West Bengal Karmarkar Wada
Email: drjaydeep_choudhury@ Sangli 416 416, Maharashtra
yahoo.co.in
Ketan Praveen Parikh
Jnanindra Nath Behera
Consultant Pediatric Surgeon and
Associate Professor of Pediatrics Pediatric Laparoscopist
SCB Medical College Kokilaben Dhirubhai Ambani
Cuttack 753 007, Orissa Hospital, Andheri West
Email:jnanindranathb@gmail.com Mumbai 400 053
Maharashtra
Joshi NC Residence
B-404 Kukreja Palace
19-B Kumkum Apartments
Vallabhbaug Lane Extension
SV Road, Vile Parle (West)
Ghatkopar (East)
Mumbai 400 056, Maharashtra Mumbai 400 075
Maharashtra
Jugesh Chhatwal Email: ketan40@hotmail.com
Department of Pediatrics
Keya R Lahiri
CMC Hospital
Professor and Head
Ludhiana 141 008, Punjab
Department of Pediatrics
Email:pediatricscmcl@rediffmail.com
Seth GS Medical College and
KEM Hospital
Kabra SK Parel, Mumbai 400 012
Additional Professor Residence
Department of Pediatrics Vijay Kunj B/10
All India Institute of Medical JN Road, Santacruz (East)
Sciences Mumbai 400 055
New Delhi 110 029 Maharashtra
Email: skkabra@rediffmail.com Email: infopediatrics@gsmc.edu
Director, Medical Research
MS Ramaiah Medical College and
Hospitals, MSR Nagar, MSRIT PO
Bengaluru 110 029, Karnataka
Email: kochupillai@gmail.com
Kotwal PP
Professor and Head
Department of Orthopedics
All India Institute of
Medical Sciences
New Delhi 110 029
Residence
C 1/19 Ansari Nagar
New Delhi 110 029
Email: prakash_kotwal@hotmail.com
Krishan Chugh
J-5/169
Rajouri Garden
New Delhi 110 027
Email: chughk2000@yahoo.co.in
Kulkarni ML
2373 MCC ‘A’ Block
Devangere 577 004
Karnataka
Email: rajappanpillai@hotmail.com
Kumud P Mehta
Mother and Child Hospital
Gita 2nd Floor
P Ramabai Road
Gamdevi
Mumbai 400 007
Maharashtra
Email: mehtakumud@hotmail.com
Kundan Kumar Mittal
227-B Medical More
Model Town
Rohtak 124 001, Haryana
Email: kundanmittal@yahoo.co.in
Lokeshwar MR
19/54 Welfare Mansion
Sion, Mumbai 400 022
Maharashtra
Email: mrl123@roltanet.com;
mrlokeshwar@gmail.com
XIV IAP Textbook of Pediatrics

Madhulika Kabra Manju Mehta Meena R Malkani

Additional Professor Professor of Clinical Psychology F-6 Model House
Genetic Unit Department of Psychiatry 158 Sion (East)
Department of Pediatrics All India Institute of Medical Sciences Mumbai 400 022, Maharashtra
All India Institute of Medical Sciences New Delhi 110 029 Email: mmalkani@hotmail.com
New Delhi 110 029, Delhi Email: drmanju.mehta@gmail.com
Email: mkabra_aims@yahoo.co.in; Meenakshi N Mehta
madhulikakabra@hotmail.com Manorama Verma Shaivali C/3 9, BMC Colony
8 SF HIG Flats Kag Khan Road, Worli
Madhusudhana SN Bhai Randhir Singh (BRS) Nagar Mumbai 400 018, Maharashtra
Department of Virology Ferozepur Road
National Institute of Mental Health Ludhiana, Punjab Meharban Singh
and Neurological Sciences A-47 Sector 31, Noida
Bengaluru, Karnataka Gautam Budh Nagar 201 301
Marwaha RK
Professor of Pediatrics Uttar Pradesh
Mahadeviah M Email: meharbans_singh@gsk.com
Incharge, Division of Pediatric
518 Rajmahal Vilas Extension
Hematology-Oncology
Sadashiv Nagar Menon PSN
Advanced Pediatric Centre
Bengaluru 560 080 Consultant and Head
Postgraduate Institute of Medical
Karnataka Department of Pediatrics
Education and Research
Email: rmv518@yahoo.com Jaber Al-Ahmed Armed Forces
Chandigarh 160 012
Hospital, Kuwait
Maiya PP Email: rammarwaha1@rediffmail.com
Residence
343 25th Cross W1C 055 Wellington Estate
9th Main Road Mathur RC
DLF City Phase V
Banashankari II Stage 4-1-1233/5
Gurgaon 122 002, Haryana
Bengaluru, Karnataka Subhodaya Apartments
Email: psnmenon@hotmail.com
Email: p_maiya@hotmail.com Bogulkunta, ABIDS
Hyderabad 500 001 Milind S Tullu
Major K Nagaraju Andhra Pradesh Associate Professor
Senior Consultant in Email: rcmathur@hotmail.com Department of Pediatrics
Pediatric Allergy Seth GS Medical College
Kanchi Kamakoti Childs TRUST Mayilvahanan Natarajan KEM Hospital
Hospital Professor and Head Parel, Mumbai 400 012
12 A Nageswara Road Department of Orthopedic Surgery Residence
Nungambakkam Madras Medical College and 1 Sankalp Siddhi
Chennai 600 034 Government General Hospital Service Road, Kher Nagar
Email: majorknr@yahoo.co.in Chennai 600 003 Bandra East
Mumbai 400 051
Tamil Nadu
Malathi Sathiyasekaran Residence Nagabhushana S
# 16th Cross Street 4 Lakshmi Street Visiting Consultant
Indira Nagar Kilpauk Columbia Asia Hospital
Chennai 600 020 Chennai 600 010 Hebbal, Bengaluru
Tamil Nadu Tamil Nadu Residence
Email: mal.bwcs@gmail.com ’Aditya’ # 37/22/1
Meena P Desai
2nd Cross 1st Main
Mamta V Manglani 307 Samudra Mahal Sundarnagar
A-202 Casuarina, Evershine Greens Dr AB Road, Worli Post Gokula
New Link Road, Andheri (West) Mumbai 400 018 Bengaluru 560 054, Karnataka
Mumbai 400 102, Maharashtra Maharashtra Email: nagabhushana_s@rediffmail.com;
Email: mmanglani@hotmail.com Email: drmeenadesai@gmail.com respicon2005@yahoo.co.in

Nair MKC
TC 24/2049
Near Rose House
Women’s College Junction
Thycand
Thiruvananthapuram 695 014,
Kerala
Email: nairmkc@rediffmail.com;
nairkc@rediffmail.com
Nammalwar BR
2 Main Road, Seetha Nagar
Nungambakkam
Chennai 600 034
Tamil Nadu
Email: brn@biosys.net
Nandini Mundkur
Bangalore Children Hospital
’City Centre’ # 6 Chitrapur
Bhavan 8th Main 15th Cross
Malleswaram
Bengaluru 560 055
Karnataka
Email: bchrc@vsnl.com
Naveen Thacker
Past President, IAP
Deep Children Hospital
Plot 208, Sector 1-A
Opposite Hero Honda Showroom
Gandhidham, Kutch 372 201
Residence
D-70 Shaktinagar
Gandhidham
Kutch 370 201, Gujarat
Email: drnaveenthacker@gmail.com
Neeraj Jain
Associate Professor
Department of Pediatrics
Himalayan Institute of Medical
Sciences
Jolly Grant, Dehradun 248 140
Uttarakhand
Residence
A1/2 Maa Ganga Vaatika
Rishikesh, Uttarakhand
Email: neerajjain@vsnl.net
Contributors XV
Niranjan Shendurnikar Pankaj Hari
C/21 Nandigram # 2 Additional Professor
Sindhwai Maata Road Department of Pediatrics
Vadodara 390 004, Gujarat All India Institute of Medical
Email: drnsps@gmail.com Sciences, New Delhi 110 029
Email: pankajhari@hotmail.com
Nitin Chandra Mathur
4-1-1233/5 Subhodaya Panna Choudhury
ABIDS Consultant Pediatrician
Hyderabad 500 001 Department of Pediatrics
Andhra Pradesh Maulana Azad Medical College
Email: nitincmathur@gmail.com and Lok Nayak Hospital
New Delhi 110 002, Delhi
Nitin Shah Email: pannachoudhury@gmail.com;
186-A Vaswani Villa drpchoudhury@gmail.com
1st Floor Block # 3
Jain Society, Near Jain Temple Paramesh H
Sion (West), Mumbai 400 022 Medical and Managing Director
Maharashtra Lakeside Medical Center and
Email: drnitinshah@hotmail.com Hospital
33/4 Meanee Avenue Road
Noel Narayanan S Near Ulsoor Lake
TC 1/1991 9(1) Bengaluru 560 042, Karnataka
Keezhchira, Doctor’s Lane Email: dr_paramesh1@yahoo.com
Kumarapuram
Thiruvananthapuram 695 001 Parang N Mehta
Kerala 2/C Anjani Towers
Nupur Ganguly Parle Point
Assistant Professor of Pediatrics Athwa Lines
Institute of Child Health, Kolkata Surat 395 007
107 Garfa Pratapgarh Gujarat
Kolkata 700 075 Email: parang@rediffmail.com
Email: nupur_diya@yahoo.com
Parthasarathy A
Omprakash S Shukla ’Brindavan’
33-B Shilalekh Bunglows 166 Park Road
Opposite Nandanvan Society Western Extension
Behind Railway Station, Alkapuri Anna Nagar
Vadodara 390 007, Gujarat Chennai 600 101
Email: opshukla2004@yahoo.co.in Email: apartha2000@yahoo.com
Pandian K Phadke KD
9B Medawakkam Road 707 14th Cross
Adambakkam JP Nagar II Phase
Chennai 600 088, Tamil Nadu Bengaluru 560 078
Email: pandianking@yahoo.com Karnataka
XVI IAP Textbook of Pediatrics

Piyush Gupta Residence Rakesh Lodha

Professor of Pediatrics B 301 Greenfields Assistant Professor of Pediatrics
University College of Medical Sciences Lokhandwala Complex All India Institute of
New Delhi Andheri West Medical Sciences
Editor-in-Chief, Indian Pediatrics Mumbai 400 053 New Delhi 110 029
Email: purna.kurkure@gmail.com Residence
Residence
Block # R-6-A A-5 Type # 5
Purvish M Parikh
Dilshad Garden IARI, Pusa, New Delhi 110 012,
9 Neeta Building
Near Telephone Exchange Above Computer Point Email: rakesh_lodha@hotmail.com,
Delhi 110 095 Opposite Poddar Hospital rlodha1661@gmail.com
Email: prof.piyush.gupta@gmail.com 227 Annie Besant Road
Worli, Mumbai 400 025 Ramachandran P
Potdar RD Maharashtra Institute of Child Health and
Laxmi Gruha
Hospital for Children
69 DV Pradhan Road Raghupathy P
Egmore, Chennai
Dadar (East) # 39 6th Cross 35th Main
KAS Officer’s Colony Tamil Nadu
Mumbai 400 014
Email: rdpotdar@snehamrc.com BTM Layout IInd Stage
Bengaluru 560 068 Ramakrishnan S
Prahlad N Karnataka ’Shreyas’
Email: p.raghupathy@gmail.com 15/7 Vidya Marg
22/1 Poes Road, II Street
Teynampet Old Fatehpura
Rajeshwar Dayal
Chennai 600 018 Udaipur 313 004
Opposite Kidwai Park
Tamil Nadu Rajamandi Rajasthan
Email: drprahlad@yahoo.com Agra 282 002, Uttar Pradesh
Email: r_dayal123@rediffmail.com Ramaswamy Ganesh
Pratibha D Singhi Registrar in Pediatrics
Chief Pediatric Neurology and Rajniti Prasad Kanchi Kamakoti Childs TRUST
Neurodevelopment Senior Lecturer Hospital
Department of Pediatrics Department of Pediatrics 12-A Nageswara Road
Postgraduate Institute of Institute of Medical Sciences Nungambakkam
Medical Education and Research Banaras Hindu University Chennai 600 033
Varanasi 221 005
Chandigarh 160 012 Tamil Nadu
Residence
Email: pratibhasinghi@yahoo.com Residence
7 FF Kabir Colony
Banaras Hindu University 3-A Raju Street
Prisca Colaco Varanasi 221 005 West Mambalam
D-107 Gasper Enclave Email: rajaniti_prasad@hotmail.com Chennai 600 033
St John’s Road, Bandra
Rajput CS Ramesh S
Mumbai 400 050
C/o Dr Mrs MC Rajpur Consultant Pediatrician
Maharashtra
Department of OBGYN BRS Hospital
Purna A Kurkure Wanless Hospital 28, Cathedral Garden Road
Professor-in-Charge Miraj 416 410, Maharashtra Chennai 600 034
Pediatric Endocrinology Division Residence
Raju C Shah
HOD, Departemnt of Ankur Children Hospital New No 28 Old No 37
Medical Oncology Behind City Gold Cinema Madava Road
Tata Memorial Hospital Ashram Road Navarangpura Mahalingapuram
Dr Ernest Borges Marg Ahmedabad 380 009, Gujarat Chennai 600 034, Tamil Nadu
Parel, Mumbai 400 012 Email: rajucshah@rediffmail.com; Email: rameshsanthanakrishnan
Maharashtra rajucshah@lycos.com @gmail.com
 Contributors XVII

Rana KS Ritabrata Kundu Sachdev HPS

Senior Advisor Pediatrics and Professor of Pediatrics E 6/12, Vasant Vihar
Pediatric Neurology Institute of Child Health New Delhi 110 057
Army Hospital R & R, Delhi Cantt Kolkata, West Bengal Email: hpssachdev@hotmail.com
New Delhi 110 010 Residence
Email: kamersinghrana@yahoo.com.in 26A Sarat Chatterjee Road Sajid Qureshi
Lake Town Assistant Professor
Rao KS
Kolkata 700 089 Pediatric Surgical Oncology
’Ragasudha’
Email: rkundu22@gmail.com Tata Memorial Hospital
13/242 Matwada
Warangal 506 002 Dr Ernest Borges Marg
Andhra Pradesh Riyaz A
Parel, Mumbai 400 012
”Arakkal”
Maharashtra
Rashmi Dalvi Chalappuram
C/o Dr BV Dalvi Residence
Kozhikode 673 002
A-10 Mutual CHS 1/26 Merchant Building
Kerala
Mogul Lane, Mahim 3rd Sankli Street
Email: saif_gem@hotmail.com
Mumbai 400 016, Maharashtra Byculla, Mumbai 400 008
Maharashtra
Rashmi Kumar Rohit C Agrawal
Email: sajidshafique@rediffmail.com
HIG 111 Sector E Director
Aliganj, Lucknow 226 020 Chandra-Jyoti Children Hospital
Sandeep B Bavdekar
Uttar Pradesh Mumbai, Maharashtra
Email: rashmik2005@gmail.com; A-2/9 Worli Seaside CHS
Residence
rashmik06@yahoo.co.in Kag Khan Road, Worli
603/4 Vindyachal
Neelkanth Valley Mumbai 400 018
Ravichander B Maharashtra
Senior Pediatric Consultant 7th Road Raja Wadi
Ghatkopar (East) Email: drsbavdekar@vsnl.com
Military Hospital
Bengaluru, Karnataka Mumbai 400 077
Maharashtra Sankaranarayanan VS
Email: drrohitag@hotmail.com 16 Balaji Avenue
Ravikumar T
New # 31 Old # 14 T Nagar, 1st Street
Jaganathapuram Roshani N Taori Chennai 600 017, Tamil Nadu
3rd Street Chetpet Research Officer Email: drvssankaranarayanan@gmail.com
Chennai 600 031 Department of Pediatrics Santosh K Bhargava
Tamil Nadu Seth GS Medical College D 7 Gulmohar Park
Email: trkoomar@hotmail.com KEM Hospital, Parel New Delhi 110 049
Mumbai 400 012, Maharashtra
Ravikumar VR Email: santoshb@ndf.vsnl.net.in
Email: roshanitaori@hotmail.com
66 Cooperative Colony Saradha Suresh
KK Pudur Roshni Bhagwat Director and Superintendent
Coimbatore 641 038 Consultant Pediatric Oncologist Institute of Child Health and
Tamil Nadu Mahakoshal Hospital Hospital for Children
Email: masr.mar@usa.net
Jabalpur, Madhya Pradesh Egmore, Chennai 600 008
Renu Sexena
Residence Tamil Nadu
Professor and Head Vatika Duplex
Department of Hematology 65 Napier Town Saroj Mehta
All India Institute of Jabalpur 482 001 1159/15C, Chandigarh 160 015
Medical Sciences Madhya Pradesh Chandigarh
New Delhi 110 029 Email: roshni26@yahoo.com Email: ssmehta100@yahoo.com
XVIII IAP Textbook of Pediatrics

Shah MD Shobha Banapurmath Chennai 600 017

51 2nd Floor Jashoda Niwas 390 8th Main Tamil Nadu
Nehru Road PJ Extension Email: dr.srinivas@gmail.com
Vile Parle (East) Devangere 577 002
Mumbai 400 057 Karnataka Srinivasan S
Maharashtra Email: sbanapurmath@hotmail.com C II/4 Dhanvanthari Nagar
Email: shahmdip@vsnl.net JIPMER, Puducherry 605 006
Shreekant W Chorghade
Puducherry
Shailesh Kanvinde ’Rajeev’
Email: srinivasan_jip@yahoo.co.uk
Consultant Pediatric Hematologist Dharampeth
and Oncologist Nagpur 440 010, Maharashtra
Srivastava RN
Deenanath Mangeshkar Hospital Email: chorghade1@hotmail.com
487 Mandakini Enclave
Pune, Maharashtra
Alaknanda
Residence Shripad Banavali
New Delhi 110 019
Prerana Society Professor of Pediatric Oncology
Email: rnsri@vsnl.net
Opposite New Abhinav Vidyalaya Department of Medical Oncology
37/2 Erandavane Tata Memorial Hospital
Srivastava SP
Pune 411 038 Dr Ernest Borges Marg
S-104 Udai Giri Bhavan
Maharashtra Parel, Mumbai 400 012
Email: skanvin@vsnl.net; Budh Marg Road, Patna 800 001
Maharashtra
skanvinde@123inida.com Bihar
Residence
Email: spsrivastava13@yahoo.com
# 11-A Jyoti Sadan,
Shanti Ghosh
5 Sri Aurobindo Marg Sheetla Devi Temple Road, Mahim
Subhash J Dalal
New Delhi 110 016, Delhi Mumbai 400 016
Consultant Pediatric Surgeon
Email: sghosh@del13.vsnl.net.in Email: banavali_2000@yahoo.com
Former Dean, Wadia Children’s
Hospital
Shashi N Vani Soumya Swaminathan
Residence
10 ‘Shamiana’ B-8 Sagarika
3 Maheshwar Niketan
61 Brahmin Mitra Mandal Society 15-III Seaward Road
Peddar Road, Mumbai 400 026
Ahmedabad 380 006, Gujarat Valmiki Nagar
Maharashtra
Chennai 600 041
Sheila Bhave Tamil Nadu
9 Solapur Road Email: doctorsoumya@yahoo.com Subramanyam L
Pune 411 001 9-A Karneeswarar Koil Street
Srikanta Basu Santhome, Chennai 600 004
Maharashtra
# 318 Aashirwad Enclave Tamil Nadu
Email: sheilabhave@vsnl.net
104 IP Extension Email: shivbalam1@rediffmail.com
Patparganj
Shivananda
Siddhi 608 3rd Stage New Delhi 110 092
Suchitra Ranjit
3rd Block, 7th Main Email: srikantabasu@hotmail.com;
G/A Ranga Nivas
Basaveshwaranagar srikantab@yahoo.com
40 Barnaby Road, Kilpauk
Bengaluru 560 079 Chennai 600 010, Tamil Nadu
Srinivas S
Karnataka Email: chitrasona@rediffmail.com
Department of Gastroenterology
Email: sssidhi@rediffmail.com
Royal Children's Hospital
Shivbalan SO Melbourne Sudeshna Mitra
Consultant Pediatrician and Australia Department of Pediatrics
Pulmonologist Residence Postgraduate Institute of Medical
Sundaram Medical Foundation 14 Balaji Avenue Education and Research
Chennai, Tamil Nadu 1st Street Chandigarh 160 012
Email: sivabalan.somu@gmail.com Thiagarajanagar Email: mitrasudeshna@hotmail.com
 Contributors XIX

Sumathi B Surjit Singh Tapan Kumar Ghosh

Assistant Professor Department of Pediatrics Scientific Coordinator
Department of Pediatric PGIMER, Chandigarh 160 012 Institute of Child Health
Gastroenterology Chandigarh Kolkata
Institute of Child Health and Email: surjitsinghpgi@hotmail.com; Residence
Hospital for Children surjitsingh@sify.com 13 Neogi Pukur Bye Lane
Egmore, Chennai 600 008 Kolkata 700 014
Residence Sushil Madan West Bengal
New No 6 (Old 24) 804-2A Brindaban Apartments Email: dr_tkghosh@rediffmail.com,
Kutchery Lane Poonam Nagar, Andheri (East) dr.tkghosh@yahoo.in
Mylapore Mumbai 400 093, Maharashtra
Chennai 600 004
Swati Kanakia Tewari AD
Tamil Nadu
2/10 Shreeji Sadan 1459 Sector 3, Rohtak 124 001
Email: drbsumathi@rediffmail.com
Vrindavan Society Haryana
Sunanda K Reddy Vrindavan Chowk Email: ad_tewari@hotmail.com
Consultant Neurodevelopmental Sion, Chunabhatti
Pediatrician Mumbai 400 022
Thangadorai C
K-118 Ground Floor Maharashtra
18 Taylors Road, Kilpauk
Hauz Khas Enclave Email: drkanakia@vsnl.com
Chennai 600 010
New Delhi 110 016 Tamil Nadu
Email: write2sunanda@gmail.com; Swati Y Bhave
C II/47 Shahjahan Road Email: thangadorai@yahoo.com
carenidhi@gmail.com
Opposite UPSC Office
Sunil Karande New Delhi 110 003, Delhi Thangavelu S
Flat # 24 Joothica, 5th Floor Email: sybhave@yahoo.com;
H-15, G-2 Sea Breeze Apartments
sybhave@gmail.com
22A Naushir Bharucha Road Thiruvalluvar Nagar
Mumbai 400 007 Thiruvanmiyur
Tanmay Amladi
Maharashtra Chennai 600 041, Tamil Nadu
Honorary Neonatologist
Email: karandesunil@yahoo.com Email: thangavelu_s@yahoo.com
Nowrosjee Wadia Maternity
Hospital and NICU Parel, Mumbai
Sunit C Singhi
Residence Thapa BR
Professor and Head
A/50/1368 MIG Division of Pediatric
Department of Pediatrics
Adarsh Nagar CHS Ltd Gastroenterology
Advanced Pediatric Centre
Prabhadevi PGIMER
PGIMER, Chandigarh 160 012
Mumbai 400 025
Email: sunit.singhi@gmail.com; Chandigarh 160 012
Maharashtra
dr_singhi@yahoo.com Chandigarh
Email: tanmayamladi@gmail.com
Email: brthapa1@yahoo.co.in;
Supriyo Ghose Tanu Singhal pgimer@chd.nic.in
Chief, Professor and Head of Consultant Pediatrician
Department of Ophthalmology Kokilaben Dhirubhai Ambani Thirugnanasambandham C
Rajendra Prasad Centre for Hospital and Medical Research Institute 8 I Block
Ophthalmic Sciences Four Bungalows, Andheri West 2nd Main Road
All India Institute of Medical Sciences Mumbai 400 053, Maharashtra Chennai 600 102
New Delhi 110 029 Email: tanusinghal@yahoo.com Tamil Nadu
XX IAP Textbook of Pediatrics

Uday B Nadkarni Vasanthi T Vijay Agarwal

2 Vaibhav, Plot # 12-13 Old # 4/123 New # 4/693 Cottage # 15
Linking Road Extension 7th Main Road, Swaminatha Nagar Oberai Apartments
Santacruz (West) Kottivakkam 2 Sham Nath Marg
Mumbai 400 054 Chennai 600 041 Delhi 110 054
Maharashtra Tamil Nadu Email: vijay@webcottage.com
Email: drvasanthi@hotmail.com
Upadhyay SK Veena Kalra Vijay N Yewle
402 Bhimarathi Building Senior Consultant Pediatrics Yewale Hospital
Road # 3 Daulal Nagar (Pediatric Neurology) Plot 6B Sector 9
Borivali (East) Indraprastha Apollo Hospitals Vashi 400 703
Mumbai 400 066 Sarita Vihar, Delhi Mathura Road Navi Mumbai
Maharashtra New Delhi 110 076 Maharashtra
Residence Email: vnyewale@vsnl.com;
Utpal Kant Singh 101 Jorbagh vntewale@gmail.com
Professor and Head New Delhi 110 003, Delhi
Department of Pediatrics Email: kalra.veena@gmail.com
Vijayakumar M
Nalanda Medical College
Flat # 4 Muktha Vandan
Patna, Bihar Vibha Jain Old # 4 New # 7
Residence Consultant Ramanathan Street
8 Rajendra Nagar Department of Pediatrics Kilpauk
Patna 800 016, Bihar Himalayan Institute of Chennai 600 010
Email: utpalkant.singh@yahoo.co.in Medical Sciences Email: drmvk@vsnl.net
Jolly Grant, Dehradun 248 140
Vaman V Khadilkar
Uttarakhand
B-3 Shashi Kiran Apartment Vijayalakshmi Bhatia
Residence
Ashok Path Professor
77 SBM Complex
Off Law College Road Department of Endocrinology
Haridwar Road
Erandwane Sanjay Gandhi Postgraduate
Rishikesh
Pune 411 004, Maharashtra Institute of Medical Sciences
Email: vkhadilk@vsnl.com; Vibha Mangal Post Box # 375
akhadilkar@vsnl.net Consultant Lucknow 226 001
Department of Pediatrics Uttar Pradesh
Varshney MK Email: vbhatia@sushrut.s.gpgi.ac.in
Himalayan Institute of
Senior Research Associate
Medical Sciences
Department of Orthopedics
Swami Rama Nagar
All India Institute of Medical Sciences Vijayasekaran D
Dehradun 248 140
New Delhi 110 029 # 43rd Cross Street
Uttarakhand
Residence Dr Subbaraya Nagar
521 Masjid Moth Doctor’s Hostel Vibhu Kwatra Kodambakkam
Masjid Moth Vibhu Nursing Home Chennai 600 024
New Delhi 110 049 11/137 Malviya Nagar Tamil Nadu
Email: drmkvarshney@gmail.com New Delhi Email: vijsekar@hotmail.com
 Contributors XXI

Vimlesh Seth Walia BNS Yuvaraj Chandra Mathur

N-14/D DDA Flats (SFS) 1004 Sector 11-C 4-1-1233 Boggul Kunta
Mandir Marg, Saket Chandigarh 160 011 Subodaya
New Delhi 110 017, Delhi Email: bnswalia@hotmail.com Hyderabad 500 001
Email: drsdseth@yahoo.com
Wilson CG Andhra Pradesh
Vinod K Paul House # 117 Sector A Email: ycmathur@hotmail.com
Professor and Head A WHO Colony
Department of Pediatrics Gautam Enclave Zeenat Currimbhoy
All India Institute of Medical Sciences Secunderabad 500 009
Ansari Nagar Division of Pediatric
Andhra Pradesh Hemato-Oncology
New Delhi 110 029, Delhi
Email: info@kimsmedicalcollege.org Department of Pediatrics
Email: vkpaul@medinst.ernet.in;
vinodkpaul@hotmail.com LTMG Hospital and
Yogesh C Govil
LTM Medical College
Vipin M Vashishtha 4006/1/2, A-2 Balda Colony
Consultant Pediatrician and Sion, Mumbai 400 022
New Hyderabad
Neonatologist, Mangla Hospital Maharashtra
Lucknow 226 007
Shakti Chowk, Station Road Email: currimbhoyzinet@gmail.com
Uttar Pradesh
Bijnor 246 701, Uttar Pradesh Email: yogeshgovil@usa.net
Email: vipin@iappec.com,
vipinipsita@gmail.com Zulfikar Ahamed M
Yogesh Jain
SAJAN, TC 1072/4
Vrajesh P Udani Jan Swasthya Sahyog
Pazhaya Road MCPO
69 Al Jebreya Court I-4 Parijat Colony
Nehru Nagar Thiruvananthapuram 695 011
Marine Drive, Mumbai 400 020
Maharashtra Bilaspur 495 001 Kerala
Email: vrajesh@vsnl.com; Chhattisgarh Email::mzulfikarahamed@rediffmail.com;
vrajeshudani@yahoo.co.in Email: janswasthya@gmail.com zulfikarahamedm@sancharnet
Foreword
Child health needs of developing countries are altogether different. Indian Academy of Pediatrics is dedicated for
total child welfare from zero to eighteen years of age. With this aim, the first edition was published in 1999 and in
ten years it has been so popular, not only in India but in SAARC and many developing countries. It speaks of its
receptivity, utility, affectivity and relevance. And now with much enthusiasm and pleasure, the fourth edition is in
your hands.
I sincerely appreciate Dr A Parthasarathy’s dedication and commitment to the children and in the professional
front in our country. His untiring efforts will serve as an inspiration for young pediatricians to emulate and encourage
them to contribute to ailing society along their professional path with sincere services.
It is certainly a matter of pride to note that many senior pediatricians have been taking time off their innumerable
social commitments to pool valuable knowledge in the form of this book. I admire all the editors and contributors
for this rich compilation.
The contents of the book have been chosen very carefully for developing as well as developed countries and
have broadly covered the relevant and vital issues of Comprehensive Child Health Care. Considering the caliber
and expertise of contributors and authors, I am convinced that the book will be a treasure of knowledge to be
cherished by the pediatricians across the world.

RK Agarwal
National President, 2008
Indian Academy of Pediatrics
Foreword
Specialty of Pediatrics covers more than 50 percent of the population. Infant and childhood morbidity continue to be
very high and adolescent health problems are still not adequately addressed by medical profession. Thus, it is
imperative that budding doctors need to have sound training to look after the children from birth to 18 years.
Pediatrics is a part of undergraduate curriculum and there is tremendous demand for a textbook on pediatrics. For
credibility it is also necessary that the book is evidence based. IAP Textbook of Pediatrics fulfills an important void
in this direction and has become immensely popular with all its editions. The book has been well received in many
developing countries having similar health scenario.
Contributors of this book are renowned experts in their respective fields. An invariable problem with multi-
authored texts is the diversity of presentations adopted by a multitude of contributors. Dr A Parthasarathy, Editor-
in-Chief of the book since inception and an accomplished academician with tremendous zeal, managed this issue by
carefully crafting a common editorial style. In this venture he has been aptly assisted by Dr PSN Menon and
Dr Piyush Gupta, along with many highly reputed chapter editors. Keeping with time, the text of the book has been
aptly modified and all the chapters have been thoroughly revised.
The book is designed to be relevant to the need of the developing countries. Emphasis has been on common
prevalent conditions though allied subjects seen in children have also received due attention. Section on Community
Pediatrics deserves special mention as most textbooks with western approach hardly provide any information in
this respect. The book is voluminous which is inherent in a textbook trying to cover all aspects related to pediatric
care.
Apart from fulfilling the main function of an excellent undergraduate textbook, this edition would be invaluable
for residents and medical practitioners interested to know in detail various childhood conditions. Even postgraduate
students will find much useful information. The book certainly will continue to remain as a very prestigious
publication of Indian Academy of Pediatrics and serve the nation by helping doctors engaged in the care of children
needing latest updates.

Panna Choudhury
Consultant Pediatrician
Lok Nayak Hospital
New Delhi 110 002 and
National President
Indian Academy of Pediatrics 2009
Preface to the Fourth Edition
The last few years have witnessed a rapid progress in medicine and technological advances in biological sciences.
The specialty of Pediatrics has perceived further advances in preventive and therapeutic care. These have provided
impetus to revise knowledge, harvest new information and thus continue the process of learning. There was a felt
need for publication of an updated fourth edition of this book after a gap of three years. This was also prompted by
the enthusiastic response to the previous editions from practicing pediatricians, postgraduates, undergraduates as
well as faculty of Departments of Pediatrics throughout the country.
It has been our endeavor to present this subject in a simplified, practical manner to provide adequate clinical
guidance to pediatricians so that children derive the benefits of early diagnosis and optimal treatment. The basic
outline of the book is retained. We have tried our best to oversee that the ‘art and science’ of clinical pediatrics
maintains its central position without being overshadowed by newer technical advances.
This fourth edition of the IAP Textbook represents a substantial revision and reorganization of the text based on
a complete review of the field of Pediatrics. It has 36 chapters and is being published in two volumes for the first
time. The first volume consists of 16 chapters with 195 subchapters contributed by 171 authors and the second
volume contains 20 chapters with 95 subchapters by 89 authors. The first volume features 28 new authors while the
second volume has 14 new authors representing the continuum of the best available talent, both experienced and
young with vast experience and expertise. Almost all the chapters have been thoroughly revised and updated in a
lucid and readable style.
Several new chapters have been added keeping in mind the changing concepts of pediatric care in the global
scenario. Some of these include child and adolescent school health education, vaccine storage and handling adverse
effects following immunization, parent counseling, practical approach to fever in children, pneumococcal infection
and its prevention, chikungunya fever, hemoptysis, gastroesophageal reflux, allergen-specific immunotherapy,
antiphospholipid syndrome, vasculitis, intravenous immunoglobulin, polycystic ovarian syndrome, etc. The chapters
on research methodology and computers serve a long felt need.
In addition, the IAP Infectious Diseases Chapter Protocols on selected infectious diseases viz. malaria, enteric
fever, pyogenic meningitis and rabies have been incorporated in the ‘Miscellaneous Topics’. This edition also provides
the most recent IAP recommendations on immunization of children and adolescents. The current IAP and WHO
growth charts have been appended with details on the techniques of measurement and interpretation. Unfortunately
many children, especially from the rural and remote areas have not yet benefited from the significant advances in
the prevention and care of many health problems. In this context the two chapters viz. National Rural Health Mission
and Pediatric Priorities in the 21st Century are rewritten. The chapter on Common Procedures has been updated.
The Academy would like to place on record its appreciation to all the authors for their contributions to the fourth
edition. It also gratefully acknowledges the efforts and time spent by Senior Editors and Chapter Editors who have
devoted great deal of their time reviewing and editing the manuscripts. The support from the office-bearers and
staff of the IAP Central Office Secretariat at all stages is appreciatively accredited. The book would not have seen the
light of the day but for the support and excellent cooperation of M/s Jaypee Brothers Medical Publishers (P) Ltd,
New Delhi.
It is our earnest hope that this new edition of the IAP Textbook will help in early diagnosis and efficient
management leading to optimal outcome and improving the quality of patient care.

A Parthasarathy
PSN Menon
Piyush Gupta
MKC Nair
Preface to the First Edition
Pediatrics has grown and developed with significant milestones in preventive and therapeutic care over the past
few decades. The WHO and UNICEF in their Primary Health Care (PHC) approach, have given due importance for
effective child survival programs. So much so the medical students need to be well oriented towards these approaches
in Pediatrics as the future middle level managers in Primary Health Care.
Several luminaries in the Indian pediatric scenario, have contributed their might in bringing out books for the
undergraduate medical students. However, the rapid advances made in the various pediatric subspecialties have
necessitated the updating of these books from time to time. Nevertheless, the need for a full fledged textbook was
felt for long. The Indian Academy of Pediatrics thought it fit, to shoulder the responsibility of bringing out such a
need based Textbook in Pediatrics for medical students. Our erudite and enthusiastic editors and contributors
made it possible at a record time. The Academy owes its gratitude to all these experts for their worthy contribution.
The book has been divided into several sections. A few chapters included in this book are entirely newer concepts
which are not usually found in the conventional pediatric textbooks. It has also worthy annexures to the main
contents. However, editing the text to suit the needs of medical students was a Himalayan task. The idea is to equip
the medical students with adequate knowledge in Pediatrics in order to make them confident to shoulder the
responsibilities concerned with preventive and curative Pediatrics. Thus, it is hoped that the practitioners of Pediatric
Medicine will benefit from this book.
We are confident that this book will serve the needs of medical students especially at a time when the Medical
Council of India has made Pediatrics as a major examination subject. Thus, the publication of the book is not only
timely but also out of necessity.
The Academy would like to place on record its appreciation to the senior editors, chapter editors, contributors,
and staff members of IAP Central Secretariat for help rendered in the creation of this book and M/s Jaypee Brothers
Medical Publishers (P) Ltd., New Delhi, for their excellent cooperation in bringing out the First Edition at record
time.

A Parthasarathy
PSN Menon
MKC Nair
Acknowledgements
We are indebted to the President and members of the Executive Board 1997 of the Indian Academy of Pediatrics
(IAP) for the initiation and completion of the project of bringing out the first ever Academy’s textbook for medical
students and practitioners. We are also thankful to the successive Presidents and members of the Executive Boards
1998-2008 for their encouragement in sustaining the project towards the publication of the Fourth Edition.
Our grateful thanks go to the various contributors and senior editors, past and present teachers of Pediatrics who
have made this ‘Himalayan task’ a reality by their precise and updated text. We are indebted to the faculty and
residents of the All India Institute of Medical Sciences, New Delhi for shaping the contents of the First Edition which
has made the production of the subsequent editions an easy task and to Ms Manju, Ms Chitra and Ms Suman for
their assistance in typing and drafting the text of the book for the first edition.
The secretarial and organizational skills of Mr Joseph A Gonzalves and his supportive staff of IAP Central Office,
Mumbai, so ably and meticulously guided by Dr Rohit Agrawal, Secretary General and Dr Tanmay Amladi, Treasurer
are also gratefully acknowledged. The coordination efforts of Mrs Lokanayaki Ethirajan, Mrs Nirmala Parthasarathy,
Dr (Mrs) Pratibha Janardhanan, Mrs Kavitha Balaji, Mr A Sriramulu and Mr Louis Francis are acknowledged with
thanks.
Mr R Janardhanan, Mr P Balaji, Ms Shruthi Pavana, Ms Swathi Pavana, Ms Kavya Balaji and Ms Mahia Balaji at
Chennai need special mention for their untiring assistance in correspondence and formatting of the book with
updated contents.
Our grateful thanks are due to Mr Shaji Jacob Ninan and Dr Nazeer Ahamed at Kuwait for the assistance rendered
to the senior editor in editing, scrutinizing and proofreading of the individual chapter files.
Our sincere and grateful thanks go to the family of Jaypee Brothers Medical Publishers (P) Ltd, New Delhi,
especially Shri Jitendar P Vij (Chairman and Managing Director), Mr Tarun Vij (Director-Pharma), Mr Tarun Duneja
(Director-Publishing), Mr KK Raman (Production Manager), Ms Samina Khan (PA to the Director-Publishing),
Mr Ashutosh Srivastava (Assistant Editor), Ms Yashu Kapoor and Ms Kamlesh Bisht (DTP Operators) and
Ms Sonia Mehta (Graphic Designer) for their untiring coordination efforts in the production of the Fourth Edition.
We also place on record our sincere appreciation of the help rendered by the local branch managers of the Jaypee
Brothers — Mr Mukherjee, (Chennai), Mr Uday Honnemadi (Mumbai), Mr Jayanandan (Author Co-ordinator,
Chennai), Mr Damodharan (Field Executive, Chennai) — and the headquarters staff at New Delhi for the help
rendered to the Editor-in-Chief and Academic/Senior Editors.
All attempts have been made to acknowledge the sources of information and illustrations. Inadvertent omission,
if any, is regretted.

A Parthasarathy
PSN Menon
Piyush Gupta
MKC Nair
Contents
Volume 1
1. PEDIATRIC CARE IN DEVELOPING COUNTRIES
Chapter Editor: Piyush Gupta
1.1 Importance of Pediatrics ............................................................................................................................ 2
RD Potdar
1.2 Attaining Proficiency in Pediatrics .......................................................................................................... 3
BNS Walia
1.3 Pediatric Care in Developing Countries ................................................................................................. 5
BNS Walia
1.4 Primary Health Care ................................................................................................................................... 7
Yuvraj Chandra Mathur, Nitin Chandra Mathur
1.5 Primary Neonatal Care .............................................................................................................................. 9
Santosh K Bhargava
1.6 Management of Primary Health Center ............................................................................................... 12
Piyush Gupta
1.7 Training of Medical Graduate as Middle Level Manager ................................................................ 16
C Thirugnanasambandham, T Arunmozhi

2. HISTORY ELICITATION AND PHYSICAL EXAMINATION

Chapter Editors: PSN Menon, Piyush Gupta
2.1 History Elicitation ..................................................................................................................................... 24
T Ravikumar, C Thangadorai
2.2 Physical Examination and Clinical Skill Development .................................................................... 30
C Thangadorai, T Ravikumar
2.3 Parent Counseling .................................................................................................................................... 40
Parang N Mehta

3. NEWBORN CARE
Chapter Editor: Ashok K Deorari
3.1 Neonatal Nomenclature and Definitions ............................................................................................. 46
Meharban Singh, Vinod K Paul
3.2 Resuscitation of an Asphyxiated Newborn Baby ............................................................................... 50
Meharban Singh, Ashok K Deorari
3.3 Care of a Normal Newborn Baby .......................................................................................................... 56
Meharban Singh, Ashok K Deorari
XXXIV IAP Textbook of Pediatrics

3.4 Common Developmental and Physiological Problems in Newborn Babies ................................. 61

Meharban Singh, Vinod K Paul
3.5 Management of Low Birth Weight Babies ........................................................................................... 65
Vinod K Paul, Ashok K Deorari, Meharban Singh
3.6 Common Diseases of Newborn Babies ................................................................................................ 71
Meharban Singh, Vinod K Paul, Ashok K Deorari

4. GROWTH AND DEVELOPMENT

Chapter Editor: KN Agarwal
4.1 Growth and Development: Basic Concepts ......................................................................................... 80
AB Desai, Dilip Mukherjee
4.2 Growth—Birth to Puberty ....................................................................................................................... 83
KN Agarwal, DK Agarwal, SK Upadhyay
4.3 Physical Growth and Sexual Development in Adolescence ............................................................. 96
KN Agarwal, DK Agarwal, SK Upadhyay
4.4 Development ........................................................................................................................................... 105
KN Agarwal, DK Agarwal, SK Upadhyay
4.5 Failure to Thrive ...................................................................................................................................... 111
Madhulika Kabra, PSN Menon

5. INFANT FEEDING
Chapter Editor: RK Anand
5.1 Infant and Young Child Feeding ......................................................................................................... 116
RK Anand, SP Srivastava
5.2 Breastfeeding and Weaning .................................................................................................................. 122
RK Anand, SP Srivastava, Arun Gupta, JP Dadhich

6. NUTRITION
Chapter Editor: Meenakshi N Mehta
6.1 Protein Energy Malnutrition ............................................................................................................... 136
Meenakshi N Mehta
6.2 Water Soluble Vitamins: B Complex Vitamins ................................................................................ 163
Shashi N Vani
6.3 Fat Soluble Vitamins ............................................................................................................................. 166
Panna Choudhury
6.4 Trace Elements ....................................................................................................................................... 171
B Bhandari
6.5 Child and Adolescent School Health Education .............................................................................. 176
Sushil Madan
 Contents XXXV

7. COMMUNITY PEDIATRICS
Chapter Editor: Piyush Gupta
7.1 Community Pediatrics .......................................................................................................................... 188
Shashi N Vani
7.2 National Health Programs .................................................................................................................... 190
Shashi N Vani, Piyush Gupta
7.2.1 National Rural Health Mission (NRHM) 2005-2012 ........................................................... 191
Piyush Gupta
7.2.2 Maternal and Child Health (MCH) Programs ...................................................................... 193
Shashi N Vani
7.2.3 Integrated Child Development Services (ICDS) Program ................................................. 194
BNS Walia
7.2.4 Child Survival and Safe Motherhood (CSSM) Program .................................................... 196
BNS Walia
7.2.5 Reproductive and Child Health (RCH) Program ................................................................. 197
BNS Walia, Shashi N Vani
7.2.6 Integrated Management of Neonatal and Childhood Illness (IMNCI) Strategy .......... 200
BNS Walia
7.2.7 National Programs on Immunization .................................................................................... 200
A Parthasarathy, Shashi N Vani, BNS Walia
7.2.7.1 Universal Immunization Program (UIP) .................................................................. 200
KM Ganessan
7.2.8 Acute Respiratory Infections (ARI) Control Program ........................................................ 202
Keya R Lahiri, BNS Walia, Shashi N Vani
7.2.9 Control of Diarrheal Disease (CDD) Program ..................................................................... 203
BNS Walia, Shashi N Vani
7.2.10 National Leprosy Eradication Program ................................................................................. 204
BNS Walia
7.2.11 National Vector Borne Disease Control Program (NVBDCP) .......................................... 206
Piyush Gupta
7.2.11.1 National Malaria Control Program ................................................................... 206
BNS Walia
7.2.11.2 National Filaria Control Program ...................................................................... 207
BNS Walia
7.2.12 National AIDS and STD Control Program ........................................................................... 207
BNS Walia
7.2.13 Nutrition Programs ................................................................................................................... 208
Shashi N Vani
7.2.14 Mid-day Meal Program ............................................................................................................ 209
HPS Sachdev
7.2.15 Anemia Control Program ......................................................................................................... 209
Shashi N Vani
7.2.16 Control of Vitamin A Deficiency ........................................................................................... 210
BNS Walia
7.2.17 National Iodine Deficiency Disorders Control Program ................................................... 210
N Kochupillai
XXXVI IAP Textbook of Pediatrics

7.2.18 National School Health Program .......................................................................................... 211

BNS Walia
7.2.19 National Cancer Control Program ......................................................................................... 211
BNS Walia
7.2.20 National Mental Health Program (NMHP) ......................................................................... 211
BNS Walia
7.2.21 National Program for Control of Blindness ........................................................................ 211
BNS Walia
7.3 Community Newborn Care .................................................................................................................. 212
Shashi N Vani
7.4 Under Five Clinics ................................................................................................................................. 215
Ajit Kumar
7.5 The Girl Child ........................................................................................................................................ 218
Shanti Ghosh
7.6 Customs and Beliefs in Child Rearing .............................................................................................. 220
Anil Mokashi
7.7 International Agencies and Child Health ......................................................................................... 225
Shashi N Vani
7.8 Adoption and Care of Orphans ........................................................................................................... 226
RD Potdar

8. CHILD ABUSE, NEGLECT AND CHILD LABOR

Chapter Editors: Meenakshi N Mehta, SR Banerjee
8.1 Child Abuse and Neglect ...................................................................................................................... 230
Meenakshi N Mehta
8.2 Child Labor .............................................................................................................................................. 244
Meenakshi N Mehta, SR Banerjee

9. IMMUNIZATION AND INFECTIOUS DISEASES

Chapter Editors: A Parthasarathy, Tapan Kumar Ghosh
9.1 The Principles and Practice of Immunization ................................................................................... 258
T Jacob John
9.2 Vaccines and Vaccine Preventable Diseases: Today and Tomorrow ............................................ 262
AB Desai
9.3 Newer Vaccines ....................................................................................................................................... 265
AK Dutta, Anju Aggarwal
9.4 Vaccine Storage and Handling ............................................................................................................. 271
RK Agarwal, Digant D Shastri
9.5 Management of Adverse Effects Following Immunization (AEFI) ............................................... 277
M Indra Shekhar Rao, Tanmay Amladi
9.6 Approach to Management of Fever in Newborns, Children and Adolescents
in Office Practice ..................................................................................................................................... 285
Digant D Shastri
 Contents XXXVII

9.7 Fever and Fever of Unknown Origin .................................................................................................. 295

PP Maiya
9.8 An Approach to a Child with Fever and Skin Rash ......................................................................... 302
Jayakar Thomas
9.9 Tuberculosis in Children....................................................................................................................... 315
Vimlesh Seth
9.10 Abdominal Tuberculosis ....................................................................................................................... 332
Saroj Mehta, Vimlesh Seth
9.11 Neurotuberculosis .................................................................................................................................. 336
Vimlesh Seth
9.11.1 Revised National Tuberculosis Control Program (RNTCP) including
Directly Observed Treatment .................................................................................................. 342
Vimlesh Seth
9.12 Poliomyelitis ............................................................................................................................................ 350
Ashok K Gupta
9.12.1 Differential Diagnosis of Acute Flaccid Paralysis ............................................................... 354
AD Tewari
9.12.2 National Immunization Days (NIDs) as a Vital Component of Polio Eradication
Strategy ......................................................................................................................................... 359
Vipin M Vashishtha, Naveen Thacker
9.13 Diphtheria ................................................................................................................................................ 362
AP Dubey, Jaydeep Choudhury
9.14 Pertussis (Whooping Cough) ................................................................................................................ 364
YK Amdekar
9.15 Tetanus ..................................................................................................................................................... 366
AP Dubey, Jaydeep Choudhury
9.16 Measles ..................................................................................................................................................... 368
AP Dubey, Jaydeep Choudhury
9.17 Mumps: Epidemic Parotitis ................................................................................................................... 370
Ashok Gupta
9.18 Rubella ...................................................................................................................................................... 372
AP Dubey, Jaydeep Choudhury
9.19 Staphylococcal Infections ...................................................................................................................... 374
AK Dutta, Anju Aggarwal
9.20 Pneumococcal Disease and its Prevention ......................................................................................... 376
Rohit C Agrawal
9.21 Hemophilus Influenzae b Disease ...................................................................................................... 383
RK Agarwal, Anju Aggarwal
9.22 Typhoid Fever ......................................................................................................................................... 383
YK Amdekar
9.23 Leprosy ..................................................................................................................................................... 387
Rajeshwar Dayal
9.24 Leptospirosis in Children ...................................................................................................................... 392
S Ramesh
9.25 Chickenpox (Varicella) .......................................................................................................................... 394
AP Dubey, Jaydeep Choudhury
XXXVIII IAP Textbook of Pediatrics

9.26 Dengue Illnesses ..................................................................................................................................... 396

Ashok S Kapse
9.27 Infectious Mononucleosis ..................................................................................................................... 404
S Ramesh
9.28 Respiratory Syncytial Virus Infection ................................................................................................ 405
A Balachandran, SO Shivbalan
9.29 Rotavirus Disease ................................................................................................................................... 408
Raju C Shah
9.30 Rabies ........................................................................................................................................................ 409
Tapan Kumar Ghosh, A Parthasarathy
9.31 Pediatric HIV Disease ............................................................................................................................ 414
Meena Malkani
9.32 Chikungunya Fever ................................................................................................................................ 419
Utpal Kant Singh, Rajniti Prasad
9.33 Malaria in Children ................................................................................................................................ 423
Ashok S Kapse
9.34 Kala-azar (Visceral Leishmaniasis) ..................................................................................................... 440
Yogesh Jain, Rakesh Lodha

10. DISEASES OF CENTRAL NERVOUS SYSTEM

Chapter Editors: Veena Kalra, PSN Menon
10.1 Anatomical Localization of Neurological Problems ....................................................................... 444
CS Rajput, DP Karmarker
10.2 Normal Development and Malformations of Central Nervous System ..................................... 448
Veena Kalra, Rashmi Kumar
10.3 Degenerative Disorders of the Central Nervous System ............................................................... 453
Veena Kalra
10.4 Seizure Disorders in Children ............................................................................................................ 455
Veena Kalra
10.5 Infections of the Central Nervous System ........................................................................................ 462
Veena Kalra
10.6 Coma in Children .................................................................................................................................. 470
CR Banapurmath, Shobha Banapurmath, G Guruprasad
10.7 Brain Tumors in Children .................................................................................................................... 477
KS Rana
10.8 Raised Intracranial Pressure ................................................................................................................ 486
AD Tewari, Kundan Kumar Mittal
10.9 Benign Intracranial Hypertension ...................................................................................................... 489
AD Tewari, Kundan Kumar Mittal
10.10 Motor Weakness in Infancy and Childhood—Clinical Approach ............................................... 491
Vrajesh Udani
10.11 Floppy Infant Syndrome ...................................................................................................................... 495
R Anandam, D Kalpana
10.12 Muscular Disorders in Children ......................................................................................................... 499
K Pandian
 Contents XXXIX

11. DISEASES OF CARDIOVASCULAR SYSTEM

Chapter Editors: Anita Khalil, Srikanta Basu
11.1 Congenital Heart Disease: General Aspects ..................................................................................... 504
NC Joshi
11.2 Common Congenital Heart Diseases in Children ........................................................................... 509
Anita Khalil, M Zulfikar Ahamed
11.3 Medical Management of Congenital Heart Diseases ..................................................................... 518
Anita Khalil, Bharat Dalvi
11.4 Surgery for Congenital Heart Diseases ............................................................................................. 521
KS Dagar, KS Iyer, Srikanta Basu
11.5 Rheumatic Fever and Rheumatic Heart Disease .............................................................................. 526
Anita Khalil
11.6 Congestive Heart Failure in Children ................................................................................................ 534
Anita Khalil
11.7 Systemic Arterial Hypertension in Children .................................................................................... 538
Srikanta Basu, S Srinivasan
11.8 Pericardial Diseases and Disorders .................................................................................................... 548
S Srinivasan, Srikanta Basu
11.9 Cardiac Arrhythmias in Children ....................................................................................................... 551
S Srinivasan, Srikanta Basu

12. DISEASES OF RESPIRATORY SYSTEM

Chapter Editor: A Balachandran
12.1 Examination of the Respiratory System ............................................................................................ 558
YK Amdekar
12.2 Diagnostic Procedures and Investigations in Respiratory Diseases ............................................ 560
Archana S Kher, Soumya Swaminathan, Milind S Tullu
12.3 Flexible Fiberoptic Bronchoscopy (FFBS) ......................................................................................... 564
D Vijayasekaran
12.4 Respiratory Distress .............................................................................................................................. 567
MD Shah
12.5 Upper Respiratory Tract Infection ..................................................................................................... 573
SK Kabra
12.6 Infections of Larynx, Trachea and Bronchi ....................................................................................... 576
Keya R Lahiri, Roshani N Taori
12.7 Pneumonia in Children ........................................................................................................................ 578
A Balachandran, SO Shivbalan
12.8 Acute Bronchiolitis ................................................................................................................................ 583
Uday B Nadkarni
12.9 Empyema ................................................................................................................................................. 586
A Balachandran, Swati Y Bhave, S Thangavelu
12.10 Bronchiectasis ......................................................................................................................................... 588
A Balachandran, Swati Y Bhave, NC Gowrishankar
XL IAP Textbook of Pediatrics

12.11 Lung Abscess .......................................................................................................................................... 589

A Balachandran, Swati Y Bhave, S Thangavelu
12.12 Hemoptysis ............................................................................................................................................. 591
Vibha Mangal, Neeraj Jain, Vibhu Kwatra
12.13 Bronchial Asthma .................................................................................................................................. 593
H Paramesh, L Subramanyam, SO Shivbalan

13. DISEASES OF GASTROINTESTINAL SYSTEM AND LIVER

Chapter Editor: VS Sankaranarayanan
13.1 Diarrheal Diseases ................................................................................................................................ 602
Ashok K Patwari
13.2 Persistent and Chronic Diarrhea in Children ................................................................................... 609
Gadadhar Sarangi, Jnanindra Nath Behera
13.3 Parenteral Nutrition in Children ........................................................................................................ 613
Anand N Pandit, Ashish R Bavdekar
13.4 Parasitic Bowel Diseases ...................................................................................................................... 616
BD Gupta
13.5 Vomiting in Infants and Children ...................................................................................................... 620
S Nagabhushana
13.6 Gastroesophageal Reflux in Infants and Children .......................................................................... 622
Neeraj Jain, Vibha Jain, Deepak Seth
13.7 Gastrointestinal Bleeding in Infants and Children ......................................................................... 624
Saroj Mehta, RC Mathur
13.8 Constipation ........................................................................................................................................... 627
VR Ravikumar
13.9 Abdominal Pain ..................................................................................................................................... 629
S Srinivas
13.9.1 Acute Abdominal Pain in Children ...................................................................................... 629
13.9.2 Chronic Abdominal Pain in Children .................................................................................. 632
13.10 Helicobacter Pylori Infection in Children ........................................................................................ 637
Neeraj K Jain, Vibha Mangal
13.11 Cystic Fibrosis ........................................................................................................................................ 639
Sushil K Kabra, Madhulika Kabra
13.12 Juvenile Tropical Pancreatitis ............................................................................................................. 644
A Riyaz
13.13 Liver and Biliary System ...................................................................................................................... 646
B Bhaskar Raju, B Sumathi
13.14 Hepatosplenomegaly: A Practical Diagnostic Approach ............................................................... 650
Sheila Bhave, Ashish Bavdekar
13.15 Differential Diagnosis of Jaundice in Infancy ................................................................................. 653
MK Jain, Sunil Karande
13.16 Viral Hepatitis ........................................................................................................................................ 655
Malathi Sathiyasekaran, Ramaswamy Ganesh
 Contents XLI

13.17 Chronic Hepatitis in Children ............................................................................................................. 667

BR Thapa
13.18 Chronic Liver Disorders in Children ................................................................................................. 672
VS Sankaranarayanan, S Srinivas
13.19 Cirrhosis of Liver ................................................................................................................................... 675
VS Sankaranarayanan, S Srinivas
13.20 Neonatal Cholestasis Syndrome ......................................................................................................... 682
BR Thapa
13.21 Fulminant Hepatic Failure ................................................................................................................... 692
Rajiv Chandra Mathur
13.22 Ascites ...................................................................................................................................................... 695
Balvir S Tomar, Anurag Tomar

14. DISEASES OF KIDNEY AND URINARY TRACT

Chapter Editors: Arvind Bagga, RN Srivastava
14.1 Renal Anatomy and Physiology ......................................................................................................... 714
Arvind Bagga
14.2 Diagnostic Evaluation ........................................................................................................................... 715
RN Srivastava, Aditi Sinha
14.3 Imaging of the Urinary Tract ............................................................................................................... 719
Arvind Bagga, Aditi Sinha
14.4 Developmental Anomalies .................................................................................................................. 722
M Vijayakumar
14.5 Acute Proliferative Glomerulonephritis ........................................................................................... 724
BR Nammalwar, T Vasanthi, M Vijayakumar
14.6 Renal Vasculitis ..................................................................................................................................... 729
BR Nammalwar, N Prahlad
14.7 Acute Renal Failure ............................................................................................................................... 737
Arvind Bagga, Aditi Sinha
14.8 Nephrotic Syndrome ............................................................................................................................. 743
RN Srivastava, Arvind Bagga
14.9 Urinary Tract Infection, Vesicoureteric Reflux and Reflux Nephropathy .................................. 750
M Vijayakumar, RN Srivastava
14.10 Obstructive Uropathy ........................................................................................................................... 754
Kumud P Mehta
14.11 Disorders of Micturition ...................................................................................................................... 755
Kumud P Mehta
14.12 Chronic Kidney Disease ....................................................................................................................... 757
KD Phadke, Pankaj Hari
14.13 Hypertension .......................................................................................................................................... 761
Kumud P Mehta
14.14 Renal Tubular Disorders ...................................................................................................................... 763
Aditi Sinha, Arvind Bagga
XLII IAP Textbook of Pediatrics

15. PEDIATRIC HEMATOLOGY

Chapter Editor: MR Lokeshwar
15.1 Anemia in Children ............................................................................................................................... 768
MR Lokeshwar, VP Choudhry
15.2 The Value of a Complete Blood Count in Children ........................................................................ 771
Zeenat Currimbhoy
15.3 Anemia in the Newborn ....................................................................................................................... 775
Jayashree A Mondkar, Mamta Manglani, Armida Fernandez
15.4 Nutritional Anemias in Infancy and Childhood ............................................................................. 780
Niranjan Shendurnikar, Omprakash Shukla, Sushil Madan
15.5 Nutritional Anemias in Adolescence ................................................................................................. 785
Sushil Madan
15.6 Thalassemia ............................................................................................................................................ 794
MR Lokeshwar, Nitin Shah, Swati Kanakia, Mamta Manglani
15.7 Sickle Cell Disease ................................................................................................................................ 816
VS Dani
15.8 Red Cell Membrane Disorders ........................................................................................................... 820
Rashmi Dalvi, Bharat Agarwal, R Agarwal
15.9 Autoimmune Hemolytic Anemia ....................................................................................................... 822
Bharat Agarwal, Rashmi Dalvi
15.10 Bone Marrow Failure Syndrome ........................................................................................................ 824
Nitin Shah, MR Lokeshwar
15.11 Physiology of Hemostasis: Approach to a Bleeding Disorder ...................................................... 828
Renu Saxena
15.12 Platelet and Bleeding Disorders ......................................................................................................... 831
VP Choudhry, Amit Upadhyay
15.13 Disseminated Intravascular Coagulation (DIC) .............................................................................. 843
Anupam Sachdeva, VP Choudhry
15.14 Bleeding Disorders in the Newborn .................................................................................................. 854
Jayashree A Mondkar, Mamta Manglani, Armida Fernandez
15.15 Hematopoietic Growth Factors ........................................................................................................... 858
Purvish M Parikh, MR Lokeshwar
15.16 Transfusion Medicine and Component Therapy in Pediatrics ..................................................... 861
RK Marwaha, Sudeshna Mitra, Deepak Bansal

16. PEDIATRIC ONCOLOGY

Chapter Editor: Purna A Kurkure
16.1 Malignancies in Children .................................................................................................................... 874
Purna A Kurkure
16.2 Acute Leukemia ..................................................................................................................................... 874
Anupama Borker, SH Advani
16.3 Hodgkin’s Disease ................................................................................................................................. 880
Purna A Kurkure, Brijesh Arora, Roshni Bhagwat
 Contents XLIII

16.4 Non-Hodgkin’s Lymphoma ................................................................................................................. 883

Purna A Kurkure, Brijesh Arora, Roshni Bhagwat
16.5 Wilms’ Tumor ......................................................................................................................................... 887
Purna A Kurkure, Brijesh Arora, Shailesh Kanvinde
16.6 Neuroblastoma ....................................................................................................................................... 890
Purna A Kurkure, Brijesh Arora, Shailesh Kanvinde
16.7 Soft Tissue Sarcoma .............................................................................................................................. 895
Sajid Qureshi, Purna A Kurkure
16.8 Retinoblastoma ...................................................................................................................................... 901
Sripad Banavali
16.9 Bone Marrow Transplantation ............................................................................................................ 903
Brijesh Arora, Purvish M Parikh, MR Lokeshwar

Volume 2
17. ENDOCRINOLOGY
Chapter Editor: PSN Menon
17.1 Disorders of Growth ............................................................................................................................. 912
PSN Menon
17.2 Disorders of Pituitary ........................................................................................................................... 919
PSN Menon
17.3 Obesity ..................................................................................................................................................... 925
Anju Virmani
17.4 Disorders of the Thyroid Gland ......................................................................................................... 931
Meena P Desai
17.5 Disorders of Bone and Mineral Homeostasis .................................................................................. 935
Vijayalakshmi Bhatia
17.6 Disorders of Puberty ............................................................................................................................. 941
Prisca Colaco
17.7 Disorders of Sexual Differentiation .................................................................................................. 947
P Raghupathi
17.8 Disorders of Adrenocortical Biosynthesis ........................................................................................ 951
P Raghupathy
17.9 Disorders of Adrenal Glands .............................................................................................................. 955
PSN Menon
17.10 Diabetes Mellitus .................................................................................................................................. 962
Vijayalakshmi Bhatia

18. GENETICS
Chapter Editor: ML Kulkarni
18.1 Basic Genetics for Genetic Counseling ............................................................................................. 972
ML Kulkarni
XLIV IAP Textbook of Pediatrics

18.2 Common Genetic Disorders ................................................................................................................ 989

ML Kulkarni
18.3 New Genetics and Advances in Genetics ....................................................................................... 1013
ML Kulkarni
18.4 Inborn Errors of Metabolism ............................................................................................................. 1029
ML Kulkarni

19. CHILDHOOD DISABILITIES

Chapter Editor: MS Mahadeviah
19.1 Developmental Disabilities in Children ......................................................................................... 1044
MS Mahadeviah
19.2 Cerebral Palsy ...................................................................................................................................... 1045
Pratibha D Singhi
19.3 Attention Deficit Hyperactivity Disorders ..................................................................................... 1049
Nandini Mundkur
19.4 Learning Disability ............................................................................................................................. 1051
MS Mahadeviah
19.5 Childhood Autism ............................................................................................................................... 1053
MS Mahadeviah
19.6 Early Detection and Early Intervention Therapy for Developmental Delay ........................... 1055
MKC Nair, Babu George
19.7 Mental Retardation ............................................................................................................................. 1072
Sunanda K Reddy

20. PEDIATRIC IMMUNOLOGY, ALLERGY AND RHEUMATOLOGY

Chapter Editor: Surjit Singh
20.1 Basics of Immune System in Children ............................................................................................ 1080
Keya R Lahiri, Roshani N Taori
20.2 Immunodeficiency Disorders ............................................................................................................ 1085
Surjit Singh, H Paramesh
20.3 Allergic Rhinitis ................................................................................................................................... 1087
H Paramesh
20.4 Food Allergy and Related Gastrointestinal Tract Diseases ......................................................... 1091
VS Sankaranarayanan
20.5 Value of Allergy Tests in Pediatrics ................................................................................................. 1095
L George Moses, A Parthasarathy
20.6 Allergen Specific Immunotherapy ................................................................................................... 1099
K Nagaraju
20.7 Rheumatological Disorders in Children ......................................................................................... 1101
S Ramakrishnan, A Parthasarathy
20.8 Antiphospholipid Syndrome ............................................................................................................ 1112
Surjit Singh
20.9 Approach to Vasculitis in Children ................................................................................................. 1113
Surjit Singh
 Contents XLV

20.10 Kawasaki Disease ................................................................................................................................ 1115

Noel Narayanan
20.11 Intravenous Immunoglobulin ........................................................................................................... 1118
Surjit Singh

21. THERAPEUTICS
Chapter Editor: Sandeep B Bavdekar
21.1 Basics of Pediatric Therapeutics ....................................................................................................... 1122
Sandeep B Bavdekar, S Ramesh
21.2 Adverse Drug Reactions, Drug Interactions and Therapeutic Drug Monitoring .................... 1126
Archana Kher, Milind S Tullu
21.3 Rational Drug Therapy in Children ................................................................................................. 1130
Arun Phatak

22. PEDIATRIC INTENSIVE CARE

Chapter Editor: Sunit C Singhi
22.1 The Need and Scope of Intensive Care in Pediatrics .................................................................... 1136
Krishan Chugh
22.2 Organization of a Pediatric Intensive Care Unit ........................................................................... 1138
Sunit C Singhi
22.3 Cardiopulmonary Resuscitation ....................................................................................................... 1141
Yogesh C Govil
22.4 Shock ...................................................................................................................................................... 1148
Jayashree Muralidharan
22.5 Acute Respiratory Failure .................................................................................................................. 1153
Uday B Nadkarni
22.6 Assisted Ventilation in Children ...................................................................................................... 1156
Suchitra Ranjit
22.7 Monitoring a Child on Intensive Care ............................................................................................. 1160
Archana Sathe
22.8 Interpretation of Laboratory Findings in a PICU .......................................................................... 1168
Anil Sachdev

23. ADOLESCENT CARE

Chapter Editor: MKC Nair
23.1 Introduction: Why Adolescent Care? ............................................................................................... 1176
MKC Nair, SS Kamath
23.2 Adolescent Care and Family Life Education .................................................................................. 1178
Manorama Verma
23.3 Adolescent Nutrition .......................................................................................................................... 1180
Jugesh Chhatwal
23.4 Adolescent Psychology ....................................................................................................................... 1183
Jugesh Chhatwal
XLVI IAP Textbook of Pediatrics

23.5 Identity Crisis and Adolescents ........................................................................................................ 1186

Shrikant W Chorghade
23.6 Adolescent Sexuality ........................................................................................................................... 1189
Jugesh Chhatwal
23.7 Common Health Problems in Adolescents ..................................................................................... 1192
Manorama Verma, Jugesh Chhatwal
23.8 Polycystic Ovarian Syndrome ........................................................................................................... 1200
MKC Nair

24. ACCIDENTS AND POISONINGS

Chapter Editor: CG Wilson
24.1 Injuries in Children and Injury Control ......................................................................................... 1204
CG Wilson
24.2 Poisoning in Children ......................................................................................................................... 1207
KS Rao, B Ravichander

25. CHILD PSYCHIATRY

Chapter Editor: Manju Mehta
25.1 Child Psychiatry ................................................................................................................................... 1216
Manju Mehta
25.2 Child Guidance Clinic (CGC) ........................................................................................................... 1229
T Ravikumar

26. PEDIATRIC SURGERY

Chapter Editor: Ketan Praveen Parikh
26.1 Common Pediatric Surgical Problems ............................................................................................. 1232
Subhash J Dalal, Ketan Praveen Parikh, Amrish Vaidya

27. PEDIATRIC ORTHOPEDICS

Chapter Editor: Mayilvahanan Natarajan
27.1 Congenital Anomalies ........................................................................................................................ 1264
PP Kotwal, Bhavuk Garg
27.2 Infections of Bones and Joints .......................................................................................................... 1268
PP Kotwal, Bhavuk Garg
27.3 Neuromuscular Disorders .................................................................................................................. 1278
Mayilvahanan Natarajan
27.4 Osteochondritis .................................................................................................................................... 1282
Mayilvahanan Natarajan
27.5 Inequality of Limb Length ................................................................................................................. 1285
Mayilvahanan Natarajan, PP Kotwal, MK Varshney
27.6 Pediatric Bone Tumors ....................................................................................................................... 1288
Mayilvahanan Natarajan, PP Kotwal, MK Varshney
27.7 Miscellaneous Orthopedic Conditions ............................................................................................ 1296
PP Kotwal, MK Varshney
 Contents XLVII

28. PEDIATRIC RADIOLOGY

Chapter Editor: Arun Kumar Gupta
28.1 Pediatric Radiology ............................................................................................................................. 1300
Arun Kumar Gupta, Chandan B Das

29. PEDIATRIC OPHTHALMOLOGY

Chapter Editor: Supriyo Ghose
29.1 Common Eye Problems in Children ................................................................................................ 1316
Supriyo Ghose

30. PEDIATRIC OTORHINOLARYNGOLOGY

Chapter Editor: Divya Prabhat
30.1 Common Problems of Ear, Nose and Throat in Children ............................................................ 1334
Divya Prabhat

31. PEDIATRIC DERMATOLOGY

Chapter Editor: Jayakar Thomas
31.1 Skin Diseases in Children ................................................................................................................. 1336
Jayakar Thomas

32. PEDIATRIC DENTISTRY

Chapter Editor: PK Baskar
32.1 Common Dental Problems ................................................................................................................. 1372
PK Baskar

33. PEDIATRIC PRIORITIES IN THE 21ST CENTURY

Chapter Editor: Piyush Gupta
33.1 Pediatric Priorities in the 21st Century ............................................................................................ 1384
RK Agarwal, Piyush Gupta
33.2 Pollution and Child Health in the 21st Century ............................................................................ 1389
NR Bhandari
33.3 Pediatric Environment Health-Hazards .......................................................................................... 1392
Anupam Sachdeva, MKC Nair, Swati Y Bhave
33.4 Research Methodology in Pediatric Practice .................................................................................. 1410
Saradha Suresh, P Ramachandran
33.5 Computers in Pediatric Medicine ..................................................................................................... 1414
Neeraj Jain, Vibha Jain
XLVIII IAP Textbook of Pediatrics

34. PEDIATRIC PROCEDURES

Chapter Editors: Piyush Gupta, PSN Menon
34.1 Common Procedures in Pediatric Practice ...................................................................................... 1420
Baldev S Prajapati, A Parthasarathy

35. PHYSICAL MEDICINE AND REHABILITATION

Chapter Editors: A K Dutta, Piyush Gupta
35.1 Physical Medicine and Rehabilitation in Pediatric Practice ........................................................ 1446
Bina Ahuja, AK Dutta
35.2 Chest Physiotherapy in Children ..................................................................................................... 1452
D Vijayasekaran

36. Miscellaneous Topics

Chapter Editors: Piyush Gupta, PSN Menon
36.1 Vital Statistics in India ....................................................................................................................... 1458
Piyush Gupta, HPS Sachdev
36.2 The Infant Milk Substitutes, Feeding Bottles and Infant Foods (Regulation of
Production, Supply and Distribution) Act, 1992 ............................................................................ 1459
SP Srivastava
36.3 Normal Laboratory Values ................................................................................................................ 1465
Piyush Gupta, HPS Sachdev
36.4 Principles of Fluids and Electrolytes in Diarrheal Dehydration ................................................ 1474
S Ramesh
36.5 Drugs and Drug Dosage ..................................................................................................................... 1480
S Ramesh
36.6 Essential Drugs in Pediatrics ............................................................................................................. 1488
Arun P Phatak
36.7 Growth Charts: ..................................................................................................................................... 1490
Vaman V Khadilkar, Dilip Mukherjee, MKC Nair
36.7.1 IAP Growth Charts ................................................................................................................... 1490
Vaman V Khadilkar
36.7.2 Appendix .................................................................................................................................... 1498
Vaman V Khadilkar
36.7.3 WHO Growth Charts ............................................................................................................... 1502
Dilip Mukherjee, MKC Nair
36.8 Safe Injection Practices ....................................................................................................................... 1507
Baldev S Prajapati, Swati Y Bhave, SS Kamath
36.9 Searching and Researching Online .................................................................................................. 1516
Vijay Agarwal
36.10 The IMNCI Case Management Process ........................................................................................... 1522
Harish Kumar, Raju C Shah, Naveen Thacker, Deepak Ugra
 Contents XLIX

36.11 IAP Infectious Diseases Chapter Protocols: ................................................................................... 1525

Ritabrata Kundu, Nupur Ganguly, Tapan Kumar Ghosh
36.11.1 Malaria .................................................................................................................................... 1525
Raju C Shah, Tapan Kumar Ghosh, Ritabrata Kundu, Nupur Ganguly
36.11.2 Enteric Fever .......................................................................................................................... 1528
Nitin K Shah, Raju C Shah, Tapan Kumar Ghosh, Ritabrata Kundu, Nupur Ganguly
36.11.3 Pyogenic Meningitis ............................................................................................................. 1531
Veena Kalra, Tapan Kumar Ghosh, Ritabrata Kundu, Nupur Ganguly, Vijay N Yewle
36.11.4 Rabies ...................................................................................................................................... 1534
Tapan Kumar Ghosh, SN Madhusudhana, Shivananda
36.12 IAP Consensus Recommendations on Immunization, 2008 ........................................................ 1538
Tanu Singhal, YK Amdekar, Piyush Gupta

Index ...................................................................................................................................................... 1545

1.1 Importance of Pediatrics: RD Potdar ....................................................................................................................................................... 2
1.2 Attaining Proficiency in Pediatrics: BNS Walia ...................................................................................................................................... 3
1.3 Pediatric Care in Developing Countries: BNS Walia .............................................................................................................................. 5
1.4 Primary Health Care: Yuvaraj Chandra Mathur, Nitin Chandra Mathur .................................................................................................... 7
1.5 Primary Neonatal Care: Santosh K Bhargava .......................................................................................................................................... 9
1.6 Management of Primary Health Centers: Piyush Gupta ....................................................................................................................... 12
1.7 Training of Medical Graduate as Middle Level Manager: C Thirugnanasambandham, T Arunmozhi ............................................... 16
2 IAP Textbook of Pediatrics
1.1 Importance of Pediatrics
Till nearly 50 years back, Pediatrics used to be considered
as subsidiary of internal medicine in India and other
developing countries. It was but natural that many
internists while treating children as small adults, realised
that children form a unique, definitive and a fairly large
segment of human population. Some of them started
studying the health and diseases of children exclusively
and in depth and established that Pediatrics was a science
and a subject by itself.
Undergraduate students of Medicine must clearly
understand the attributes, significance, importance and
the necessity of the subject of Pediatrics before they
embark on Pediatrics itself, merely as an examination
subject. Whether they aspire to become specialists in
Pediatrics or its subspecialities or otherwise, knowledge
of Pediatrics is essential for every medical student because
nearly 42 percent of our population is below 18 years and
every physician is bound to face children in his/her
medical career as frequently, if not more often than adults.
It is necessary to know the special situation of
Pediatrics as a subject because of the following reasons:
Age Group
Pediatrics, unlike the other subjects includes a wide spec-
trum of age groups. Each of these age groups have their
own physiological, pharmacological, pathological and
therapeutic characteristics which need to be remembered
while handling respective age groups in clinical
situations. The age groups are: (1) fetal period including
embryogenesis, (2) perinatal period, (3) prematurity,
(4) natal period, (5) neonatal period, (6) infancy, (7) toddler
group, (8) preschool, (9) school—primary, middle and
high, and (10) adolescence.
The pattern of health norms, presentation of diseases,
common causes of diseases as well as dosage and tole-
rance of drugs differ at these ages. Hence, age becomes a
very important consideration in treating a child.
Presenting Features
In most pediatric patients, symptoms are not directly
brought out like those in the adults. History is always
RD Potdar
second hand coming from the caregiver more often than
the child itself.
Many symptoms get converted into presenting fea-
tures which are a series of common symptoms represen-
ting different organ affections or problems as under:
Crying: It is the most common presenting feature of many
conditions such as pain, hunger, thirst, wetting, fear,
anxiety, local hurt, etc.
Vomiting: It may be a presenting feature of any system
malfunction apart from or in addition to gastrointestinal
disease.
Paucity of Signs
One may not be able to elicit all classical signs that can
be elicited in adults. In Pediatrics, clinicians have to use
comprehensive findings of history, examination,
investigations and natural history and course of the
disease to arrive at a specific diagnosis.
Growth and Development
A child is a constantly growing and developing orga-
nism making it highly susceptible and vulnerable to
various invasive, diagnostic and therapeutic actions. This
makes the responsibility of the clinician towards the child
far greater than that for the adult. Child is always the
passive recipient of treatment and hardly has any choice
taking any decision concerning itself.
Early Diagnosis and Early Intervention
These have tremendous rewards and importance in
children as compared to an adult, e.g. TB meningitis
suspected and diagnosed at an early stage can prevent
many a tragic sequelae as compared to an adult where
early intervention may not be that cost-effective.
Drug Tolerance, Interaction and Toxicity
It is different for different drugs at different ages of a
child. Since the dosage is related to the body surface or

the weight, it is essential that a drug dosage guide
should always be referred to by the treating doctor. The
drug dosage in adults, is generally, in fixed formulation
since there is no extreme variation in all ages of
adulthood unlike the pediatric age group.
Intergenerational Impact
Studies all over the world are proving that impact of
previous generations can manifest in the present gene-
ration both as far as genetic and environmental factors
are concerned. New vistas have opened in causation,
prenatal diagnosis as well as therapy in terms of genetic
engineering and gene therapy.
1.2 Attaining Proficiency in Pediatrics
The time required for mastery of the art of treatment of
sick children is not proportional to the size of the child vs
the adult human. In fact, it is longer and more arduous.
Physical, physiologic and metabolic growth which is
taking place from birth to maturity as an adult makes the
task as difficult as learning to shoot at a moving target,
which is more difficult than shooting at a sitting duck!
Learning the fundamentals of ‘growth’ are therefore a
prerequisite key to understanding several aspects of
pediatrics.
Diseases occur in humans and humans are already
nine months old on the day of birth! Therefore knowledge
of embryology and prenatal development not only helps
to understand the genesis of congenital malformations,
but also guides regarding vulnerable periods in the
evolution of a fetus, which may affect its entire life span.
Osler had said that “a physician is as good as his
pathology”. Knowledge of underlying pathology is
important to understand the symptoms observed in a
disease process and help to understand its evolution.
A sound knowledge of pharmacology helps one to
choose the right drug in the right dose. Medicines are
the main armamentarium of a physician. He must be
aware of what is available, but he must also find out more
about their indications, contraindications, side effects,
Pediatric Care in Developing Countries 3
Pediatric Specialties
Even as the science of Pediatrics has come to stay on its
own, further subspecialties are continuously being
developed. Neonatology and Pediatric Hemato-Oncology
as pediatric superspecialties have already been accepted
for DM degree which is a postgraduate qualification.
Other specialties are also increasingly developing.
It may be, therefore, said that Pediatrics, the science
related to children has come of age in 2009 with adoles-
cents forming integral part of Pediatrics, and its impor-
tance in India where most young population of coming
century in world will form the major segment.
Pediatrics thus needs a constant attention from all
medical aspirant students.
BNS Walia
interactions and dosages before he uses any. This applies
especially to uncommonly used drug.
Amongst the common drugs, about which a doctor
is expected to be well informed, suffice it to say that you
need not burden yourself with the names and details of
all the brands of a molecule available in the market. Select
some reliable brands and stick to them. It has been well
said that drugs are like friends, which must be chosen
wisely and once trusted, kept close to ones bosom.
The basic sciences enable you to understand the why
and how of clinical phenomena and therefore must form
the core foundations for your clinical progress. The
foundation must be deeper, the higher the structure you
wish to construct upon it.
The clinical years are the most interesting period of
medical studies. Learn first of all how to take a good
clinical history. A well recorded history should not only
provide clues to diagnosis and differential diagnosis but
also how the patient has responded to the treatments
offered so far as well as how advanced the condition is
and what the prognosis might be. This must be followed
by a complete and thorough examination of the patient
howsoever minor the complaint that brings him to you.
Many a time you may be able to detect a corroborative
sign or another disease, which is unrelated with the
presenting symptoms.
4 IAP Textbook of Pediatrics
Though the method of systemic examination of a child
is in no way different from that of an adult, the order of
examination should begin from least discomforting
aspects. Also several differences exist in the interpretation
of physical signs when seen in a child as compared to an
adult e.g. tremors in a newborn, brisk tendon reflexes in
a child, extensor plantar response, presence of bronchial
breathing in interscapular region or even presence of
palpable liver in childhood! You must be aware of these
differences and every book on physical examination of
the child emphasizes these.
A special effort must be made to learn—some special
aspects of physical examination in pediatrics. These
include examination of newborn, assessment of
gestational age of a neonate and toddler, neurological
examination of a neonate, developmental assessment,
assessment of growth and sexual development. Identi-
fication of signs of nutritional deficiency and ability to
conduct neurological examination of a preschool child
also require special attention.
Whereas theoretical knowledge is best obtained as
described above, clinical skills are acquired by seeing
someone perform the clinical examination. Excellent
audio and video recordings are now available to practice
clinical skills, after seeing these videos. It is important
that some one should watch you while you are perfor-
ming the developmental examination of a child or
maturity rating of a newborn infant. Both of you should
point out any faults of the partner and if necessary settle
your doubt by asking the advice of a person senior to
you. Later on practice case presentations to each other
and correct each other on history taking, clinical skills.
Make a provisional diagnosis and be able to justify it on
the basis of history and clinical sign. It is essential to write
down a provisional diagnosis or the next best possibility,
so that if you are proved wrong, you can go back to the
case and reexamine it to see what you had missed to do,
which resulted in a diagnostic error. Do not be depressed
if you are proved wrong. Only the persons, who do not
commit to a diagnosis, never make a mistake. Clinical
pediatrics is not like mathematics. There is a lot of
intelligent guess work involved depending upon family,
occupational history, epidemiologic conditions and
prevalence rates of different diseases in a country. But at
all times remember that an uncommon manifestation of
a common disease is more likely to be the cause of a
difficult diagnostic riddle than a rare disease. When faced
with a difficult diagnosis sit down with a list of
possibilities which can be considered in the differential
diagnosis. Score out those that have features that do not
fit and start investigating for those conditions, for which
the clinical possibility exists. Arriving at a diagnosis
should not be like searching for a needle in a haystack
but on the other hand, it can be compared to a concerted
pursuit of a crime investigator who is gathering evidence
against suspects, to whom the needle of suspicion points.
Inspite of learning all that is said above; your training
will be still far from complete. The ability to interpret
findings on otoscopy and fundoscopy may have to be
learnt by visits to the special clinics of department of ENT
and Ophthalmology. A week spent in the department of
dermatology will familiarize you with the common
dermatological problems seen in pediatrics. Similarly,
one requires interactions with a child psychiatrist to
understand identification and management of behavior
disorders which may masquerade with somatic symp-
toms.
Cardiopulmonary resuscitation should be learnt on
a mannequin before you enter a clinical ward. Who
knows you may be required to resuscitate a baby on your
first night duty, because none else is available!
Competence and confidence in performing proce-
dures is acquired only by doing the procedures. The more
you do, the more proficient you become. There is no place
for complacency in dealing with sick children. If you do
not know how to do a procedure competently, refer the
patient to someone who can. If you mess up the life or
limb of a child, remember, there is COPRA waiting to
sting you!
Basic science related to the disease conditions you are
being taught in clinical pediatrics must be revised at the
same time. For instance study of diseases of thyroid
should start with embryology and anatomy of thyroid
gland, the biochemistry related to synthesis of thyroxin
and proceed with clinical manifestations of thyroid deficit
or excess. This will enable you to understand why and
how certain clinical features of the disease manifest.
Information on developmental testing will enable you
to pick up children who are slow in their development.
Read about the growth parameters at the relevant age
and about procedures of bone and sexual maturity rating.
Next assess your patient. Make a diagnosis and write
down the suspected cause for the abnormality. Read
about what tests are best for establishing the diagnosis
and for repeated evaluation. Now look at treatment
options. Talk to parents of the child on how to use the
medicines and what response to expect. Explain why
medicines must be continued for life time in a dose that

may vary depending upon patient’s response. Inform
parents when to suspect side effects of drugs and when
to come for follow up to evaluate that the medicines
prescribed are acting and there are no adverse side
effects. This is just an example of how medicine should
be studied and practiced to obtain a clear idea of what
needs to be done and its scientific basis. Studied in this
way a proper understanding of medicine is obtained and
once understood, it is retained for a long time. The above
described method may appear to be too time consuming,
but infact, each aspect reinforces the other and the whole
exercise becomes enjoyable when you understand its
why and how.
When bored or tired pick up any of the numerous
atlases available on different subjects or Caffee’s book
on Pediatric Radiology. Several websites also have
excellent picture collections. Look at the pictures and try
to store these images in your memory bank. You will be
surprised at your own memory which will download a
picture several years later and provide you a diagnosis.
Even a life time is not enough to attain mastery over
entire field of pediatrics but if you can master the
diagnosis and treatment of about 50 clinical conditions,
you will be known and respected amongst your
colleagues as a competent pediatrician. Surely that is not
1.3 Pediatric Care in Developing Countries
Most of the developing countries suffer from the twin
scourges of large populations, with vast numbers living
in dire poverty and subhuman living conditions. More
than half of the population lives below the breadline,
which leads to nutritional deficits. Frequent episodes of
infectious diseases further sap away the already poor
nutritional status.
Adding to these widely prevalent disadvantages are
the complexities of living in deep interiors of countryside,
where means of transport are either scarce or nonexistent,
health centers are miles away and health service
providers are either unskilled or not available at all. These
people live on the edge, where ruthless nature and state
of neglect takes a heavy toll on the weak and the
vulnerable, i.e. women and children. Modern medical
Pediatric Care in Developing Countries 5
asking for too much. Each one of you has the potential to
achieve that status, provided you focus, continue efforts
to improve your skills and have the humility to learn
from anyone who knows more than you.
Watch the bedside manners of your seniors who are
popular with patients. Note how they approach the
patient and the way they interact with parents. When
social competence combines with clinical competence,
nothing can come between you and success. A friendly
helpful and sympathetic attitude is essential at all times
for building good relationships that last. Never exploit
the misery of a patient who is already in distress.
Remember always that a patient’s best interest must be
first and foremost in your mind.
What you learn at the medical school is a minuscule
of the vast ocean of knowledge. You mainly learn to
acquire knowledge and some practical skills, which will
form the foundation of your future career. What you
build on it depends on the inputs of hard work,
methodically carried out over span of a life time. A life
time is too a short period to master even one specialty or
sometimes even one medical disease, but if the quest is
continuous, you will enjoy the journey, whatever be the
distance you cover.
BNS Walia
care is a distant dream and mere survival is a boon from
the Gods.
How and why the situation has been allowed to
deteriorate to this extent, is an uncomfortable question.
The answer lies in the wrong policies pursued by the
government of most of the developing countries, with
few exceptions. Over the last few decades, these policies
have led to a grave imbalance in the allocation of funds
for health projects, so that urban health has been given
precedence over health of rural populations which
constitute 75–80 percent of toal population of a country.
Hospitals have been preferred to dispensaries and
maternal and child health (MCH) centers; superspecialty
hospitals devoted to cardiology and neurology have been
given priority over general hospitals, production of
6 IAP Textbook of Pediatrics
doctors have been given precedence over availability of
paramedics. This imbalance in the disbursement of scant
resources has resulted in a situation, where the interests
of many have been sacrificed for the sake of the few. Thus,
a vast number of people get no medical care. Hospitals,
and dispensaries have been starved of supplies. Doctors
and their overproduction have culminated in a situation
where doctors have to join the queue of educated unemp-
loyed, whereas the country is facing grave shortage of
nurses, physiotherapists, speech therapists, audiologists,
radiographers and laboratory technicians.
A young doctor who begins a career in medicine has
to be aware of these shortcomings in the system into
which he has stepped, so as to be able to chart his way to
be able to accomplish his life’s mission in a meaningful
way. The first few years of his professional life are to be
spent in a rural dispensary or a health center, where
leading a health team is going to be his most important
task. It is quite likely, that he will discover that his 5 years
at the medical college did not prepare him to effectively
cope with his responsibilities. The first lesson that he
learns is that he has to learn a lot and that this learning
shall continue throughout life. He also feels, that his team-
mates also, either do not know how to do what is
expected of them or are not motivated to do it. Setting
standards, and training each member of the team to fulfill
his role, meeting the standards expected, is his next
important task. Knowing the epidemiologic profile of the
geographic area where he is located, helps him to set his
priorities correctly and equip himself with medicines and
supplies for geographic pathology pertaining to that area.
Having ensured himself of a constant supply line of
medicines and other articles needed, he has the
wherewithal to get started. However, his success is
determined by the response that he gets from the
populace and its local leaders.
Illiterate, ignorant of the miracles which modern
medicine can perform, suspicious of new experiments
to be conducted by strangers and misguided by the
indigenous quacks whose vested interests, threatened by
the availability of effective medical care to population
where the quacks hold a monopoly, the villager is often
confused as to where to seek medical relief, even if he is
convinced of its greater effectiveness. There are several
hurdles to cross before he can reach a primary health
center. These include: inability of women folk to travel
alone; (none to care for children and animal stock left
behind while the family is away), loss of a day’s earnings;
lack of means of transport; and finally the cursory and
callous behavior of health workers, who are generally
overworked and steeped in their own professional and
domestic worries connected with rural living.
The prescriptions obtained after much effort are often
not purchased because the poor patient cannot afford
them or they are not locally available. Compliance with
a full course of treatment is often neglected because
instructions are not clearly given or understood and relief
of presenting symptoms is mistaken as cure. This often
leads to disastrous results in diseases like pulmonary
tuberculosis, where bacteria are liable of becoming
resistant to commonly used drugs. Supervision of
therapy by domicilliary visits of health staff, is often
lacking as numerous vertical programs functioning in
the health services encourage an attitude amongst
workers of doing their bit for their own program and
ignoring the other multiple problems being faced by the
patient. Thus, a leprosy worker will not take a malaria
slide or look at a conjunctivitis eye, because his target is
leprosy eradication. The same is true for workers engaged
in blindness control, reproductive health or malaria
eradication. Whereas most of the world is depending on
the single window approach for numerous public
services, we are going on opening new windows,
serviced by “one disease specialists” who fail to relate
with their clients, and thus fail to win their confidence.
It is often forgotten that advice on promotive health care
programs, e.g. family welfare which forms a predomi-
nant part of primary health care, can only be accepted
by a woman from a health worker who has helped her
to recover from her last episode of dysentery or assisted
her last delivery, and not from a stranger, who is chasing
her for his personal targets. The recent change in the
objectives of the family welfare program to reproductive
health program, is indeed a welcome step and is expected
to divert the attention of workers from achievements of
targets to quality services, to be provided to their clients.
Imparting health education should be an important
task of every health worker. He must try to impart some
messages related to the problems the patients are facing,
at every encounter. This is the only way to counter the
scepticism rooted in age-old beliefs in witchcraft and
supernatural powers. All traditional beliefs may not be
harmful and some indeed may be beneficial to the
patient. Unnecessary confrontation of views should be
avoided.

Patients are often brought late to the hospital, and in
a critical condition. Their patience as well as their finan-
cial resources get exhausted. Promptness in attending to
the patient, politeness in dealings, and an attitude of
concern and care by the staff is essential. Our patients
1.4 Primary Health Care
Yuvaraj Chandra Mathur, Nitin Chandra Mathur
All countries of the world are concerned about the
problem of primary health care (PHC) for their people.
This concern includes such aspects as how to provide it,
how to achieve coverage for all of the people, how to
provide primary health care of some quality, how to
make the maximum use of the country’s and commu-
nity’s existing resources, both personnel, equipment, and
supplies, and how to link up primary health care at the
local community level with secondary and tertiary health
resources.
It is for these reasons that the international conference
on primary health care was held by the World Health
Organization at Alma-Ata in 1978.
Definition
Primary health care is essential health care made uni-
versally accessible to individuals and families in the
community by means acceptable to them, through their
full participation and at a cost that the community and
country can afford. It forms an integral part both of the
country’s health system of which it is the nucleus.
Content
Primary health care addresses the main health problem
in the community, providing promotive, preventive
curative and rehabilitative services accordingly. Since
these services reflect and evolve from the economic
conditions and social values of the country and its com-
munities, they will vary by country and community, but
will include at least: promotion of proper nutrition and
an adequate supply of safe water, basic sanitation,
maternal and child care, including family planning,
immunization against the major infectious diseases, pre-
vention and control of locally endemic diseases,
education concerning prevailing health problems and the
Pediatric Care in Developing Countries 7
believe us to be “Gods”, and not mere “Docs” as
compared to our co-professionals in developed countries.
We must try to live up to the expectations of the people,
by showing compassion, and concern, in our dealings
and competence in our jobs, to deserve that appellation.
methods of preventing and controlling them, and
appropriate treatment for common diseases and
injuries.
General Principles
1. PHC should be shaped around the lifestyles of the
people to be served.
2. PHC should be an integral part of the National Health
Care System and other services, in particular supplies,
supervision, referral and technical, and it should be
designed to support the needs at the peripheral level.
3. PHC activities should be fully integrated with the
activities of the other sectors involved in community
development (agriculture, education, public works,
housing, communications).
4. The local population should be actively involved in
planning health care, so that it suits their needs and
priorities. Decisions on what are the community
needs requiring solution should be based upon a
continuing dialogue between the people and the
services.
5. The health care offered should make use of the avai-
lable community resources, especially those which
have hitherto remained untapped, and should remain
within the limits of the funds available.
6. PHC should use an integrated approach of preven-
tive, promotive, curative, and rehabilitative services
for individual, family, and community. The balance
among these services should vary according to com-
munity needs and may well change over time.
7. The majority of health interventions should take place
in or as near as possible to the patient’s home and be
carried out by the worker most simply (but
adequately) trained to give the treatment in question.
8 IAP Textbook of Pediatrics
Who Provides Primary Health Care?
Primary health care is usually delivered by community
health workers. These are public health workers, usually
from the local villages which they serve. They may be
full time or part time, they are usually paid. The PHC
worker needs to understand and be knowledgeable about
the major health problems and needs in his or her
community. For primary health care of women, infants,
and children, the traditional birth attendant (TBA) has
been the person providing primary health care in the
villages.
Training of Primary Health Care Workers
In order to provide safe basic PHC, one of the early steps
required is to define the roles, duties, and functions, the
PHC worker is expected to carryout this “job description”
for the community health worker then needs to form the
basis, for the content of the training program for the PHC
worker. This also means that the workers/trainers of the
PHC need to be prepared in the appropriate content
expected of the PHC staff.
Not only appropriate teaching/training of the PHC
staff is essential, careful supervision of the PHC staff is
also essential on the job. Responsibility for their super-
vision needs to be clearly delineated. The supervisors
need to be familiar with the job description of the PHC
staff, and with the content necessary to supervise them,
as well as methods of supervision.
In a similar fashion, there needs to be a job descrip-
tion of traditional birth attendants (TBAs). Courses for
TBAs need to contain content to enable them to provide
good safe basic prenatal, labor and delivery, and
postpartum care for the mother. They need to be able to
teach and carry out principles of safe hygiene, and health
education for mother and baby. They need to be taught
the principles and content of safe care of the newborn,
of observation of the infant, and of breastfeeding, and
carefully timed supplementary food and weaning. They
need to be trained in family planning education, and in
well child supervision of the infants and children.
Besides, all PHC staff need to be well-trained in the
content of prenatal, intrapartum, postpartum, family
planning, and child health care.
Role of Family Members, Especially the Mother
Family members, especially the mother, are often the
main providers of health care for the family. It is the
mother who raises and cares for the children, as well as
other family members. It is the mother who usually cooks
the food and feeds the family. It is she who observes the
condition of children, and who notices and attempts to
treat illness in the children. This means that women of
the family need to have a good working knowledge of
health care, including hygiene, feeding, family planning,
and how to follow the child’s development and recognize
the signs of early illness. Health education as well as
general education of women is essential. Women’s
organizations can play an important role in this matter.
The Risk Approach
PHC workers need to be taught and be able to utilize the
risk approach. This consists of the ability to follow
carefully and observe pregnant women, infants, and
children, for symptoms/signs/risk factors which might
lead to suspect the presence of a potential health problem
requiring special care and referral. The concept of high-
risk at a simple basic level needs to be taught to PHC
workers. Risk factors recognizable by the PHC worker
need to be included in the training of PHC staff. Patients
suspected of being potentially at high-risk need to be
observed and followed more carefully. Arrangements for
quick referral of high-risk patients are essential.
Linkages to Secondary and Tertiary Care,
Referral System, and Transport
Patients suspected of high-risk need to be referred to a
resource available to the community, able to provide
special diagnostic treatment, and management service
and care, especially a health center or local/district
hospital. A referral system needs to be established so that
easy, smooth, quick and efficient referrals may be made
through a prearranged system. Quick safe transport is
an important aspect of such a referral system.
Indicators of Care and Outcome
As with any activity in public health practice, evaluation
of results is essential for primary health care. Record
keeping is essential. The use of home-based mother
health records is being tested. The development of a
system and of indicators is an important aspect. Basic
indicators such as accessibility to health care, births
attended by a trained attendant, access to safe drinking
water, level of immunization, contraceptive prevalence
are frequently utilized to evaluate outcome of PHC.

1.5 Primary Neonatal Care
Primary Neonatal Care
The sustained decline in infant mortality rate, caused
largely by a decrease in post-neonatal period mortality
has focussed attention to neonatal mortality and new-
born care. If the national goals in child health care are to
be achieved then it is essential to improve neonatal care
at all the three levels namely primary, secondary and
tertiary level. The primary neonatal care deserves highest
priority as even today more than 75 percent of births occur
at home in both urban and rural community and are
attended by trained or untrained birth attendants.
Primary care is intended for all parturient mothers and
their offsprings irrespective of rural or urban community,
institutional, hospital or home delivery for successful
outcome of pregnancies. To achieve this and the birth of
a healthy newborn it is necessary to care and improve
essential prenatal, intranatal, and postnatal care to an
expectant mother and neonatal care at birth subsequently.
Antenatal Care
The most crucial period for a parturient mother and her
fetus is the antenatal period because it is during this time
Figure 1.5.1: Delivery of perinatal care at primary level
Pediatric Care in Developing Countries 9
Santosh K Bhargava
inappropriate or inadequate care may result in problems
to both. All pregnant women should have access to
antenatal care by trained health professionals. It should
include assessment of maternal health, including weight,
height, midarm circumference, nutritional assessment,
obstetric history and obstetric examination for intranatal
risk, follow-up for pregnancy complications such as
anemia, hypertension, urinary infection, etc. and
assessment for fetal growth. Figure 1.5.1 provides a plan
for antenatal care. In our limited resources it is essential
to categorize a pregnancy at low or high-risk because a
timely referral of a high-risk pregnancy for appropriate
care will prevent adverse outcome. Simple information
such as bad obstetric history, maternal weight less than
45 kg, height less than 140 cm, birth interval of less than
2 years between two successive pregnancies, pregnancy
complications, etc. are indicators of high-risk mothers.
Intranatal Care
Safe and clean delivery remains the main objective of
good intranatal care. The community must be made
aware and encouraged to use safe delivery kit
10 IAP Textbook of Pediatrics
TABLE 1.5.1: Birth attendant’s kit of safe
delivery and newborn care
• Soap
• Plastic sheet
• Cotton and gauze pads
• Thread or ligature
• Razor blade
• Mucus suction trap (may be disposable)
• Spring balance (reusable)
• Measuring tape (reusable, fiber glass)
(Table 1.5.1) and delivery by trained birth attendant.
Hand washing with soap, use of sterile thread and blade,
facilities for oropharyngeal suction and warmth at birth
are key components of ensuring safe birth.
Postnatal Care
A postnatal mother needs to be looked after not only for
postdelivery complications such as bleeding and
infections but also for initiating and maintaining succes-
sful breastfeeding. She must be informed about harmful
traditional practices for maternal and newborn care and
advised on routine newborn care.
Neonatal Care
All newborns irrespective of place of birth, person con-
ducting the birth, whether preterm, term or post-term,
normal or low birth weight, apparently well or sick need
care for their survival and well-being. This care is a
newborn’s primary need as prior to birth it is well-
protected in safe, sterile and suitably warm in utero
environment. The primary care is thus intended to
support it to establish successfully its respiration, tempe-
rature, nutrition and provide safe environment. In our
country almost two-thirds of births occur at home and
the remaining at hospital or health care facility. Thus, a
newborn is to be cared at home by traditional birth
attendants or family and at varying levels of health care
by medical professionals who themselves may or may
not have been suitably trained.
Domiciliary Care
The domiciliary care of a newborn is usually determined
by the family tradition, grandmother or any elderly lady
in the house. The family practices are usually steeped in
tradition, cultural and religious practices. It is therefore
TABLE 1.5.2: Some harmful traditional
practices of newborn care
Harmful Practices
Umbilical cord
Cord cutting Sickle- or knife-shaped instruments,
bamboo spike
Cord tying Thread, cloth, bamboo shred
Cord application Ghee, turmeric, cow dung, ash
Resuscitation Slapping, ringing bell, blowing air
across mouth, roasting placenta, etc.
Cleaning oropharynx Finger, cloth
Bath Immediately or within few hours of
birth
Prelacteal feeds Honey, jaggery, glucose, janam ghutti
Time to first feed Delayed from 6-48 hours or more
Breast milk Discarding colostrum
Eyes, ear, nose Kajal and oil application
necessary to be aware of these practices, their sensitivity
to the family to provide appropriate beneficial advice
and warning against harmful practices (Table 1.5.2). The
advice for home care should be simple and acceptable to
family. This should include provision of clean birthing
place, delivery by trained birth attendant, use of safe
delivery methods and the mother and the newborn to
be nursed in warm, clean, well-lighted rooms.
The basic features and components of primary
newborn care have been well-defined and accepted for
delivery of newborn care at primary level as a package
comprising of care at birth, in the immediate neonatal
period and subsequently. This package is known and
described as essential newborn care (Table 1.5.3). It aims
to assist the newborn in establishment of cardiorespi-
ratory effort, prevention of hypothermia and main-
tenance of body temperature, a physical clinical
examination for identification of at risk infant, congenital
malformation; early initiation and maintenance of
successful breastfeeding and referral of a high-risk or sick
newborns for appropriate care to higher level of care.
Care at Birth
The birth of a newborn should always occur in a clean
environment. The room temperature should be suitably
warm. The newborn should be received in a prewarm
clean cloth and dried immediately preferably under a

TABLE 1.5.3: Essential newborn care
• Care at Birth
— Warmth
— Initiation and Maintenance of adequate respiratory
effort
— Prevention of Infection
— Referral for appropriate care
• Care During Immediate and Early Neonatal Period
— Warmth
— Early Breastfeeding
— Prevention of Infection
— Early diagnosis, appropriate care and referral of a sick
newborn
• Care in Late Neonatal Period and Beyond
— Follow-up
— Intervention
radiant heat source and kept warm. The time to first cry
and breath should be recorded. Most of the newborn cry
immediately at birth. Those who fail to cry may need
resuscitation.
There are several methods to assess the cardio-
respiratory effort of the newborn but the most commonly
used method is the Apgar score. The Apgar score consists
of giving a score of 0, 1 and 2 to color, heart rate, reflex
irritability, muscle tone, respirations at 1, 5 and 10
minutes of birth. A score of 7 or more is considered
normal and lower score indicates the need to resuscitate
the infant as described elsewhere. However, at peripheral
level and for primary care health professional such as
traditional birth attendant the time to first cry and
whether it is lusty, feeble or poorly sustained and the
color are reasonably good indicators to reflect newborn’s
condition at birth.
A clinical examination at the earliest opportunity after
birth is mandatory for all newborns. This is aimed to
identify an infant whether he/she is normal or at risk
and for determining appropriate level of neonatal care.
It is ideal to measure an infant by recording birth weight
or by surrogate to birth weight such as midarm circum-
ference by using measuring tape or bangle. A newborn
is at a very high-risk of acquiring infection and sus-
ceptible to adverse effects of cold or hot environment
resulting in hypothermia or fever. It is therefore critical
to ensure asepsis and suitable environmental tempera-
ture of 26-28oC for protection of the newborn.
Pediatric Care in Developing Countries 11
Care in Immediate Neonatal Period
Warmth
A newborn continues to remain susceptible to hypo-
thermia and hence it is necessary to provide warmth to
him by radiant heat source such as infant warmers,
lighted bulb or other suitable means such as nursing of
the mother and the infant in same bed. A heat source
should never come in direct contact with the infant or
very close to him as this may cause burn or hyperthermia.
The child should be appropriately clothed.
Early and Sustained Breast Milk Feeding
All newborns should be put to mother’s breast as soon
as possible after the birth. Early and sustained breast milk
feeding is vital for a newborn’s survival not only in the
immediate neonatal period but also in later months. It is
constant suckling of the breast by the infant which results
in successful breastfeeding. In case it is not possible for
an infant to directly breastfeed, the breast milk should
be expressed and the infant fed the same by cup and
spoon. Feeding of a newborn with artificial milk feeds
endangers it to preventable morbidity and mortality.
Prevention of Infection
A newborn is at a very high-risk of acquiring infections
from surroundings and/or by people visiting or handling
him. It is therefore necessary to wash hands with soap
and water before handling the newborn, avoid unneces-
sary handling by person other than mother or visiting of
the newborn by relatives and friends. All newborn must
be exclusively breastfed and water, prelacteal feeds such
as honey, ghutis, gripe water or unnecessary medication
by mouth must be prohibited. The dangers of such
practices must be explained to family and mother.
Early Diagnosis, Appropriate Care for a High-risk or
Sick Newborn
A good history and clinical examination will help in
identifying almost all at risk and sick newborns. Birth
weight, gestational age, cry at birth, color, movement,
activity, body temperature, abdominal distention,
tachypnea, refusal or decrease in feeds are dependable
signs or symptoms for an early diagnosis. Infants with
birth weight less than 2 kg, preterm irrespective of birth
12 IAP Textbook of Pediatrics
weight, feeble, ill-sustained or excessive crying, poor
color and decreased activity warrant careful observation
and need for appropriate or higher level of supervised
medical care preferably in a health care facility.
Immunization
It is preferrable to immunize the newborn at birth or
within two weeks with oral polio and BCG vaccination.
Hepatitis B vaccine may be administered in high-risk
infants or where the family is able to afford it.
Care in Late Neonatal Period and Beyond
The care of the newborn does not end with the discharge
from the health care facility or postnatal follow-up of
the mother. All infants should be advised adequately on
need to follow-up in well baby/immunization clinics for
1.6 Management of Primary Health Centers
The basic aim of the Primary Health Center is to provide
primary health care to the people it serves.
WHAT IS PRIMARY HEALTH CARE?
Primary health care is essential health care based on
practical, scientifically sound and socially acceptable
methods and technology made universally accessible to
individuals and families in the community through their
full participation and at a cost that the community and
country can afford to maintain at every stage of their
development in the spirit of self-reliance and self-
determination.
Thus the doctor at a Primary Health Center (PHC)
has a different role to play. He/she not only delivers the
health care but manages the center in totality, trains and
leads the team, involves with the community, gets to
know the local people, geography and epidemiology of
diseases, devises strategy, and coordinates with other
managers and stakeholders (both in public and private
domains) under the jurisdiction of the PHC.
Steps in the Management of Primary Health Care
1. Assessment of the situation
2. Selection of priorities
nutritional advice, growth assessment, immunization
and for an early diagnosis of developmental delay or
disability for appropriate optimal care.
BIBLIOGRAPHY
1. Bhargava SK. Recent Trends in Neonatal Health and Care
in India-International Workshop—Improving Health of
the Newborn Infant in Developing countries.
Kathmandu-Nepal, 1997;7-10.
2. Health Information of India 1994.
3. National child survival and safe motherhood program,
integrated clinical skills course for physicians, MCH
division, Ministry of Health and Family Welfare, 1993.
4. National Health Policy, Govt. of India, Ministry of Health
and Family Welfare, 1985.
5. National Neonatology Forum, Proceedings of National
Workshop on traditional practices of neonatal care in
India, 1991.
Piyush Gupta
3. Defining objectives and deciding possible strategies
to accomplish them
4. Involving community
5. Mobilization of resources
6. Selection and training of personnel
7. Identification and supply of essential drugs and
equipment
8. Patient management
9. Monitoring and supervision of the progress of work
10. Team management
Assessment of the Situation
Health situation in the PHC area should be reviewed with
reference to health profile of the people. Availability of
local resources should be estimated. Details of other
demographic and cultural characteristics of the popu-
lation in the catchments of the PHC should be obtained.
Before hand knowledge of the following factors is
generally valuable in planning out of health facility:
demography (age and sex distribution, spread of
education, average income and economic stratification,
religion and caste groups, cultural beliefs and taboos,
attitudes towards health, expectations from the proposed
health facility and identification of influential as well as

functional community leaders), health profile
(prevailing disease pattern, number of people with
disability or handicap, proportion of expectant mothers,
infants and young children; age-related death rates, food
habits, other health practices, the level of sanitation and
hygiene in the community), available resources (the state
of agricultural development and irrigation facilities in
the area, income stratification, availability of food and
sources of potable water, existing health facilities in the
area and their utilization, presence and number of
available traditional faith healers, traditional birth
attendants, practitioners of indigenous systems of
medicine, and information regarding organized
voluntary agencies or establishments such as village
panchayat, health clubs, youth or women’s clubs and
other voluntary non governmental bodies), and the
catchment area (geographic terrain, climate, roads and
other means of communication).
Selection of Priorities
There may be several compelling health problems
necessitating attention in the territory. With the meager
health resources generally made available through
government agencies for primary health care, every
health need of the community cannot be satisfied. It is
necessary to be selective. The health issues and the target
group of people who merit preferential attention should
be recognized and looked after first. Most people seek
prompt relief from pain and affliction. Provision should
be made for emergency treatment of life threatening
conditions. It is more realistic and expedient to try to
prevent large number of deaths due to vaccine prevent-
able diseases by immunization than using enormous
money to extend the life of a few terminally-sick cancer
patients. Cost effective health interventions should
receive precedence in planning in relation to those
illnesses which though common are hard to prevent or
manage.
Defining Objectives and Deciding Strategies
The next step is to identify the objectives proposed to be
achieved through the health care activities. It is not
always necessary to formulate idealistic health objectives.
It is more important to be rational and set objectives,
which are feasible and attainable within a reasonable
time, with the given resources. The objectives should also
be pertinent to the country’s national health policy and
Pediatric Care in Developing Countries 13
needs. It should be possible to quantify the results of
health interventions so that their cost-benefit or cost-
effectiveness can be evaluated.
An objective may be achieved by several possible
alternate strategies. As a general principle, relatively
inexpensive and flexible strategies should be adopted for
the management of prevalent common health problems.
After carefully reviewing various alternate strategies,
their advantages, disadvantages, cost-effectiveness,
scientific soundness and cultural acceptability, decision
should be made about the activities that should actually
be undertaken in accordance with the declared national
health policy. The decisions should be technically sound
and correct. Possible constraints and obstacles in
implementing these activities should be carefully looked
into. Adequate prior planning should be done by interac-
tion between the community, members of the health team
and the administrative officers.
Community Involvement in Primary Health Care
Active participation of community in health care is vital
to make health services readily accessible to the people
and for better utilization of the PHC. This approach relies
on creating increasing awareness among local people
about health and health related activities, so that they
can commit themselves and have stakes in the success of
health activities. People should be actively mobilized to
take more interest in development of health services in
their area by explaining the purpose of health activity
and describing an action plan. Individuals who can
assume leadership role are identified. A health committee
should be formed from among these influential
community leaders to analyze health needs of people and
to plan and execute health projects. The committee
should interact with health professionals to find locally
feasible solutions to the identified problems. The
Committee should assess and mobilize resources and
assign responsibility for achieving objectives.
Mobilization of Resources
Money, personnel and time are the three most important
resources that need proper mobilization at a PHC. There
should be adequate working space at the health post for
members of the health team to operate from a base.
Means of communication with the referral centers should
also be easily available. A critical minimum amount of
resources is needed to maintain the quality of health
14 IAP Textbook of Pediatrics
services at an effective level. The resources can be
mobilized, either from the government, community, non-
government-voluntary agencies or recognized inter-
national agencies. It is advisable to rely only on those
funding agencies, who assure help on a longterm basis
and who create a permanent infrastructure, so that the
projects aided by them can become self reliant in the long
run.
Selecting and Training Personnel
It is almost impossible for a developing country to
employ fully trained graduate physicians for all aspects
of primary health care. At a PHC, you will need to
delegate some of the simpler health tasks to the
paramedical workers. Increasing dependence on other
categories of personnel with limited on the job training
in specific areas of work becomes necessary. Preferably,
they should be drawn from as well as chosen by the
community they are expected to serve. It does not matter
even if they have a lower academic background. These
paramedical workers will have to be increasingly
employed for assisting the busy and overworked
physician for routine and simpler health related tasks.
The latter will, then be able to devote more of his time
for complex health chores, administration and planning.
It is necessary to supervise the work of these specially
trained health workers and retrain them periodically for
the expected job requirements. Physician should provide
technical guidance and support to these workers. The
training can be extended to the practitioners of
indigenous or traditional systems of medicine, traditional
birth attendants, local priest, faith healer or exorcist in
the village who performs witchcraft, branding or other
rituals; and even the quacks.
Identification and Supply of
Essential Drugs and Equipment
Essential medicines (those that satisfy the priority health
care needs of the population) should be made available
at the PHC. Selection of these drugs also depends on local
health needs and health services. Ensure adequate and
timely supplies of drugs, and immunizing agents. You
should be aware of the sources of supply of drugs and
procedure for ordering these. The requirements of drugs
should be estimated for at least a quarter of the year.
The drugs are best stored in a cool-dry place away from
direct sunlight. Vaccines should be stored in refrigerator
and electricity supply should be ensured. Drugs should
be arranged by their generic names in shelves in
alphabetical order or according to the therapeutic class
(their usage or indications) but not according to the
manufacturer or suppliers. Drugs with a recent date of
expiry should be used early. Record of all drugs should
be kept in a stock book. Drugs should be issued by the
storekeeper to the dispenser against issue vouchers and
an entry should always be made in the stock book and
stock card. Only the minimum essential quantity of drugs
required for use on that day or week should be issued at
a time, to prevent excessive wasteful use and to minimize
the possibility of pilferage.
Medical, surgical equipment, furniture, stationery
and other consumable and nonconsumable stores are also
essential resources for primary health care posts. Non-
expendable stores such as furniture, weighing scales,
bedpans, screens, surgical equipment, microscopes and
motor vehicles if properly handled, are not easily
damaged and can be kept in use for several years. These
should be maintained in working order by regular and
timely repairs. Drugs, food, paper, syringes, laboratory
reagents, kerosene, petroleum, candles, match boxes,
torch cells, cotton wool and surgical dressings etc. are
actually expended and are called expendable stores.
Architecturally, the space within the building should be
so arranged, that it facilitates smooth and orderly work,
and does not cause inconvenience or obstruct the
movement of staff or the patients. A to and fro flow of
patients or a common entrance and exit are not conducive
to good working arrangement. Records and paper work
are essential and unavoidable in a primary health care
setting. Stock books and ledgers have to be maintained
and general correspondence attended. Periodic report of
work is to be submitted to the higher authorities. Poorly
maintained and disorganized records books indicate
poor management, inefficient patient care, inadequate
supervision, mishandling and wasteful use of resources.
Stationery and printed forms should be available for
outpatient registration, treatment, referral laboratory and
X-ray requisition, growth monitoring, immunization and
follow up of special diseases such as tuberculosis and
leprosy. If the primary health care post has some
maternity or general beds, inpatient admission forms,
record forms and discharge summary will also be
needed.
Health care forms should be designed for easy and
effective use. Paper should be used economically, but

there should be enough space for writing the data. A
badly printed form may be used badly, making if difficult
to retrieve useful information.
Patient Management
Disease management is a priority as it relieves distress
of the patient and develops confidence. A delay in
initiation of medical care raises the tensions and temper.
First Aid should be provided promptly. If a patient
requires referral, arrangement for a transfer should be
made, transport arranged and a summary of treatment
received by the patient should be provided. Emergencies
should be given priority. Outpatients should be seen
during a fixed time. Other services, which are not run
on daily basis, should be clearly advertised. A para-
medical worker or a physician should be the first person
of contact at the primary health center.
Monitoring the Progress of Work
The leader of the health team is expected to set targets
for different members of the health team. He should
define the tasks to be accomplished within an agreed
schedule of time.
The efficiency of different workers may vary and
certain essential inputs for optimal functioning may not
be available at the appropriate time. To achieve the best
results, you should periodically review the progress of
all work at specified intervals. You should judge the pace
of the work by relating it to the earlier agreed job
schedules, reports of their achievements and site visits
for personal observations and discussion with the staff.
Periodic monitoring helps in recognizing obstacles or
unforeseen difficulties in accomplishing the desired
objectives. Monitoring is useful in good management but
it should be minimal, flexible and timely.
Leading the Health Team
Because of the nature of his training, education and
status, the primary health center doctor has to assume
the role of a natural leader of the PHC team. All personnel
working in the PHC constitutes the health team. As a
team leader, you should be able to induce colleagues and
teammates to work to the best of their capacity, and
motivate them. The team leader should be able to achieve
perfect coordination and cooperation with all members
Pediatric Care in Developing Countries 15
of the team, so that the efficiency and output of the health
team are high and the work is interesting, satisfying and
rewarding.
The leader of the health team should realize that the
health team consists of individuals, who have feelings,
personal interest, anxieties, stresses, conflicts, likes and
dislikes, just as other people. People like to be useful and
important. Their emotional needs are better satisfied, if
they are given the responsibility and authority to carry
out the jobs assigned to them. Their efficiency and work
output improves, if their working conditions are
congenial, peaceful and relaxed with the least tensions
and conflicts. The efficiency of a worker declines if he or
she remains preoccupied with personal needs, such as
lack of adequate lodging close to the place of work, long
hours of work, want of personal security, financial
worries, inadequate facility for children’s education, poor
health or perfunctory personal medical care. It is
distressing to them if their salaries are not paid in time.
Monetary incentive by itself is not adequate for
motivating a health worker to do his work more
conscientiously. Monetary reward should be judiciously
combined with recognition and approbation for his good
work .
The leader should be competent in his own technical
work, so that his team mates respect him for his
knowledge and skills. He should zealously guard his own
credibility for fairness, impartiality, honesty and
integrity. The leader should be easily approachable, so
that the team members can reach him and seek his help
and guidance for solution of their personal, technical and
official administrative problem. The leader should
always appear to be disciplined and well organized in
his thought and work. Delegation of responsibility and
authority to the health team is equally important in the
PHC.
Health team is like a chain: One weak link in the chain
breaks the entire chain. A good leader identifies the weak
links by constant supervision at regular intervals. He then
reinforces them by appropriate measures such as
technical guidance, administrative support and correc-
tive retraining. Regular supervisory control helps the
leader to discover other constraints such as non-
availability or delay in supplies of such needed items.
16 IAP Textbook of Pediatrics
1.7 Training of Medical Graduate as
Middle Level Manager
The World Health Organization, at Alma-Ata conference
on 12th September, 1978, declared that ‘Health’, a state
of complete physical, mental and social well-being and
not merely the absence of disease or infirmity, is a
‘fundamental human right’. There is also an increased
realization, backed by scientific evidence, that neither
the individual nor the nation can achieve optimal health
until we tackle what are commonly known determinants
of health-broadly associated with and arising out of
physical, social, economic, cultural and political
environment. The national and state governments are
committed to the achievement of ‘Health for All’, as early
as possible through the primary health care approach.
That these efforts have had substantial success can be
seen from some of the indices like reduction in crude
birth rate (CBR) from 40.8 (1951) to 25.8 (2002); halving
the infant mortality rate from 146 per thousand live births
(1951) to 60 (2001); reduction in crude death rate from 25
(1951) to 8.5 (2002); addition of 31 years to life expectancy
from 32 to 64 (2000); and reduction in total fertility rate
from 6.0 (1951) to 3.0 (2000). In spite of these successes,
the unfinished task for achievement is still high as can
be seen from the sociodemographic goals set for the 11th
Five Year Plan. Currently India is committed to become
a developed nation by the year 2020, which calls for very
substantial improvement in health, education, economic
development and other areas. A revised strategy for the
achievement of these goals have also been formulated
and consists of provision of integrated service delivery
for reproductive and child health care; decentralized
planning and program implementation; convergence of
service delivery at village level and empowering women
to function as change agents in addition to being
consumers of health care services; removal of gender
inequalities, and special attention to removing inequity
in health care by focusing services to underserved areas
like urban slums and hilly and tribal areas and
disadvantaged groups like women, female children and
adolescents; diverse health care providers; collaboration
with Non- Governmental Organizations (NGOs);
intensified information, education and communication
C Thirugnanasambandham, T Arunmozhi
activities; intersectoral coordination and providing for
older population. In addition, the strategy provides for
social inputs like increasing literacy and raising age of
marriage. In general, the program will continue to be
community and maternal and child health (MCH) based.
Primary Health Care
The health infrastructure for the delivery of services in
health and family welfare consists of the primary health
care system. Presently, one primary health centre (PHC)
caters to about 30,000 population (20,000 in hilly and
tribal areas), one subcentre to about 5000 population
(3000 in hilly and tribal areas). In addition, there is one
community health centre (CHC) with 30 beds for every
3 PHCs. Both the Taluk and District headquarters
hospitals are being equipped and staffed to provide for
referral services.
Epidemiological Transition
Technological advances in medical and allied sciences
have brought down the mortality rate to the targeted
level, but the morbidity burden on the society continues
to remain high. Both communicable and non communi-
cable diseases rank almost equally in contributing to the
high level of morbidity. An additional challenge is the
wide disparity in health status between states, within
the state and between social groups.
While the disease burden remains unchanged, the
pattern has been changing. It is now certain that the
health challenges for the next few decades will consist
of communicable diseases like HIV/AIDS, drug resistant
malaria, tuberculosis, diarrhea and acute respiratory
infection among children. The second challenge concerns
non communicable diseases like the upsurge of cancer
and cardiovascular diseases and other life-style related
diseases such as diabetes, high blood pressure, mental
depression and suicide and accidents. Increase in tobacco
consumption is a cause for added concern. The spread
of HIV/AIDS has the potential to offset the hard gains
achieved in child survival and life-expectancy.
Widespread malnutrition, poverty and illiteracy, as well

as the generally low status of women impede equitable
health development in the country.
Significant changes have taken place in the health
scenario in the country since independence.
1. The predominantly clinical approach in solving
health problems has given rise to a mix of curative,
preventive, promotive and rehabilitative approach.
2. A huge infrastructure has been created in the rural
areas for delivery of health care and family welfare
services. The workload of the medical officers,
custodian of health in their areas, has very much
increased and consists of integrated curative,
preventive and promotive service delivery. Over and
above, are the essential management functions in
terms of planning, coordination, supervision, training
and others.
3. Renewed emphasis on community involvement,
through the recently introduced Panchayati Raj
system, in planning and implementing various
programs resulting in a need to readjust responsibility
and authority and changes in the working of the
bureaucracy.
4. Integration of a number of vertical programs into the
rural health services.
5. The realization that national/state governments
working through health sector, by themselves can
never achieve the health and demographic goals set.
The private sector, NGOs and sectors other than
health, like education, industry, social welfare, rural
development and civic society can and should play a
critical role in health development. Partnerships with
all sectors of society and at all levels are imperative if
we are to bridge the equity gap in health.
6. Major shift from the clinic-catered approach to one
of a suitable mix of clinic and outreach services.
7. The total expenditure on the health system has been
increasing every year, but has remained static at about
0.9% of the Gross National Product (GNP) over the
past two decades. The current level of expenditure is
inadequate to bring about reduction in infant
mortality rates envisaged under the eleventh plan and
reach the millennium development goals. The
government has planned to increase the expenditure
to 2-3% of GDP by the year 2010 and it is hoped it
will materialize.
The above shifts have resulted in major changes in
the roles and functions of the middle level managers of
health delivery system, particularly of medical officers
Pediatric Care in Developing Countries 17
from that of a pure clinician to include public health
practice, communication and health management.
Health Services Management
A neglected area so far is that of health services
management. The effectiveness and efficiency of the
health care delivery system cannot improve significantly,
unless sound administration or management practices
are adopted to improve the system. It has been the
assumption till recently that persons trained in medicine
or public health automatically qualify to become
managers. Only in the last few years, it has been
recognized that this assumption needs change and good
managers need sound training in principles and practice
of health management or administration.
Administration or management could be defined as
a process by which, the potentials of men, money and
materials are synthesized and synchronized for the
achievement of well-defined goals. It is a way to structure
and direct human groups function cooperatively to
achieve predetermined goals. Generally, administrative
process involves: (i) technical functions, (ii) political
functions, and (iii) conflict resolution functions.
Technical functions are best indicated by the well-
known seven letters namely POSDCoRB: P for planning,
O for organizing, S for staffing, D for directing, Co for
coordinating, R for reporting and B for budgeting.
Political function is not to be conceived as partisan
function of politics, it is concerned with making of
policies and structuring of power relationship in an
organization. Conflict resolution process aims at resolving
conflicts amongst individuals, organizations and
between individual and organization goals.
The middle level functionaries in health system
should possess sound knowledge and skills in the process
of planning, coordination, supervision, training,
monitoring and evaluation, communication, community
participation and management of subsystems like office
management, logistics, budgeting, vehicle management,
etc.
Planning
A plan is predetermined course of action, it involves the
intelligent use of resources and working out the broad
outline of things that need to be done and the methods
for doing them. The middle level managers are concerned
with operational level planning. They are concerned with
area planning, area being determined by geographic
18 IAP Textbook of Pediatrics
jurisdiction of workers and also governed by those of
panchayats and panchayat unions.
The essential steps of planning include collecting
baseline information, setting objectives, deciding on
courses of actions and programming. Monitoring and
evaluation is an integral part of planning. The planning
cycle consisting of: planning, implementation, moni-
toring, replanning with repeat, contributing to a greater
progress. However, it will also call for increased
managerial skills on the part of medical officers.
Collection of baseline data is a prelude to community
diagnosis which helps to define community health
problems, their severity, place of occurrence, etc. The
process involves decision on information to be gathered,
framing and administration of questionnaire, data
analysis and report writing. Maximum use has to be
made of existing sources of information, restricting
household/community surveys to a bare minimum.
Once the problems are identified, various options to solve
these have to be considered and the ones that are
technically feasible, cost-effective, administratively
feasible and politically acceptable are chosen.
A problem usually encountered at this level is the
need to strike a balance between what community
perceives as their felt needs, epidemiologically deter-
mined needs of the area and nationally determined
priority needs. The medical officer will have to feed all
necessary information at this stage to the community and
of which they are not aware of. It has been the experience
that the community will be able to make sound decisions
irrespective of illiteracy, when once they have the
information to base the decisions upon. This way, an
agreed level of needs with priorities could be reached.
Planning process should also ensure that consumer
representatives are involved in the planning process at
every stage. Involvement of community through leaders,
teachers, students and others in the information
gathering process is highly rewarding as it helps to
conserve time and energy and arouses the perceptual
curiosity of the people and successful implementation
of programs decided upon.
Detailed programming for each activity is also part
of planning. Programming calls for decision of the
agencies involved, manpower, roles of agencies and
workers, training, coordination, supervision, logistics,
budget, etc. Finally, program developed for separate
activities are synthesized into a complete plan.
The middle level manager should possess not only
knowledge about planning, but also skills in the planning
process.
Coordination
Health delivery system consists of a number of workers
belonging to different disciplines. Usually, even for
achievement of a single goal, work is divided among
people, resulting in need to secure coordination or
teamwork. Health administration at all levels are faced
with bringing about two types of coordination-
intradepartmental and interdepartmental.
Within the present setup, even intradepartmental
coordination is not an easy task to achieve. Integration
of a number of vertical programs into the PHC system
resulting in pooling of workers belonging to various
agencies and changes in their job descriptions and
patterns of work make coordination difficult. A number
of factors like status, beliefs, leadership, clarity of
functions act as major blocks to coordination. The
manager should know various coordinating measures
and which combination to use under particular
circumstances. The measures available to him include
hierarchial control, organizational charts, manuals,
reports, staff conferences, supervision, training,
consultation, etc.
There will be major factors that inhibit inter-
departmental cooperation. These should be identified
and solved. Naming a nodal agency for coordination,
nodal officers at various levels, clear definition of roles
of agencies, training, coordinating mechanisms are
important measures to bring about coordination.
Coordination should be in all phases of planning,
implementation and evaluation.
Good coordination also involves getting the right
things done, in the right place, at the right time, in the
right way and by the right people.
Supervision
A major function of medical officers, at intermediate
levels is supervision. It is an educational process in which
the supervisor takes responsibility for helping the
supervisee develop himself and become more competent
in discharging his duties. Supervision aims at goal
achievement, work facilitation and building human
relations. Staff usually look to the manager for a standard
of leadership. Thus, the way in which the managers

conduct themselves, manage a program and its people
will affect how the staff work. It will also influence the
thinking and behavior of future managers. One has to
lead by example for success.
There are a number of supervisory methods, about
which supervisor should be familiar with. These include
individual conferences, staff meetings, in work situations,
evaluations, etc.
Authority and leadership are concepts which
influence supervisory style, i.e. the way a manager
behaves when trying to influence the behavior of
someone else. Authority is the right to command and is
vested in the supervisor by the organization. Leadership
is a process of influence. Supervisory style will fall at
some point in a continuum between authority and
leadership. The mix to be adopted will depend upon the
forces in the supervision and situation.
Appraisal of supervisions should form a basis for
supervision. Apart from ascertaining the quantitative
achievement of those supervised, the supervisor should
know what traits he is looking for in the supervision,
viz., knowledge, quality of performance, ability to learn,
initiative, cooperative attitude, commonsense, etc.
Feedback to staff on their performance is rarely
carried out despite its importance. Clear and direct
feedback induces certainty, solves problems, builds trust,
strengthens relationships and improves work.
Communication
Medical officers, to be effective, must be able communica-
tors. The communication skills has to extend to various
levels. At the first level, being manager, he/she should
be skilled in various methods of official communication.
He/she should encourage vertical communications, both
from top to bottom and from bottom to top and also
horizontal communication between workers at various
levels. Two-way communication should be encouraged
as a rule, since this leads to better understanding and
reduces gaps in communication. As a supervisor, he/
she has to be a good listener. Instructions issued orally
or in writing should be clear and unambiguous.
In dealing with communication with community the
emphasis should be on empowerment of people. People
do take responsibility for their own health, their family’s
health and the community’s health, provided they are
given adequate information and technical support.
The communication strategy should be to use a
combined approach of mass media, group and individual
Pediatric Care in Developing Countries 19
approach. Audiovisual aids can help communication
provided they are relevant and used effectively. Village-
based communication should make use of established
channels of communication in the village and of indi-
genous media. Training of village leaders, individual and
group meetings should be strengthened. Efforts should
be made to utilize workers of health-related develop-
mental agencies having contact at the grass root level.
Training in communication methods and media and
evaluation of their effectiveness should be an integral
part of training.
Teamwork
One of the managerial functions of medical officers is to
promote teamwork. By sharing skills and knowledge as
a team, people can work more effectively than an indivi-
dual. Teams can work better when members feel accepted
and trust one another, goals are set and tasks defined,
roles are clarified, members listen, communicate and
participate, conflicts are resolved equitably, leadership is
shared and members are mutually supportive. Incentives
for team commitment go beyond salaries. People are also
driven by their pride in producing excellence.
Training
The goal of training is to provide staff with knowledge
and skills they do not have and as such an assessment of
training needs will be the first and useful step, and
managers, employees and clients should be involved. The
training curriculum will depend on the assessment. The
next step is to identify good trainers from within and
outside since a training program is only as-good as the
trainer. Other inputs that need attention are development
of lesson plans, procurement of training materials, place
of training, proper mix of theory and practice, training
evaluation and feedback.
Looking holistically, the medical officers are
concerned with human resources development, for which
training is a tool. Apart from the staff of the health sector,
training has to be imparted to community representatives,
elected representatives of the civic society and others.
Under these circumstances, focus should be on team
training which will contribute to teamwork.
Building Partnership
It is now widely recognized that we must face new
challenges in health that arise out of lack of attention to
20 IAP Textbook of Pediatrics
factors influencing health like poverty, illiteracy,
nutrition, population, globalization, gender inequalities,
pollution and many others. This calls for new forms of
action and the challenge is to unlock the potential for
health promotion inherent in many health related sectors,
societies, local communities, local bodies and families.
Health should be the responsibility of all. The primary
health care system should therefore focus on building
partnerships with all sectors at that level and involve
them in health planning and implementation.
Community Involvement
Involvement of the community both as individuals and
collectively, in the process of decision- making for health
and health development is the essence of community
involvement. They should be responsible for health needs
identification, prioritization of identified needs,
preparation of action plans, monitoring and evaluation.
Community involvement helps in improving coverage,
reduction in inequity and promotion of self-reliance.
Management of community involvement in health
requires both knowledge and skills on the part of medical
officer. The medical officer should be prepared to work
with the people rather than for the people. Success of
community involvement, depends upon a number of
factors. First is political commitment to transfer
responsibility to people. Second is a high degree of
bureaucratic commitment to translate the policies into
action. Thirdly, the role of the agencies shift to one of
directing, supporting and facilitating the process of
community involvement in health. Fourthly, the district
health organization needs to be reoriented to provide the
necessary support. Finally, action is required to
decentralize authority and responsibility to the lower
levels of PHCs and community.
Involvement of women in health care delivery is
crucial as they are the key to primary health care and
general welfare of the communities in all developing
countries and hence community involvement should pay
special attention to participation by women.
Monitoring and Evaluation
Monitoring and evaluation is an important management
activity. It is an integral part of the program plan and
must be built into it. It is an effective tool for testing
program promises, planning and improving the program
performance.
Monitoring generally refers to the .process of checking
the status of the program by comparing the actual
implementation of the activities against work plan,
including the time frame.
On the other hand, evaluation is directed at
measuring progress towards the achievement of
objectives and the impact of the program. Evaluation is
linked to program planning and implementation cycle
and assists the program management in making
midcourse corrections in the program.
The monitoring system should be designed to provide
disaggregated data to reflect the health condition of the
disadvantaged groups, so as to enable to mount more
focused responses to them. This will contribute to
promote equity in health.
To sum up, effective discharge of managerial
functions are critical to the success of all our health and
family welfare programs. Managers have to see that both
the organization and program goals are achieved. No
organization can function without competent managers
and, indeed, in their absence organizations are often
paralyzed or chaotic.
Building up competencies of the medical officers in
the planning process, program implementation,
supportive supervision, training of health care providers,
building partnerships, provision of leadership to health
team, promote social action for health, making the system
responsive to the health care needs of the population,
monitoring and evaluation and many others is therefore
vital. Those competencies are in addition to those related
to making them effective clinicians and public health
program implements.
XI FIVE YEAR PLAN
Monitorial Socioeconomic Targets
Income and Poverty
• Accelerate growth rate of GDP from 8 to 10% and
then maintain at 10% in the 12th Plan in order to
double per capita income by 2016-17.
• Increase agricultural GDP growth rate to 4% per year
to ensure a broader spread of benefits .
• Create 70 million new work opportunities.
• Reduce educated unemployment to below 5%.
• Raise real wage rate of unskilled workers by 20
percent.
• Reduce the head count ratio of consumption poverty
by 10 percentage points.

Education
• Reduce dropout rates of children from elementary
school from 52.2% in 2003-04 to 20% by 2011-12.
• Develop minimum standards of educational attain-
ment in elementary school, and by regular testing
monitor effectiveness of education to ensure quality.
• Increase literacy rate for persons of age 7 years or
more to 85%.
• Lower gender gap in literacy to 10 percentage points.
• Increase the percentage of each cohort going to higher
education from the present 10 to 15% by the end of
the 11th Plan.
Health
• Reduce infant mortality rate (IMR) to 28 and maternal
mortality ratio (MMR) to 1 per 1000 live births.
• Reduce Total Fertility Rate to 2.1.
• Provide clean drinking water for all by 2009 and
ensure that there are no slip-backs by the end of the
11th Plan.
• Reduce malnutrition among children of age group
0-3 to half its present level.
• Reduce anemia among women and girls by 50% by
the end of the 11th Plan.
Women and Children
• Raise the sex ratio for age group 0-6 to 935 by 2011-12
and to 950 by 2016-17.
• Ensure that at least 33 percent of the direct and
indirect beneficiaries of all government schemes are
women and girl children.
• Ensure that all children enjoy a safe childhood,
without any compulsion to work.
Infrastructure
• Ensure electricity connection to all villages and BPL
households by 2009 and round-the-clock -power by
the end of the Plan.
• Ensure all-weather road connection to all habitation
with population 1000 and above (500 in hilly and
tribal areas) by 2009, and ensure coverage of all
significant habitation by 2015.
• Connect every village by telephone by November
2007 and provide broadband connectivity to all
villages by 2012.
• Provide homestead sites to all by 2012 and step up
the pace of house construction for rural poor to cover
all the poor by 2016-17.
Pediatric Care in Developing Countries 21
Environment
• Increase forest and tree cover by 5 percentage points.
• Attain WHO standards of air quality in all major cities
by 2011-12.
• Treat all urban waste water by 2011-12 to clean river
waters.
• Increase energy efficiency by 20 percentage points by
2016-17.
MDG-THEN AND NOW
India’s MDG 2005 Report Released
On February 13, 2006, the Union Ministry of Statistics
and Program Implementation released India’s first
Millennium Development Goals country report for the
year 2005.
The Millennium Declaration adopted by the General
Assembly of the United Nations in September 2000
committed member countries to achieving eight Millen-
nium Development Goals (MDGs) within a specified
timeframe. The 2005 report on the MDGs gives an
indication of the current status of progress achieved in
the country.
MDG 1: Eradicate Extreme Poverty and Hunger
India’s target: Reduce the proportion of people below the
poverty line to 18.75% by 2015.
Status: As on 1999-2000, the poverty headcount ratio
stood at 26.1%. The share of the poorest quintile in
national consumption is 10.1% for the rural sector and
7.9% for the urban sector. Prevalence of underweight
children is in the order of 47%.
MDG 2: Achieve Universal Primary Education
India’s target: Increase the primary school enrolment rate
to 100%, with no dropouts, by 2015.
Status: Dropout rate for primary education during 2002-
03 was 34.89%. The gross enrolment ratio at primary
schools was near 100% for boys and 93% for girls. The
literacy rate (seven years and above) in 2000-01 was
65.4%.
MDG 3: Promote Gender
Equality and Empower Women
India’s target: There should be gender parity in the
number of boys and girls enrolled in schools by 2015.
22 IAP Textbook of Pediatrics
Status: Female-male proportion in primary education is
78:100, and 63:100 in secondary education (2000-01).
MDG 4: Reduce Child Mortality
India’s target: Under-five mortality rate (U5MR) must be
reduced to 42 for 1,000 live births by 2015.
Status: U5MR was 98 per 1,000 live births in 1998-2002.
Infant mortality rate was 60 per 1,000 live births (2003).
Proportion of one-year-old children immunized against
measles was 58.5% (2002-03).
MDG 5: Improve Maternal health
India’s target: Reduce the Maternal Mortality Rate (MMR)
to 109 per 100,000 live births by 2015.
Status: MMR for 1998 was 407. The proportion of births
attended by skilled health personnel was 39.8% in 2002-
03.
MDG 6: Combat HIV/AIDS, Malaria and
other Diseases
Status: The prevalence rate for HIV/AIDS increased from
0.74 per 1,000 pregnant women in 2002 to 0.86 in 2003.
This trend needs to be reversed in order to achieve MDG
6. The prevalence and death rate associated with malaria
is consistently dropping. The death rate associated with
tuberculosis came down from 67 deaths per 100,000
population in 1990 to 33 per 100,000 population in 2003.
The proportion of TB patients successfully treated rose
from 81% in 1996 to 86% in 2003.
MDG 7: Ensure Environmental Sustainability
Status: In 2003, the total land area covered by forests was
20.64%. Reserved and protected forests together
accounted for 19% of total land area. Energy use declined
from around 36 kilogram oil equivalent in 1991-92 to
about 32 kilogram oil equivalent in 2003-04.
The proportion of people without sustainable access
to safe drinking water and sanitation is to be halved by
2015. India is on track to achieving this target, says the
report.
Goal 8: Develop a Global Partnership for
Development
According to the report, developed countries must
provide development assistance to developing countries.
The report says the financial support needed to achieve
targets under this goal for less developed countries and
smaller countries falls short of what developed countries
pledged. It notes, however, that actual disbursements of
overseas development assistance in recent years have
shown a reversal of the declining trend that lasted for
almost a decade since the early 1990s.
In one of the targets under this goal—to make
available the benefits of new technologies in cooperation
with the private sector—India has made considerable
progress:
• Overall tele-density increased from 0.67% in 1991 to
9.4% in June 2005.
• Use of personal computers increased from 5.4 million
PCs in 2001 to 14.5 million in 2005.
• There are 5.3 million Internet subscribers, as on March
2005 (2.3 Internet users per 100 population).
2.1 History Elicitation: T Ravikumar, C Thangadorai ................................................................................................................................. 24
2.2 Physical Examination and Clinical Skill Development: C Thangadorai, T Ravikumar ................................................................... 30
2.3 Parent Counseling: Parang N Mehta .................................................................................................................................................... 40
24 IAP Textbook of Pediatrics
2.1 History Elicitation
‘Treatment begins the moment the family walks in the door.’
— Richard B Goldbloom
The interview and history elicitation are very important
tools in the field of Pediatric Medicine. Though it is of
much diagnostic value, the very process of interaction
with the parents and the child during history taking also
has therapeutic value. A pleasant and patient interaction
is what any parent desires. There should be fewer distrac-
tions during the interview. It is good to use lay terms
when talking to the parents and avoiding medical jargon.
In pediatrics the most important and distinct aspect
is the fact that the person giving the history is usually
not the patient (unless the child is about 4 or 5 years old).
The parents are the usual source of information and in
certain cases when caretakers (other than the parents)
are bringing up the children then they will be the source
of information.
Demography
Make a note of the name of the child, his/her age in years
(with months and days), parent’s names, address, date
and time of interview, information’s name and
relationship to child and their reliability (with regard to
the consistency of the information they provide).
Presenting Complaints
The main problem or complaints for which the child has
been brought for medical attention should be recorded
in the information’s own terms and should be recorded
in chronological order with the duration of each
complaint.
Examples: Fever—5 days
Vomiting—4 days
Loose motions—4 days
Decreased urine output—2 days
Lethargy—1 day
Fast breathing—1 day
History of Present Illness
It is important to gather more information on the specific
complaints mentioned above. Find out the onset of the
T Ravikumar, C Thangadorai
complaints (the time up to which the child was apparently
well). The evolution of the problems should then flow in a
clear, concise, temporal sequence, leading up to the present
moment. They should be evaluated in order of occurrence
and an account of any repeated episodes of symptoms
(like seizures or respiratory infections) should be given.
Complications expected for the primary complaint and
other symptoms that will help in detecting associated
conditions and in differential diagnosis should be
enquired. The details of treatment given so far and the
response should also be noted.
Past History
Ask for details of relevant past illness, whose knowledge
will help you in diagnosis or management. History of
occurrence of similar complaints in the past should be
noted. In child with chronic suppurative lung disease or
malnutrition a history of previous exanthematous illness
or whooping cough will help, in failure to thrive a history
of recurrent diarrhea and in a child with fever and fits a
history of febrile fits will be supportive. Past medication
history will also be helpful, for example past history of
antiepileptic drugs or antituberculous drugs [history of
red urine (rifampicin) while on treatment with anti-TB
drugs]. Information on previous significant hospitaliza-
tions, accidents or surgeries may also be helpful.
Contact History
History of contact with communicable illnesses (like TB,
chickenpox) must be elicited with tact and patience. It is
often denied and repeated probing with leading
questions may be necessary.
Antenatal History
As many illnesses in children have their origin in the
womb it is important to get a good history about the
period of pregnancy of the index child. Note the three
‘I’s for the mother during pregnancy—illness, irradia-
tion and injections (i.e., drugs). Maternal illnesses like
syphilis, toxoplasmosis, AIDS, rubella, cytomegalovirus
and herpes virus infections (STARCH) are associated with
specific syndromes in the child. Folic acid supplementa-
tion during early pregnancy (the first trimester) prevents
neural tube defects like meningomyelocele, etc.
 History Elicitation and Physical Examination
Birth History
The actual events occurring during delivery must be
enquired. The period of gestation, duration of labor, nature
of delivery, drugs administered during labor and any
complications during delivery (like cord around neck, low
Apgar score) should be noted. The normal first stage of
labor, from the onset of labor pains to the rupture of
membranes, is about 12 to 24 hours and 6 to 12 hours in a
primi and multigravida respectively. The second stage of
labor, from the rupture of membranes to the delivery of the
child, is about 1 to 2 hours in a primi and 1/2 to 1 hour in
a multigravida. The third stage, which is the delivery of
the placenta, lasts about 15 minutes. The duration of every
stage of labor (especially the second stage) is important as
prolonged labor may result in fetal hypoxia.
Postnatal History
The neonate and its state afterbirth should be enquired.
The term of the child, birth weight, cry, activity and color
immediately after birth should be noted. Presence of
jaundice or cyanosis, resuscitation steps used (if any) and
whether hospitalized afterbirth must be detailed. Poor cry
and lethargy suggest perinatal depression. Paucity of
movements of one side or a particular limb may suggest
stroke or birth injury. The sucking effort of a child usually
gives a clue to the neurological status of the child. All
infants pass meconium within the first 24 hours, any delay
would suggest cystic fibrosis while absence of passage
would indicate intestinal obstruction or anal atresia. Most
infants void urine on the first day while all will void within
48 hours, any delay would point towards an obstruction
or agenesis of the renal system.
Developmental History
Development is one aspect of pediatrics that makes it
unique as compared to adult medicine. The developmental
milestones that a child attains are a good reflection of its
physical and neurological maturity. They may be divided
into gross motor (head control, rolling over, crawling,
sitting, standing, walking, etc.), fine motor or adaptive
(grasping reaching tranferring objects, scribbling, etc.),
social (smile, recognition, response to calls, etc.) and
language (cooing, babbling, saying syllables, vocabulary,
etc.). Tailor the development history to the child’s age. In
case of more than one child in the family and if the other
siblings are normal, the parents may be asked if the index
child developed similar to the other siblings. The pace of
development differs from child to child. As the child grows
25
older the age range of attainment of specific developmental
milestones usually widens. For example, a normal child
may begin to sit without support between 5 to 8 months as
compared a young infant developing social smile between
6 to 8 weeks. Notice the range of normality becoming more
in the older child. Always tabulate the attained milestones
against the normal age for attainment of that particular
milestone (Table 2.1.1).
Dietetic History
This history is highly problem oriented and age dependent.
Details of the food and dietary patterns help in diagnosing
protein energy malnutrition and failure to thrive. In
addition it helps us to formulate a diet plan for nutritional
rehabilitation of the child for specific diseases. The
calculation of the dietary values of the food consumed
should provide the actual value of proteins, calories and
fats and must mention whether it is sufficient in vitamins,
minerals and other micronutrients. Always state the
amount of calories and proteins the child is getting for
that age as compared to what is expected which will help
us to calculate the calorie and protein gap. Any problem
like feeding difficulty, regurgitation or vomiting should
be noted. Any possible natural toxins in the food consumed
(fungal aflatoxins, copper, etc.) and feeding patterns
during times of illnesses should also be mentioned. In
young children the complete breast-feeding history
including whether colostrum was given, duration of
exclusive breastfeeding, weaning pattern, etc. must be
elucidated. In children given other milk substitutes detail
the type of formula or cow’s milk, its dilution, bottle or
cup and spoon-feed, frequency and the amount taken
during each feeding (Table 2.1.2).
Family History
The health details of all the family members must be
obtained. This includes their age, sex, present and past
health status, treatment taken and their proximity to the
child. History of similar illness in the family must be looked
for. History of stillbirths or abortions in the family should
be noted (habitual abortions occur in maternal syphilis).
The birth of abnormal or children with illness in the family
and the reasons for death of children or adults at a young
age should be specifically enquired into. The consangui-
nity pattern with the degree of relationship may be helpful
for genetic disorders. The pedigree chart will help record
26 IAP Textbook of Pediatrics

TABLE 2.1.1: Developmental milestones

Milestones Gross motor Fine motor Personal social Language

1 month Grasp reflex Starts to smile

2 months
3 months Head mostly held up but
still bobs forwards
4 months Head held steady
7 months Rolls over, creeping-
crawling, sits with hands
leaning forwards
10 months Sits without support,
cruises
1 year Walks with one hand held
15 months Walks alone, crawls
upstairs
18 months Runs stiffly, goes upstairs
by holding the rails
2 years Runs well, walks upstair
and downstair one foot
at a time, jumps
2½ years Goes upstairs with
alternating feet
3 years Rides tricycle, stands
momentarily on one foot
4 years Hops on one foot, throws
ball overhead, climbs well
5 years Skips
Hands closed Social smile Cooing
Hand open most often Sustained social smile Says aah
Reaches for objects, grasps Excited at site of food Laughs out aloud
objects and brings to mouth,
hands in midline
Reaches out and grasps larger Smiles at mirror Babbling
objects, palmar grasp, transfers
objects from hand-hand
Pincer grasp Waves bye-bye Baba, mama
Releases object to other Plays simple ball game 2-3 words with
person on request/gesture meaning
Tower of 3 cubes Asks for objects by Follows simple
pointing commands
Tower of 4 cubes, initiates Feeds self. Dry by day Speaks 10 words,
vertical stroke scribbles Identifies parts of the
body
Makes tower of 7 cubes, Handles spoon well and Puts sentence of 3
initiates horizontal stroke helps to undress words
Makes tower of 9 cubes Helps put things away Knows full name
Draws circle, makes tower of Dresses and undresses Knows age and sex
10 cubes, constructs bridge of fully when helped with
3 cubes buttons, joins in play
Draws cross and square, copies Plays with several children Tells story
a bridge, constructs a gate of with beginning of social
5 cubes interaction, goes to toilet
alone
Draws triangle Dresses and undresses Names 4 colors,
self, Asks question about Repeats sentence of
meaning of words 10 syllables

the family history in a pictorial manner helping us to
derive the inheritance pattern of a particular illness.
Usually three full generations are recorded. Individuals
of the same generation should be recorded in the same
horizontal line and numbered from left to right using
arabic numerals. Males are usually placed on the left
side of the pedigree and sib-ship listed in both orders.
The maternal age at the time of child delivery is also
important. Young mothers (less than 18 years) have more
chance of preterm, IUGR babies while older mothers
(more than 32 years) have more chance of having
children with Down syndrome and Klinefelter
syndrome. In children with diseases showing
hereditary traits, an enquiry of a much wider circle of
relatives must be made.
Sociocultural and Economic History
This has a bearing on the type of disease the child might
be suffering from and it also helps in planning
rehabilitation and treatment options in addition to helping
in giving preventive advice.
 History Elicitation and Physical Examination 27

TABLE 2.1.2: The recommended caloric — Per-capita income (total income divided by the number
and protein requirements of dependent family members)
Ages Calories required/day Protein/day — Type of housing, ventilation, toilet and potable water
facilities
1 month-1 year 100-110 kcal/kg/day 2 g/kg
— Psychiatric illness and substance abuse (alcoholism,
1 year 1000 kcal/day 20 g/day
drugs)
2 year 1100 kcal/day 20 g/day
— Marital stability
3 year 1200 kcal/day 20 g/day
— Traditional beliefs and child rearing practices
4 year 1300 kcal/day 30 g/day
5 year 1400 kcal/day 30 g/day Immunization History
6 year 1500 kcal/day 30 g/day
7 year 1600 kcal/day 40 g/day It is important to record the details of vaccines given to the
8 year 1700 kcal/day 40 g/day child in chronological order. The vaccination schedule of
9 year 1800 kcal/day 40 g/day the Indian Academy of Pediatrics or at least the Universal
10 year 1900 kcal/day 50 g/day Immunization Program should have been followed.
11 year 2000 kcal/day 50 g/day Special vaccines (like pulse polio vaccine) must also be
12 year 2100 kcal/day 50 g/day enquired. Look for BCG scar at the outer aspect of the left
Adolescent boy 2400 kcal/day 70 g/day arm at the insertion of the deltoid. If any vaccine has not
Adolescent girl 2100 kcal/day 65 g/day been given, note the reason for not doing so.

The following points are worthwhile noting: History of Allergies

— Type of family: joint or nuclear It is important to note down any known specific allergies
— Occupation and employment history in the child, either for drugs or food.

2.1.1 MODEL PEDIATRIC CASE RECORD

DEMOGRAPHY
Name: ............................... Date of birth: ...................... Age: ...................... Sex: ...........................
Address: ..........................................................................................................
Informant: ......................... Relationship: ..................... Reliability: ...........
Date and time of examination: .......................................

HISTORY TAKING
Presenting complaints: ... ............................................ History of present illness: ......................................................
Past history: ..................... ............................................
(including treatment history)
Contact history. ............... ............................................ Antenatal history:
Birth history: .................... ............................................ Postnatal history:
Developmental history: .. ............................................ Dietetic history: ..
........................................... ............................................ (including nutrition chart)
Family history: ................. ............................................ Sociocultural history: .............................................................
Immunization history: .... ............................................ History of allergies: .................................................................
28 IAP Textbook of Pediatrics

PHYSICAL EXAMINATION
General examination:............................................ .............. Vital signs: ...............................................................................
(including ENT, skin, eye, spine and cranium) .................. SMR: .........................................................................................
Anthropometry: ............... ............................................ Developmental assessment: ..................................................

SYSTEMIC EXAMINATION
Cardiovascular system ... ............................................ Respiratory system .................................................................
Abdomen .......................... ............................................ Nervous system ..

PROVISIONAL DIAGNOSIS
Differential diagnosis ....................................................................................
Investigations .................................................................................................
Final Diagnosis ...............................................................................................

2.1.2 MODEL NEONATAL CASE RECORD

DEMOGRAPHY
Name: .............................. Sex: .............................................. Identity number: ............................................
Age (in hours/days/months): .............................................. Date and time of birth: ..................................
Date and time of examination: ... .................... ........................
Name of mother: ................... Name of father: ....................
Address: ................................. Informant: ............................ Relationship: .................................................
Reliability:

CLINICAL HISTORY OF CHILD

Maturity: ................................
Anthropometry: .................... Birth weight: ........................ Length: ............................................................
Head circumference: ............. Chest circumference:.......... .
Presenting complaints: ..........................................................
History of present illness: ......................... Previous illness: .........................................................................
Feeding history: ............................................ Family history: .........................................................................
..................................................................... (including previous congenital anomalies/neonatal problems in siblings)

MATERNAL HISTORY
Age of mother: .......................................... Date of last childbirth: .................................. Blood group: ............................

Para: .......................................................... Gravida: .............. ....................................... Abortions: ................................

Weight of mother: .................................... Nutritional status: ............ Consanguinity:

Last menstrual period: ............................ Expected date of delivery: ............................ Paternal age: ............................

Maternal transfusion: ..........................

 History Elicitation and Physical Examination 29

Antenatal period(illnesses/drugs/radiation, etc): ....................

Antenatal ultrasound: ............................. 1st Trimester ........ 2nd Trimester ................ 3rd Trimester .............................

Labor (spontaneous/induced/not known):

Duration of labor: .................................... 1st Stage ............... 2nd Stage ......................

Drugs used during labor (analgesic/anesthetic/others/not known): ..................................

Mode of delivery: ....................................................................

(Spontaneous/manipulated/breech/forceps/vacuum/cesarean/others)

Indication for assistance (if any): ..........................................

Complications during delivery (if any): ...............................

Place of delivery: ......................................

(Hospital/health post/primary health center/private nursing home/others)

Single/twin/others: ..................................... Birth order (if applicable): ...............................

Fetal distress: .........................................

Evidence of fetal distress: ....................

Apgar score: .............................. 1 minute ................................ 5 minutes

Resuscitation: ........................................
(The actual procedures done, in detail)

EXAMINATION OF THE BABY Neurological sign Score

Scoring for assessment (shown below): Posture

External sign Score Square window

Edema Ankle dorsiflexion

Skin texture Arm recoil

Skin color Leg recoil

Skin opacity Popliteal angle

Lanugo Heel to ear

Plantar creases Scarf sign

Nipple formation Head lag

Breast size Ventral suspension

Ear form TOTAL SCORE

Ear firmness Gestational age By history: By assessment:

(in weeks):
Male genitalia
Female genitalia Impression:
Term/Pre-term/Post-term
TOTAL SCORE
AGA/SGA/LGA
30 IAP Textbook of Pediatrics

GENERAL APPEARANCE Nervous system:

Cry: Color: Muscle:
Activity/Movement: Posture:
Skin: PROVISIONAL DIAGNOSIS
Head: Face Eyes:
Mouth: Palate: Throat: INVESTIGATIONS
Ears: Nose: Neck:
FINAL DIAGNOSIS
Cardiovascular system:
(including heart rate, femoral pulse) BIBLIOGRAPHY
1. Barness LA. In pediatric history and physical examination.
Respiratory system: In McMillan JA, DeAngelis CD, Feigin RD, Warshaw JB
(including respiratory rate and pattern) (Eds): Oski’s Pediatrics—Principles and Practice, 3rd edn.
Philadelphia, JB Lippincott Williams and Wilkins, 1999;39-
Abdomen: Spleen: Liver: 52.
Kidney: Genitalia: Anus: 2. Harris R. The examination of children. In Swash M (Ed):
Hutchison’s Clinical Methods, 20th edn. London, ELBS-
WB Saunders Co, 1995;365-86.
Limbs and bones: Arms: Hands: 3. Rees PE. Evaluating the newborn infant: Diagnostic
Feet: Legs: Toes: approach. In: Pediatric Clinical Skills, 2nd edn.
Philadelphia, Churchill Livingstone, 1997;47-76.
Spine and back: 4. Singh M. Pediatrics clinical methods, 1st edn. New Delhi:
Sagar Publication, 1992;1-94,174-211.

2.2 Physical Examination and

Clinical Skill Development
C Thangadorai, T Ravikumar

The physical examination in a child is distinct in certain
areas from that of the adult. In this discussion, only the
facts that differ from that of an adult examination have
been mentioned. As far as possible, no child should cry
or get irritated while you are examining. “If a child cries
when you examine it, then it’s probably your fault”. This
statement by John Apley sums up the care one should
take, while handling the child. There is no definite order
to be followed while examining a child. Individualize
the examination for every child. Do the invasive and
potentially discomforting examinations at the end. Allow
the child to be in its most comfortable position, and place
it in the mother’s lap. Both the child and the mother,
must feel secure and confident about the examining
doctor.
GENERAL EXAMINATION
Before starting general examination; analyse the history
and based on that, look for the specific features that you
think to be relevant to the history which will help you to
give a perfect diagnosis. Examining aimlessly is unhelpful,
time consuming and irritating to the child and parents.
General examination must be thorough from head to foot.
Always examine the child’s throat irrespective of the
complaint. The golden rule is “Head to foot and back, but
 History Elicitation and Physical Examination 31

forget not the ear, throat and urine”. The sensorium (e.g., TABLE 2.2.1: Few of the features to be looked for in the
stuporous or unconscious in intracranial pathology), head and the associated conditions
posture and attitude (e.g., frog like and limp in floppy infant), Features Few associated conditions
activity (e.g., apathetic in kwashiorkor), looks (acutely or
Microcephaly Familial, craniostenosis, intrauterine
chronically ill looking), nutrition (i.e., marasmic, infections,
undernourished or moderately nourished) need special Trisomy 13 and 21 (Down syndrome)
mention. Macrocephaly Hydrocephalus, hydranencephaly,
Note the shape of the head (Fig. 2.2.1) whether micro- porencephaly, some neurodegenerative
cephaly, macrocephaly (Table 2.2.1), plagiocephaly disorders like metachromatic
(asymmetrical due to lying of the normal infants with their leukodystrophy, Alexander and Canavan
disease, certain intrauterine infections
heads persistently on one side), scaphocephaly (boat
Frontal bossing Rickets, congenital syphilis, muco-
shaped with increased AP diameter due to premature
polysaccharidoses
Cranio-tabes Physiological (in preterm), rickets,
(ping-pong skull) Congenital syphilis
Increased inter- Genetic (racial), mongolism
pupillary distance (Down syndrome),
(hypertelorism) Cri-du-chat syndrome, hypothyroidism
Proptosis Thyrotoxicosis, orbital leukemic
(Sclera is visible deposits, orbital cellulitis,
above and below Arteriovenous aneurysm (pulsatile),
the cornea) Cavernous sinus thrombosis,
Neurofibromatosis, Crouzon’s disease
Cataract Idiopathic, traumatic, intrauterine
infections, galactosemia, diabetes
mellitus, Down syndrome
Mongoloid eyes Down syndrome, racial, Prader-Willi
(upward slant) syndrome
Antimongoloid Turner syndrome, cri-du-chat
slant (downward syndrome, Treacher-Collins
slant) syndrome

Depressed Down syndrome, mucopolysacchari-

nasal bridge doses, hypothyroidism, familial
Low set ears Down syndrome, mucopolysacchari-
doses, Turner syndrome, Potter facies
(renal agenesis)

Facial puffiness Renal disorder, kwashiorkor, congestive

cardiac failures, angioneurotic edema,
cavernous sinus thrombosis

Large tongue Hypothyroidism, mucopolysacchari-

doses, glycogen storage disorders,
Down syndrome (relative)
Small mandible Pierre Robin syndrome
Short neck Turner’s syndrome, Down syndrome,
mucopolysaccharidoses, hypothyroidism

closing of sagittal suture), brachycephaly (decreased AP

Figure 2.2.1: Different shapes of the cranium in a child diameter) and oxycephaly (tower-shaped skull).
32 IAP Textbook of Pediatrics
Figure 2.2.2: Method of measuring the size
of the anterior fontanelle
The size of the anterior fontanelle (AF) (about 2.5 cm ×
2.5 cm) must be measured across the borders as shown in
Figure 2.2.2. It normally closes by 9 to 18 months. Delayed
closure is seen in rickets, hypothyroidism, hydrocephalus,
Down syndrome, achondroplasia and mucopolysacchari-
doses. The AF in a quiet child usually shows a very slight
depression from the surface and may pulsate. It is bulging
when the child cries and in hydrocephalus, intracranial
hypertension and pseudotumor cerebri, i.e. after drugs
like nalidixic acid, tetracyclines, steroids and hypervita-
minosis A. A sunken fontanelle is a sign of dehydration.
The posterior fontanelle can be felt by running the finger
along the sagittal suture to its junction with the lambdoid
sutures. It normally closes by 2 to 4 months of age. Ridging
and overriding of sutures may normally be seen in the first
few hours afterbirth, due to moulding of the skull during
delivery. It may also be seen in craniostenosis due to
premature fusion of the sutures. Sutures normally get
ossified by 6 months of age (Fig. 2.2.3).
The Macewen’s sign is useful in clinically detecting
raised intracranial tension after the sutures have closed.
It is the crack pot sound elicited by percussing the skull.
Transillumination of the skull in a dark-room, is useful
in children below one year, to detect subdural effusion or
hematoma, if transluceny extends beyond 2 cm in the
frontal and 1 cm in the occipital region.
The face must be observed for any dysmorphic
features that may suggest chromosomal or developmental
anomalies. Table 2.2.1 shows some common abnormal
features and a few conditions where they are seen. The
inter-palpebral line of the eyes when continued
horizontally backwards, normally divides the ears into
the upper one-third and lower two-thirds. If the line
passes above the ears, it is suggestive of low set ears. The
Figure 2.2.3: The sutures and fontanelles in an infant
neck should be examined for lymph node enlargement,
short neck (normal neck length : height ratio is 1:13) and
low hair line (below C5). The examination should also
include the hair (e.g. pale hair with ‘flag sign’ in
kwashiorkor), eyes (signs of vitamin A deficiency, icterus,
pallor, etc.) ears (examine tympanic membrane and for
chronic suppurative otitis media—CSOM), oral cavity
(with special reference to the dentition), extremities (limb
deformities in skeletal dysplasias, widened wrists in
rickets), nails (koilonychia in anemia) and skin for pallor,
icterus, scabetic lesions, impetigo, etc. Fundus examination
is important to make out papilledema, optic atrophy or
retinitis pigmentosa. The mouth is examined for the state
of the gums, dental caries and dentition. Delayed denti-
tion may be familial or due to rickets or osteogenesis
imperfecta.
The correct position for doing the ear, nose and throat
examination is shown in Figure 2.2.4 but this should be
done preferably at the last. While examining lymph nodes,
note the site, size, consistency, tenderness, warmth,
matting and scarring. Always remember to examine the
drainage areas, for focus of sepsis, if there is significant
lymph node enlargement. In older children, discrete and
non-tender lymph node enlargement up to 1.5 cm in the
cervical and inguinal region is not significant.
The skin is examined (Fig. 2.2.5) by rolling a fold of
loosely adherent skin on the abdominal wall between
the thumb and forefinger to determine its consistency,
the amount of subcutaneous tissue present and the
degree of hydration. Examination of the hips must always
be carried out in younger children and infants, to look for
 History Elicitation and Physical Examination 33

Temperature above 41°C is hyperpyrexia. In conditions

like PEM, where hypothermia is a problem, special low
reading thermometers (30-40°C) must be used.

Respiratory Rate
The rate of respiration in children is important for diag-
nosing respiratory disease and certain other non-respi-
ratory conditions like acidosis and congestive cardiac
failure. The rate varies in different age groups (Table 2.2.2).
But for practical purposes, the guidelines offered in the
child survival and safe motherhood (CSSM) Program,
serve as a good guide to clinically suspect respiratory
disease (Table 2.2.3).The pattern of respiration must also
Figure 2.2.4: The correct position of the child for
be noted whether regular, irregular, Cheyne-Stokes type,
ENT examination
acidotic, etc. In children the respiration is predominantly
abdominothoracic.

Pulse Rate
The pulse is felt mainly over the radial artery at the wrist.
The character, regularity and volume must be observed.
All the peripheral palpable vessels must be examined.
The superficial temporal, carotid, brachial, radial, femoral,
popliteal, posterior tibial and dorsalis pedis arteries are
usually accessible. In infants and very young children, it
may not be possible to palpate the peripheral vessels and
in such situations, the heart rate must be measured using
auscultation. The normal heart/pulse rates in the different
age groups in children are given in Table 2.2.4. For

Figure 2.2.5: The method of examining the skin in a child TABLE 2.2.2: Normal respiratory rate in
with dehydration children of different age groups

Age groups Normal respiratory

dislocation. The Ortolani or Barlow procedure is done rate (Per minute)
and the typical clunk of the hip moving in and out of its
socket is looked for. Infants and young children do not Newborn 40

exhibit classical pedal edema, but because of this, they are 1 year 30

confined to the bed, sacral edema should be looked for. 5 years 20

10 years 18
VITAL SIGNS
Temperature TABLE 2.2.3: Tachypnea indicating significant
respiratory disease (from CSSM program)
Oral temperature should be taken in children older than 5
years while in infants and younger children the Age groups Respiratory rate
thermometer may be placed in the axilla, i.e. the groin also (per minute)
can be used or the rectum. The temperature in the axilla or
Below 2 months 60 or more
the groin is about 0.5°C lower and the rectal temperature
2 to 12 months 50 or more
about 0.5°C higher than the oral temperature. The normal
temperature in children is between 36.5 and 37.5°C. 12 months to 5 years 40 or more
34 IAP Textbook of Pediatrics
TABLE 2.2.4: The normal heart rates in children of
different age groups
Age groups Normal heart rate
(per minute)
Newborn 140
1 year 110
3 years 100
8 years 90
10 years 80
practical purposes, heart rate of more than 200/minute in
newborns, more than 150/minute in infants and more
than 120/minute in older children can be taken as
significant tachycardia. The radial and femoral pulse must
be palpated simultaneously to look for any radiofemoral
delay. Remember, the heart rate in a struggling or crying
child will be more.
Blood Pressure
Recording of the blood pressure is one of the most
important aspects in a pediatric examination. Yet it is
surprising, how often it is neglected. The correct size of
the cuff must be used, i.e. the cuff should be two-thirds
size of the arm. A large cuff will give an erroneously low
reading while a small cuff will give a high reading. In
infants, the ‘flush method’ may be used to check the
pressure. Here the child’s arm is raised and a tight bandage
is applied up to the level of the cuff so as empty the blood
from the upper limb. Now, the cuff is inflated and the
bandage is removed so that the limb will be pale and
bloodless. Deflate the cuff slowly and note the reading at
which the skin flushes and the limb becomes red again.
This corresponds, approximately to the systolic pressure.
In younger children where auscultation at the cubital fossa
is difficult, the systolic reading obtained by palpation may
suffice. The Doppler technique of measuring blood
pressure is more accurate and can be used in children, if
available. For every pediatric examination, both the upper
limb and lower limb pressures must be recorded to detect
coarctation of aorta while in any child with a suspected
cardiac illness, the pressure must be recorded in all four
limbs. Normally, the pressure recorded in the lower limbs
is about 10 mm Hg higher than the upper limbs. Reserve
recording the pressure to the last in order not to irritate or
scare the child. Normal blood pressure readings in
children in the different age groups is given in (Table 2.2.5).
Normal blood pressure is defined as systolic and diastolic
TABLE 2.2.5: Normal blood pressure values in children
Age groups Blood pressure
(systolic/diastolic)
Newborn 65/45 mm Hg
1 year 75/50 mm Hg
3 years 90/60 mm Hg
8 years 95/65 mm Hg
10 years 100/70 mm Hg
pressure, less than 90th percentile for that age and sex.
Hypertension is defined as average systolic and/or
diastolic blood pressure equal to or greater than the 95th
percentile for that age and sex, on at least three occasions.
As per the American Heart Association’s (Pediatric
Advanced Life Support Course) recommendations, a
formula has been deviced to approximate the 50th
percentile of systolic pressure in children over the age of 2
years [90 + (2 × age in years)]. The lower limit of the systolic
blood pressure has been approximated by the formula 70
+ (2 × age in years). An observed fall of 10 mm Hg in
systolic pressure suggests a shock.
ANTHROPOMETRY
The measuring of the various anthropometric data is
essential for assessing the growth of the child and its
nutritional status. It is also important for planning the
diet and following up the child especially while recupe-
rating from an illness or during nutritional rehabilitation.
Weight
The child must be weighed during every examination.
The weight of the child is also useful for calculating the
right dosage of the drugs to be given. The newborn loses
up to 10 percent of its weight during the first week, but
regains it in the next few days. The child doubles its birth
weight by 4 months, triples it by 1 year and increases it
4 times by 2 years. For calculating expected normal
weight, the formula shown in Table 2.2.8 may be used.
While interpreting the weight of the child, the present
weight must be compared to the expected weight for age
and the percentage must be calculated in order to find
out which grade of nutrition the child falls under (as per
Tables 2.2.6 and 2.2.7). Weight is recorded on a weigh
scale which should be frequently checked with standard
weights and zero error must be adjusted before weighing.
 History Elicitation and Physical Examination 35

TABLE 2.2.6: The Wellcome classification of

nutritional status

Nutritional Expected Presence of

status weight for age edema

Normal more than 80% no

Undernutrition 60 to 80% no
Kwashiorkor 60 to 80% yes Figure 2.2.6: The infantometer method of measuring
Marasmus less than 60% no length of child
Marasmic kwashiorkor less than 60% yes
2.2.6). In exceptions like a child with quadriplegic cerebral
TABLE 2.2.7: Indian Academy of Pediatrics—classification of palsy, where the height/length could not be measured,
nutritional status (the prefix 'K' is added to indicate pre- the length of various segments of the body are measured
sence of edema) separately and added together to get the length. The
Level of undernutrition Expected weight for age formula shown in Table 2.2.8 may be used for calculating
the height for the age or alternatively the increase in height
I degree 70 to 79%
is as shown in Table 2.2.9 may be used for calculating the
II degree 60 to 69% expected height. To make out short stature or dwarfism,
III degree 50 to 59% the McLaren’s classification (Table 2.2.12) may be used.
While measuring the height, it is also important to
IV degree less than 49%
measure the upper segment (from the vertex to the pubic
TABLE 2.2.8: Weech’s formulae for estimating weight and symphysis) and the lower segment (from the pubic
height for age of normal children symphysis to the sole of the foot). The rate of growth of
Weights Kilograms Pounds the upper and lower segments varies with age as shown
in Table 2.2.10. Hence, any difference in the proportion
At birth 3.25 7
expected for that age may suggest the presence of specific
3 to 12 months age in months + 9 age in months +11
2
TABLE 2.2.9: Rate of increase in height in children
1 to 6 years (age in years × 2) + 8 (age in years × 5) + 17
7 to 12 years (age in years × 7) + 5 (age in years × 7) – 5 Ages Height
2
At birth 50 cm

Heights Centimeters Inches 6 months + 12 cm (62 cm)

1 year 75 cm
At birth 50 20
At 1 year 75 30 2 years 85 cm (86 to 87 cm)
2 to 12 years (age in years × 6) + 77 (age in years × 2) + 30 2 to 5 years 6 to 8 cm/year
5 years and above 5 cm/year

Height TABLE 2.2.10: Normal upper segment: lower segment ratio

The height of the child is a good indicator of the chronicity in children
of any debilitating illness. Height is normally measured Ages Upper segment
using Herpendens stadiometer. The child should stand Lower segment
against a wall with his bare feet touching each other, the At birth 1.8
heel, calf, buttock, upper back and occiput touching the 1
wall and the child looking straight ahead. A firm scale is 3 to 4 years 1.3
pressed to the head to mark the point indicating height. 1
9 years 1
The standing height can be measured for children more
1
than 2 years old, while for younger children, the recumbent 18 years 0.9
length should be measured using the infantometer (Fig. 1
36 IAP Textbook of Pediatrics

TABLE 2.2.11: Conditions with altered upper segment:

lower segment ratio
Upper segment: Probable disorder
Lower segment ratio

Proportionate Delayed adolescence, hypo-

(normal ratio for age) pituitarism, constitutional
dwarfism, nutritional dwarf
High ratio Hypothyroidism, chondro-
(upper segment > lower dystrophy, achondroplasia,
segment) Ellis-van Creveld syndrome,
Turner’s syndrome
Low ratio Hurler’s syndrome, Morquio’s
(upper segment < lower syndrome, hypogonadism
segment) Figure 2.2.7: Method of measuring head circumference

be calculated from Tables 2.2.13 and 2.2.14. The adult head

TABLE 2.2.12: McLaren’s classification for interpreting
height for corresponding age
size is reached between 5 to 6 years. Microcephaly is
defined as head circumference, more than 3 standard
Height for age Interpretation
deviations below the mean or less than the 5th percentile
>105% Giant for the age and sex. Head size more than the 95th percentile
93 to 105% Normal for age suggests macrocephaly.
80 to 93% Short
<80% Dwarf
Chest Circumference
This is measured at the level of the nipples (Fig. 2.2.8). In
growth disorders (Table 2.2.11). Stature should also be the infant, the chest circumference is lesser than the head
defined with parent’s height being taken into account, cicumference by about 2.5 cm, and the two become equal
referred to as the mid-parental height. by one year after which the chest circumference exceeds
For girls: Approximate projected adult height (in cm) the head circumference. In undernutrition, the chest
circumference remains lower than the head circumference
[Mother’s height + (Father’s height – 13)]
_________________________________________________
= TABLE 2.2.13: Head circumference growth velocity
2
Ages Head circumference
For boys: Approximate projected adults height (in cm) growth velocity
[(Mother’s height + 13) + Father’s height] Till 3 months 2 cm/month
= _________________________________________________

2 3 months to 1 year 2 cm/3 months

(1/3rd of initial velocity)
Head Circumference
1 to 3 years 1 cm/6 months
The size of the head is a good indicator of the size of its (1/12th of initial velocity)
contents, i.e. viz., the brain and the ventricles. Any
abnormality in the head circumference should alert the 3 to 5 years 1 cm/year
doctor towards any problem with the brain or its related (1/24th of initial velocity)
structures. Head circumference is measured with a non-
TABLE 2.2.14: Formula for estimating head
stretchable tape passing through the maximum point of circumference in the first year (after Dine et al)
the external occipital protuberance posteriorly and a point
just above the glabella anteriorly as shown in Figure 2.2.7. Normal range of head circumference in cm (5th to 95th percentile)
The head circumference at birth varies from 32 to 35 cm at (length in cm + 9.5) + 2.5
one year, from 43 to 46 cm and from 48 to 51 cm at five __________________________________

years. The expected head circumference for the age may 2

 History Elicitation and Physical Examination
Figure 2.2.8: Method of measuring the chest circumference
even beyond one and half years whereas in well-nourished
children, the chest circumference may exceed the head
circumference even before one year.
Midarm Circumference
The midarm circumference is taken as the name suggests,
at the midpoint of between the acromion and the olecranon
with the arm hanging by the side of the body (Fig. 2.2.9). It
is useful to detect malnutrition in young children (1-4
years). Values more than 13.5 cm may be considered
normal, while values less than 12.5 cm indicate significant
wasting and undernutrition. Shakir’s tape is used for
Figure 2.2.9: Method of measuring midarm circumference
37
measuring midarm circumference (MAC) in the
community and has color bands. Green color indicates
MAC is > 13.5 cm, yellow color a MAC between 13.5-12.5
cm and red colour a MAC < 12.5 cm.
Arm Span
It is the distance between the tips of the middle fingers
with both arms held wide open, i.e. spread apart. Nor-
mally, in young children it is 1 to 2 cm less than the length/
height. It equals the height at 10 years, and after 10 years
it is 1 to 2 cm more than the height. Increased arm span is
seen in Marfan’s syndrome and homocystinuria.
Weight for Height (WFH)
This is calculated as shown below (WFH):
WFH = (weight of child ÷ weight corresponding
to height of child) × 100
Values above 90 percent are normal, while values below
90 percent indicate malnutrition and values above 120
percent indicate overweight.
Body Mass Index (BMI)
It is calculated as:
weight in kg
________________________
Body mass index (BMI) =
(height in meter)2
BMI of 15-25 is considered normal, 25-30 is grade I
obesity, 30-40 is grade II and above 40 is grade III.
BMI = [weight ÷ height2] × 100
Value less than 0.15 indicates malnutrition. This remains
constant up to 5 years of age.
Kanawati Index (KI)
This is useful in detecting protein energy malnutrition in
children between 4 months and 4 years. It is calculated as
follows:
KI = Midarm cicumference ÷ Head circumference
Interpretation—normal > 0.32, mild undernutrition 0.28
to 0.32, moderate undernutrition 0.25 to 0.28, severe
undernutrition < 0.25.
Growth Patterns
See Table 2.2.15.
38 IAP Textbook of Pediatrics

TABLE 2.2.15: Growth patterns TABLE 2.2.16: Primitive reflexes to be examined during
developmental assessment
Ages Approximate Growth in Growth in head
daily weight length circumference Reflexes Age of appearance Age of disappearance
gain (gm) (cm/month) (cm/month)
Stepping Birth 6 weeks
0-3 month 30 3.5 2
Placing Birth 6 weeks
3-6 months 20 2 1
Moro Birth 3 months
6-9 months 15 1.5 0.5
Sucking and Birth 4 months while awake
9-12 months 12 1.5 0.5
Rooting 7 months while asleep
1-3 years 8 1 0.25
Palmar grasp Birth 6 months
4-6 years 8 3 cm/year 1 cm/year
Plantar grasp Birth 10 months
Tonic neck 2 months 4 to 6 months
DEVELOPMENTAL EXAMINATION Landau 3 months 24 months
Here, the developmental history obtained must be Neck righting 4 months 24 months
confirmed by examining the child for the milestones Parachute 9 months Persists
attained or lost. A large number of accepted methods are
available for assessing development. Of this, the Gessell Sexual Maturity Rating
developmental scale and the Bayley developmental scale
Sexual maturity rating in boys/girls is shown in
are commonly used. The Baroda Developmental Screening
Table 2.2.17.
Tests and the Trivandrum Developmental Screening Chart
are useful for field assessment of chidren’s development.
SYSTEMIC EXAMINATION
The development quotient (DQ) must be calculated
separately for motor and mental development. It is beyond the scope of this chapter to cover the
Developmental age examination of every system in detail. Nevertheless it can
DQ = ——————————— × 100 be obtained from a standard textbook of clinical
Chronological age examination. Here we have attempted to give salient points
Developmental evaluation is of special value in in clinical examination that are different in children as
children with neurological diseases like neurodegenera- compared to adults.
tive disorder and chromosomal anomalies like Down’s
Respiratory System
syndrome. It is also useful for following up children with
birth asphyxia or established cerebral palsy and mental Inspect the chest wall for any deformities. Costochondral
retardation. The common developmental/primitive beading is seen in rickets (broad and dome-shaped), in
reflexes to be examined are shown in Table 2.2.16. The scurvy (sharp due to posterior subluxation of the sternum)
absence of appearance of the primitive reflexes at the and in chondrodystrophy. Look for working of the
expected time or their persistence beyond the time that accessory muscles of respiration, i.e. flaring of alae nasi,
they should normally disappear should lead to a suspicion sternomastoid contraction, suprasternal, subcostal and
of significant brain damage. intercostal recession which indicate dyspnea. Observe for

TABLE 2.2.17: Sexual maturity rating in boys/girls

SMR stage Pubic hair (boys/girls) Breasts Penises Testes

1 Preadolescent Preadolescent Preadolescent Preadolescent
2 Sparse, slightly pigmented Breast and papilla elevated, Slight enlargement Enlarged scrotum, pink
areolar diameter increased
3 Darker, beginning to curl Breast and areola enlarged,
no contour separation Longer Larger
4 Coarse, curly, abundant but Areola and papilla form Larger Larger, scrotum dark
less than adult secondary mound
5 Adult distribution, spreads to Mature, nipple projects Adult size Adult size
medial surface of thighs
 History Elicitation and Physical Examination
indrawing of the lower ribs (Harrison’s sulcus) which
indicates chronic obstructive airway disease like bronchial
asthma. Vocal fremitus is rarely of value in young children.
Grunting respiration in a child indicates severe respiratory
disease. Percuss lightly in infants and small children, tap
the chest wall directly rather than using another
pleximeter finger. Due to the thin chest wall, the chest is
more resonant than adults. Before starting to auscultate,
allow the child to play with your stethoscope, to allay its
fears. Often it is less threatening to examine the back of the
chest first. Due to the thin chest wall, breath sounds are
louder in children than in adults and their character is
more like the bronchial breathing of adults. This is called
puerile breathing. Do not be disheartened with a crying
child, as breath sounds can be auscultated better in them.
Be careful to distinguish the conducted sounds from the
upper respiratory tract as in laryngomalacia, upper respi-
ratory tract infection, etc.
Cardiovascular System
In a neonate the apical impulse is located slightly outside
the midclavicular line in the 4th intercostal space. By 2
years, it comes to the midclavicular line in the 4th
intercostal space and comes to the adult position, i.e. 5th
intercostal space 1 cm medial to the midclavicular line
between 4 to 7 years. In infants the right ventricles are
dominant as compared to adults (where left ventricle is
dominant). Due to the short neck of infants and young
children, it is difficult to see the jugular venous pulse and
pressure. Use a pediatric stethoscope with a small
diaphragm to auscultate, as the intercostal spaces are
narrow. It is preferable to auscultate the heart while the
infant is comfortably sleeping or feeding from the mother.
It is easier to hear the normal splitting of the heart sounds
and P2 is louder in young children, i.e. < 5 years.
Functional systolic flow murmurs and venous hum are
often heard in normal children.
Abdomen
The best place to examine the child’s abdomen is the
mother’s lap, preferably while the child is feeding. Even if
the child is struggling, it may be put on the mother’s
shoulder and the abdomen is palpated from behind by
‘ballottment’, i.e. palpation just when the child breathes
and the abdomen relaxes. Unlike in adults, it is not
necessary to fold the legs of the child while palpating the
abdomen. Young children normally have a protuberant
abdomen. Look for umbilical (which may be normally seen
in infants) and inguinal hernia. The liver is normally
39
palpable in children till the age of 4 years, i.e. up to 2 cm
below the costal margin. In view of this it is necessary to
measure the span of the liver in order to make out actual
enlargement. It is carried out by percussing the upper
margin of dullness and by palpating the lower edge of the
liver in the mid-clavicular line. The liver span ranges from
about 4.5 to 5 cm at 1 week of age to approximately 7 to 8
cm in males and 6 to 6.5 cm in females by 12 years of age.
The spleen may be normally palpable in infants up to 2 to
3 months. Examine the genitalia for intersex, phimosis,
undescended testis, hypospadiasis or epispadiasis. The
anus is examined for anal excoriation and pinworms.
Nervous System
Neurological examination of the young child is quite
difficult, especially sensory examination and requires
ingenuity on the part of the doctor to get the child’s
cooperation. Developmental screening and assessing of
the primitive reflexes should be carried out as already
mentioned. Much information regarding the neurological
status of the child can be learnt by just observing the child,
as the history is being elicited. Coordination is best tested
by watching the child, play. Orientation is best tested only
in children above 4 to 5 years. Handedness becomes
apparent at about 3 years of age. Signs of meningeal
irritation, i.e. neck stiffness, Kernig’s sign, Brudzinski’s
sign must be looked for. They may not be present in infants
and in the presence of severe undernutrition or overwhel-
ming sepsis. Fundus may be normally pale in infants.
Lifting the child gives a good idea about the muscle tone.
If it is hypotonic the child will slip through the hands.
The plantar reflex may be extensor up to 1 year of age. But
persistence of extensor plantar beyond 2 years, is definitely
pathological. Tendon reflexes in young infants tend to be
brisk. The deep tendon reflexes may be diagrammatically
represented as shown in Figure 2.2.10, using the notations
shown below.
0 = absent
+ = sluggish
++ = normal
+++ = brisk
++++ = exaggerated
History taking and clinical skill development in pedia-
trics are therefore to be learnt by repeated exposure to case
interviews and hands on training, in examination. The
more a student gets this type of exposure, the more he can
engage himself in self-analysis, which will help him to
carryout the clinical examination thoroughly.
40 IAP Textbook of Pediatrics
Figure 2.2.10: Diagrammatic recording of
deep tendon jerks
2.3 Parent Counseling
Once upon a time, parents would bring their sick child to
a doctor, and be happy to leave with a prescription.
Explanations, empathy, and politeness were never
expected of doctors.
Times have changed, however, and so have our patients
and their parents. In today’s scenario, patients are health
care consumers, we are providers, and the traditional
doctor-patient relationship has changed. Patients and
parents today demand information, courtesy and time.
Arrogance, taciturnity, and a generalised lack of
communication skills are no longer acceptable to health
care consumers.
Apart from the demands of patients, good communi-
cation is good medicine. It enhances patients’ under-
standing and adherence to therapy, and has a therapeutic
effect. If the parents do not understand the disease and
treatment issues well, they may not adhere to therapy,
resulting in poor outcome. It is important for doctors to be
good communicators, and most medical colleges in USA
now teach and assess communication skills. In our
THE PRACTICE OF DIFFERENTIAL DIAGNOSIS
During situations when the diagnosis of the child is not
very clear (which may be the case quite often), it becomes
necessary to make a set of most probable diagnoses. This
is called differential diagnosis. This should be based on
the history, clinical symptoms and clinical signs that have
been elicited. The differential diagnoses thus made will
help us to plan out investigations towards proving or
disproving each probable cause. Hence, to be of practical
value the list should be as short as possible and should
only include conditions that could reasonably explain
most of the child's history, symptoms and signs. The list
should be given in descending order of probability of the
various likely diagnoses, based on the positive and
negative points towards each.
Parang N Mehta
country, however, this essential component of a doctor’s
skill set is largely neglected.
COMMUNICATION SKILLS
These are, quite simply, the skills that allow human beings
to communicate with each other in an effective way. For
pediatricians, communication skills consist of:
i. The ability to talk with parents. Not to parents, not at
parents, but with them. Listening is an essential part;
communication must be a two-way process.
ii. The ability to communicate sufficiently well with patients
and parents so as to understand their concerns,
problems, and beliefs, and to elicit relevant
information.
iii. The ability to explain the child’s illness and its treatment.
The explanation should be clear, complete, and in a
language that the parents can easily understand. The
treatment options should be explained clearly and
completely, so that they can make informed
decisions about treatment.
 History Elicitation and Physical Examination
iv. The ability to convince parents to follow a treatment
plan. This is especially important when embarking
on prolonged, expensive, difficult, or culturally
unacceptable treatment for a child.
v. The ability to establish a relationship with the parents
and child, based on mutual respect and trust.
vi. “Soft skills” like being able to put all classes of parents
at their ease, being able to generate confidence, and
being comfortable holding conversations on non-
medical subjects with parents and patients. In days
of old, these were the components of a “good
bedside manner”, which was considered an
important attribute of a successful practitioner.
THE IMPORTANCE OF COMMUNICATION SKILLS
There are several advantages to possessing good
communication skills (Table 2.3.1). In general, a doctor
with these skills is more likely to have happy, satisfied
patients, than an equally technically competent doctor
who does not bother about communication. Even if a
pediatrician’s diagnosis and treatment are accurate,
thoroughly rational and successful, poor communication
leaves parents unhappy and resentful. On the other hand,
answering all questions without hesitation enhances
patients’ and parents’ belief in a doctor’s expertise. This
is especially so with chronic or incurable diseases, which
are associated with anxiety, stress, and uncertainty for
the whole family.A doctor who offers support, empathy,
and clear and complete explanations at every step can
help alleviate these to a significant extent. Good
communication also enhances adherence to long-term
therapy. On the other hand, lack of communication can
lead to treatment discontinuation and therapeutic failure.
This can extend to depression and despair, or to anger
and complaints.
Most complaints in health care systems, both public
and private, arise from poor communication. Very few
people can judge the quality of a doctor’s examination,
diagnosis, or prescription. Obviously, relatively few
complaints originate in poor performance in these areas.
TABLE 2.3.1: Advantages of good communications
• Patient satisfaction, leading to regular visits and referrals.
• Feeling of empowerment and control.
• Adherence to treatment plans.
• Loyalty even if treatment is not immediately effective.
• Less chances of complaints and legal action in the event of
a mistake.
41
TABLE 2.3.2: What patients want
• Clarity and directness.
• Listening.
• Honesty.
• More and better information about their illness, treatment
plan, and expected outcome.
• More openness about the hazards and side-effects of
treatment.
• More information about the relief of symptoms and other
concerns.
• Advice on what they can do to help themselves.
• Information on other treatments available.
• A supportive, non-judgmental, empathetic doctor.
Parents are angered by the doctor’s refusal to spend time
with them, refusal to give complete and clear explana-
tions, a casual or callous approach to the child’s problems,
and a lack of courtesy and care. When all these are followed
by a poor treatment outcome, complaints, quarrels, and
legal action are likely. On the other hand, good
communication can play a significant part in avoiding
complaints and malpractice claims.
BARRIERS TO GOOD COMMUNICATION
Traditionally, we have not paid much attention to
communicating well. Even today, few of us appreciate the
importance of communication skills, and hardly any make
a concerted effort to learn and apply such skills. This is
perhaps the single biggest barrier to good communication.
Unless we accept the contribution of good communication
to patient outcomes and parent satisfaction, poor commu-
nication is likely to remain the norm in the medical field.
Even doctors who realise the importance of good
communication are not always successful at implement-
ing it. Many of us do not realise what patients want from
us (Table 2.3.2). Some other barriers to good communica-
tion are:
Lack of time: Most pediatricians see a large number of
patients every working day. This is true of both
government and private hospitals. History taking,
physical examination, and prescription writing are of
course, essential parts of a clinical encounter. When time
is short, it is the communication with parents that is
sacrificed. We can overcome this, partially, by deputing
some explanations to paramedical staff.
Arrogance: Arrogance is deeply ingrained into doctors. We
expect our patients and their parents to follow our
commands unquestioningly. We do not understand the
need for explanations, and often give none.
42 IAP Textbook of Pediatrics
Shyness: The parents may be very shy and not ask the
questions they have in their minds. On the other hand, the
doctor may be shy, and either ignore questions, or give
minimal and incomplete answers. Shyness on either side
stands in the way of adequate information being imparted.
Language and jargon: In any major city of India, there is
likely to be a large population of people from other states
and linguistic groups. Communication with them can be
a problem, and needs a special effort.
Most such people will bring an interpreter with them
when coming to us. However, we must use such a person
well. It is necessary to give the interpreter the information
in small chunk, and have him translate it for the parents
as you go along. This is especially important with the
prescription—explain one drug at a time and have him
translate.
A major problem occurs when the parents speak
English. As soon as we meet an English speaking parent,
we start speaking in technical/medical language. This
leaves the parents confused and uninformed. When
talking in English, it is essential to make an effort to talk in
language that a non-medical person can understand.
Deafness: Deafness is a major cause of poor communication,
and is a special concern when our patients are accom-
panied by their grandparents. When we suspect a hearing
impairment, we must speak loudly, slowly and distinctly.
Other useful measures are: voice amplification, if a devide
is available; a quiet room, to improve signal to voice ratio;
use of written communication; and asking the family, at
the end of the consultation, if they have understood
everything, and if they have any questions.
An important measure is to have the relatives repeat
the prescription instructions, to ascertain they have been
understood. This ensured that the child will receive the
medication as it has been prescribed.
Phones: Earliers, a telephone would buzz discreetly on
a receptionist’s desk, and a consultation would not be
interrupted. Today, there’s a phone in everyone’s pocket
or hand, and calls can interrupt and hinder communi-
cation terribly.
INFORMATION NEEDS
When faced with a chronic/permanent condition, most
parents want to know:
i. What treatment can achieve for their child—relief of
symptoms, prolongation of life, shortening of the
course of the disease, etc.
ii. Expected progress of the child during treatment.
iii. What to expect by way of improvement, side effects,
fresh problems, etc.
iv. Chances of complete cure.
v. Treatment options.
The last point is especially important. Complemen-
tary and alternative medicine is a growing business, and
their remedies are often advertised and promoted
aggressively. Dismissing them off hand does not convince
parents. It is necessary to explain treatment goals, explain
how our treatment works, and convey to them the
unscientific basis and unreliability of advertised “magic
remedies”.
STRATEGIES FOR IMPROVING COMMUNICATION
Check what the parents know: With intelligent and
knowledgeable parents, the discussion can begin at a
higher level. However, assessing the parents’ knowledge
is important, because some of their knowledge or
understanding may be faulty. Many parents get their
knowledge from magazines, lay books, and websites. Most
of these sources have no system of review or control of the
information published.
Assess what the parents want to know: Some parents want to
know every little fact and detail about their child’s
condition. Others simply want a prescription and an
assurance that all will be well. It is important to assess the
parents’ desires, and communicate accordingly.
Assess understanding: The parents may not fully understand
what is being told to them. They are upset about the child
being sick, they have poor comprehensive skills, they have
language problems—there could be many reasons. If the
parents indicate that they are not fully understanding
what is being told to them, stopping the explanations for
that session might be appropriate and take it up next time.
Understanding can be improved by giving time to absorb,
and by repetition. At the end of the consultation, the
parents can be asked to repeat some information, to ensure
it has been understood.
Listening skills: Most of us hardly allow the parents to speak.
As soon as they start their description of the child’s
problem, we start asking questions, and attempt to keep
the consultation focussed. However, this often leads to an
incomplete description of the child’s problems.
Listening well is an essential part of communication.
This requires the provision of adequate time and patience,
and the willingness to listen to parents’ concern. A quiet
 History Elicitation and Physical Examination
TABLE 2.3.3: Do’s and Dont’s of communication
Do
• Greet the child and parent by name.
• Smile.
• Sit down when talking.
• Try to talk in the patient’s language.
• Direct the conversation to relevant directions.
• At the end of the consultation, ask if the parents have
any questions.
• Engage the parents in a dialogue.
• Give time for the parents to absorb and understand the
content of your explanations, then to ask questions.
room, lack of interruptions, provision of chairs for the
parents, sitting at an appropriate distance, good eye
contact, etc. are helpful to enhance listening and learning
from the parents.
Build confidence: The parents’ confidence must be bolstered.
We need to accept what the parents say, without judging
it. A little specific praise for the parents’ efforts so far helps
significantly in building confidence and helping parents
to cope. Some suggestions for future care improve their
confidence that they will be able to manage the situation.
Giving false hope is wrong, but we can give information
in a positive manner.
Truth: Parents like to know the truth, but the bald truth
can be harsh and shocking. Parents deserve to know the
truth, but its delivery should be tempered with common-
sense and empathy. If the facts are particularly unpleasant,
they can be delivered in small parts spread out over two
or more visits. However, if parents express a desire to know
everything, it must be told to them. Withholding
information leads to distrust.
Simplicity and clarity: Not all parents have a good
educational and intelligence level. Explaining things in
simple, clear, and direct language is very important. Clarity
and directness are particularly important with parents of
low comprehension abilities. Many people do not
comprehend words like “growth” and “tumor”, for
example. “Cancer” sounds shocking, but may be
necessary to drive home the problem to parents.
Be tolerant: Parents react in various ways, and we should
be prepared. Blame, anger, a sudden outpouring of grief—
all these are common reactions. We should be ready to
deal with these emotions with understanding and
support.
43
Don’t
• Look at your watch frequently.
• Appear to be in a hurry.
• Use too many medical terms.
• Talk with your hand on the door handle, or foot outside
the door.
• Interrupt all the time.
• Start examination and then write out a prescription
before the main problem has been identified.
• Give long lectures as explanation.
• Ignore concerns mentioned by parents.
Empathy: Parents of sick children are going through a
difficult experience. They appreciate the fact that their
doctor understands their situation and their difficulties.
While sympathy has overtones of pity and is likely to be
resented, empathy is simply an understanding of the
parents’ plight.
Apart from these broad principles, many small
factors affect communication positively or negatively
(Table 2.3.3).
KEY POINTS
• Communication skills contribute to good medical care and
patient satisfaction.
• Communication skills contribute to a doctor’s respect, a
patient’s faith, and adherence to treatment.
• Doctors with good communication skills have better clinical
and commercial success, less stress, and more job
satisfaction.
CONCLUSION
Good communication is an art that is so far acquired,
developed and improved by experience. However, it can
also be taught, and assessed, by means of structured
programs. Medical students will gradually have
increasing levels of training in this essential aspect of
medicine. Though formal training is not easily available
to doctors in jobs or practice, we can improve our
communication skills with some personal efforts. This will
lead to better patient/ parent satisfaction and perhaps
better clinical outcomes. Compassion, explanation, and
reassur-ance are valued by our patients and their families
as much as a diagnosis, treatment, and cure.
ACKNOWLEDGEMENT
The article has been reporduced from “Indian Pediatrics” with
permission from the Editor-in-Chief.
44 IAP Textbook of Pediatrics
BIBLIOGRAPHY
1. Bartel DA, Engler AJ, Natale JE, Misra V, Lewin AB, Joseph
JG. Working with families of suddenly and critically ill
children. Arch Ped Adolesc Med 2000;154: 1127-33.
2. Bull SA, Hu XH, Hunkeler EM, Lee JY, Ming EE, Markson
LE, et al. Discontinuation of use and switching of
antidepressants: Influence of patient physician
communication. JAMA 2002;288:1403-9.
3. Fook L, Morgan R, Sharma P, Adekoke A, Turnbull CJ.
The impact of hearing on communication. Postgrad Med
J 2000;76:92-5.
4. Langewitz WA, Eich P, Kiss A, Wossmer B. Improving
communication skills: a randomized controlled
behaviorally oriented intervention study for residents in
internal medicine. Psychosom Med 1998;60:268-76.
5. Levinson W, Roter DL, Mullooly JP, Dull VT, Frankel
RM. Physician patient communication. The relationship
with malpractice claims among primary care physicians
and surgeons. JAMA 1997;277:553-9.
6. Meryn S. Improving doctor patient communication. Br
Med J 1998;316:1922-30.
7. Moore PJ, Adler NE, Robertson PA. Medical malpractice:
the effect of doctor patient relations on medical patient
perceptions and malpractice intentions. West J Med 2000;
173:244-50.
8. Partridge MR, Hill SR. Enhancing care for people with
asthma: the role of communication, education, training
and self management. Eur Resp J 2000;16:333-48.
9. Yedidia MJ, Gillespie CC, Kachur E, Schwartz MD, Ockene
J, Chepaitis AE, et al. Effect of communication training
on medical student performance. JAMA 2003; 290:1157-
65.
3.1 Neonatal Nomenclature and Definitions: Meharban Singh, Vinod K Paul ........................................................................................... 46
3.2 Resuscitation of an Asphyxiated Newborn Baby: Meharban Singh, Ashok K Deorari ....................................................................... 50
3.3 Care of a Normal Newborn Baby: Meharban Singh, Ashok K Deorari .................................................................................................. 56
3.4 Common Developmental and Physiological Problems in Newborn Babies: Meharban Singh, Vinod K Paul ................................. 61
3.5 Management of Low Birth Weight Babies: Vinod K Paul, Ashok K Deorari, Meharban Singh ............................................................ 65
3.6 Common Diseases of Newborn Babies: Meharban Singh, Vinod K Paul, Ashok K Deorari ................................................................ 71
46 IAP Textbook of Pediatrics
3.1 Neonatal Nomenclature and Definitions
It is essential to have uniformly accepted definitions to
express perinatal-neonatal morbidity and mortality for
ease of comparison with other national and international
studies. The adoption of standard nomenclature is
essential for generating meaningful data and for surveil-
lance of impact of interventional strategies. The majority
of definitions and terminologies described below are
based on the standard sources such as tenth revision of
International classification of diseases (ICD) by WHO and
are duly approved and adapted by the Task Force of
National Neonatology Forum of India.
Fetus
Fetus is a product of conception, irrespective of the
duration of pregnancy, which is not completely expel-
led or extracted from its mother. Up to 9 weeks of
gestation, it is designated as embryo.
Live Birth
Live birth is defined as complete expulsion or extraction
from the mother of a product of conception (irrespective
of the duration of pregnancy) and which after such
separation, breathes or shows any other evidence of life
such as beating of the heart, pulsation of umbilical cord
or definite movements of the voluntary muscles
irrespective of the attachment of placenta and/or cord.
In 1970, WHO recommended that babies weighing
less than 500 g at birth should show signs of life for at
least one hour before they are designated as live born.
Fetal Death
Death prior to the complete expulsion or extraction from
its mother of a product of conception irrespective of the
duration of pregnancy, the death is indicated by absence
of any signs of life.
Early fetal death Death at a gestational age of less than
22 weeks or of a fetus weighing less than 500 g or crown-
heel length (CHL) of less than 25 cm.
Intermediate fetal death Death at a gestational age of 22
to 27 weeks or of a fetus weighing 500 to 999 g or CHL
between 25 cm to less than 35 cm.
Meharban Singh, Vinod K Paul
Late fetal death Death at a gestational age of 28 weeks or
more of a fetus weighing 1000 g or more or CHL of at
least 35 cm. The body may be fresh or macerated.
Early fetal deaths are called abortions, while inter-
mediate and late fetal deaths are designated as stillbirths.
Birth Weight
Birth weight is the first weight of a live or stillborn baby
which should preferably be taken within the first hour
of life and certainly during the first day of life before any
significant postnatal weight loss has occurred. If weight
is recorded after 24 hours, the age at which weight is
taken should be specified.
Birth Weight Groups
Low birth weight (LBW) babies Babies with a birth weight
of less than 2500 g (up to and including 2499 g)
irrespective of the period of gestation. These include
preterm (one-third) and small-for-dates term (two-thirds)
babies. In India, for purposes of according specialized
care, babies with a birth weight of less than 2000 g are
considered as high-risk and are admitted to the special
care neonatal unit (SCNU).
Very low birth weight (VLBW) babies Babies with a birth
weight of less than 1500 g (up to and including 1499 g).
Extremely low birth weight (ELBW) babies Babies with a
birth weight of less than 1000 g (up to and including
999 g).
Gestational Age
Gestational age is calculated from the first day of the last
normal menstrual period till the date of birth and is
expressed in completed weeks, e.g. 34 weeks + 6 days
are considered 34 weeks only.
Gestational Age Groups
Preterm (Immature, born early, "premature") Preterm is
defined as a baby with a gestation of less than 37 comp-
leted weeks, (up to 36 weeks or less than 259 days).
Term Babies with a gestational age between 37 to 41
weeks are called as term babies (259-293 days).
 Newborn Care 47

Post-term (postmature) Babies with a gestational age of
42 weeks or more are classified as post-term babies (294
days or more).
Classification by Birth Weight and
Gestational Age Groups
Small-for-dates (SFD) babies (Small-for-gestational age, light-
for-dates, intrauterine growth retardation) Babies with a birth
weight of less than tenth percentile for their gestational
age are designated as SFD babies (Fig. 3.1.1). For purposes
of specialized care and monitoring of blood glucose
levels, babies with a birth weight of less than third
percentile for the period of their gestation are admitted
in the special care nursery unit (SCNU). Dysmaturity
refers to the characteristic marasmic appearance of a baby
reflecting placental dysfunction. This term should
preferably be avoided.
Ideally, regional intrauterine growth charts should
be constructed from a population of high socioeconomic
level with optimal maternal nutrition, and after
excluding known maternal and fetal conditions, which
cause intrauterine growth retardation (IUGR). It also
appears justified to employ one universally accepted
international reference standard for purposes of
comparison of the data.
Appropriate-for-dates (AFD) babies (Appropriate-for-
gestational age) Babies with a birth weight between 10th
to 90th percentile for the period of their gestation.
Large-for-dates (LFD) babies (Large-for-gestational age, heavy-
for-dates) Babies with a birth weight of more than
ninetieth percentile for the period of their gestational age.
The babies with a birth weight of more than 97 percentile
for their gestation are considered high-risk and
monitoring for hypoglycemia.
By combining classification of the babies on the basis
of gestational age alone and gestational age with birth
weight, the newborn population can be divided into the
following 9 subgroups.
1. Preterm
I. SFD
II. AFD
III. LFD
2. Term
I. SFD
II. AFD
III. LFD
3. Post-term
I. SFD
II. AFD
III. LFD
The neonatal mortality is high among preterm babies
due to anatomical and functional immaturity of various
body organs. The least neonatal mortality is seen in term
appropriate-for-dates babies. In each gestational group
(whether preterm, term or post-term) mortality is higher
among LFD and SFD babies as compared to AFD babies.

Perinatal Period
Perinatal period extends from the twenty-eighth week
of gestation (or more than 1000 g) to the seventh day of
life (early neonatal).
Total perinatal deaths
PMR = __________________________________ × 1000
Total number of births
Extended PMR =
Intermediate Late Early
stillbirths + stillbirths + neonatal deaths × 1000
_____________________________________________________________

Total number of births

Figure 3.1.1: Intrauterine growth curve. This helps in classi- In view of the increasing survival of the babies
fying neonates into three categories, viz. small-for-dates (SFD), weighing less than 1000 g as a result of improvements in
appropriate-for-dates (AFD) and large-for-dates (LFD) the perinatal care, the concept of extended perinatal
48 IAP Textbook of Pediatrics
period has been introduced. This period extends from
twenty-second week of gestation (or more than 500 g) to
7th day of life.
Perinatal Mortality Rate (PMR)
Perinatal mortality rate (PMR) is defined as late fetal plus
early neonatal (first week) deaths of babies weighing
more than 1000 g (or 28th week of gestation or more) at
birth per 1000 total births weighing over 1000 g. It is
suggested that for international comparisons, the
numerator as well as the denominator in perinatal-
neonatal statistics should be restricted to fetuses and
infants weighing 1000 g or more.
Neonatal Period
Neonatal period extends up to 28 days of life. Infant up
to 28 days of life is called a newborn baby or neonate.
Early neonatal period refers to first 7 days or 168 hours
of life, while late neonatal period signifies period from
7 days to under 28 completed days of life.
Neonatal Deaths
First day death is defined as deaths occurring within 24
hours of age (exclude if baby had completed 24 hours of
age).
Early neonatal deaths include deaths within 168 hours
of age (exclude if baby had completed 168 hours of age).
Neonatal deaths include all deaths within 28 days of
age.
Neonatal Mortality Rate (NMR)
Early NMR Neonatal deaths of babies weighing over
1000 g during first 7 days per 1000 live births.
Late NMR or unspecified NMR Neonatal deaths of babies
weighing over 1000 g during 28 days of life per 1000 live
births.
The extended neonatal mortality rate can be calcu-
lated by including babies weighing up to 500 g. It is
suggested that the hospital-based neonatal-perinatal
statistics may be presented separately for booked and
unbooked cases.
Birth Weight Classification for
Perinatal-neonatal Data
The morbidity and mortality can be expressed by weight
intervals of 500 g, i.e. 1000 to 1499 g, 1500 to 1999 g, 2000
to 2499 g and so on.
Gestational Age Classification for
Perinatal-neonatal Data
• Less than 28 weeks (less than 196 days)
• 28–31 weeks (196–223 days)
• 32–36 weeks (224–258 days)
• 37–41 weeks (259–293 days)
• 42 weeks and more (294 days and more)
Calculation of Incidence
The incidence of neonatal conditions (e.g. LBW babies,
preterm and birth asphyxia, etc.) should be calculated
per 100 live births, while that of pregnancy and labor
related conditions (e.g. toxemia, maternal anemia,
cesarean deliveries, etc.) should be calculated per 100
total births.
Maternal Mortality
The maternal death is defined as a death of a woman
known to be pregnant within 42 days of termination of
pregnancy, irrespective of the duration or site of the
pregnancy. The death may be due to any cause related
to or aggravated by the pregnancy or its management
but not from accidental or incidental causes. The maternal
mortality rate is expressed as maternal deaths per 1000
live births.
Direct obstetric death Death resulting from complications
of pregnancy, childbirth or puerperium including
interventions, omissions, incorrect treatment or from a
chain of events resulting from any of the above causes.
Indirect obstetric death Death resulting from previous
existing disease or a disease that developed during preg-
nancy, childbirth or the puerperium which was not due
to direct obstetric causes, but which was aggravated by
physiologic effects of pregnancy.
Clinicopathological Classification of
Perinatal Deaths
There is a lack of unanimity and considerable confusion
exists regarding the most acceptable method for classi-
fication of deaths during perinatal period. It is essential
that all perinatal centers should adopt an identical or
uniform protocol for clinicopathological classification of
perinatal deaths so that mortality data is comparable in
order to identify any regional differences. During
perinatal period, many deaths cannot be classified merely
on the basis of clinical findings unless it is complemented
 Newborn Care 49

by autopsy data. Efforts should always be made to obtain TABLE 3.1.1: Neonatal and infant mortality rates by state
an autopsy in each and every case of perinatal death. It
State Neonatal Postneonatal Infant
is generally easier to obtain permission for autopsy in a mortality mortality mortality
case of perinatal death due to relatively less emotional (PNM) (IMR)
bondage of parents and their concern for having a normal
India 39.0 18.0 57.0
healthy baby during next pregnancy. A routine autopsy
performed by an adult-oriented pathologist may not be North
informative and may be unable to identify the cause of Delhi 29.3 10.5 39.8
Haryana 23.6 18.1 41.7
death. Himachal Pradesh 27.3 8.9 36.1
Jammu & Kashmir 29.8 14.9 44.7
Neonatal and Perinatal Mortality Punjab 28.0 13.7 41.7
Rajasthan 43.9 21.4 65.3
When NMR was 70 per 1000 live births (Fig. 3.1.2), it Uttaranchal 27.6 14.3 41.9
contributed to 63 percent of infant mortality rate (IMR
Central
of 110 per 1000 live births). The current NMR is 39 per
Chhattisgarh 51.1 19.7 70.8
1000 live births and the current IMR is 57 per 1000 live Madhya Pradesh 44.9 24.7 69.5
births at the national level (Table 3.1.1). The most Uttar Pradesh 47.6 25.0 72.7
important causes of NMR are bacterial infections (sepsis,
East
pneumonia), LBW and birth asphyxia. Congenital Bihar 39.8 21.9 61.7
malformations also contribute to neonatal deaths to a Jharkhand 48.6 20.2 68.7
small extent. Tetanus neonatorum which was the single Orissa 45.4 19.3 64.7
most important cause of neonatal deaths until a few years West Bengal 37.6 10.4 48.0
ago has now been virtually eradicated. This is responsible Northeast
for the decline of neonatal mortality from 70 per 1000 Arunachal Pradesh 34.0 26.7 60.7
live births in 1981 to the current level. Assam 45.5 20.6 66.1
Manipur 18.7 11.1 29.7
Meghalaya 23.6 21.0 44.6
Neonatal Mortality in Different States
Mizoram 16.3 17.7 34.1
India is an immense country with a wide range of Nagaland 19.8 18.5 38.3
neonatal mortality rates in different states, from as low Sikkim 19.4 14.3 33.7
Tripura 33.1 18.3 51.5
as 1.3 per 1,000 live births in Kerala to around 51 in
Chattisgarh and 48.6 in Jharkhand (Table 3.1.1). ENMR West
and late neonatal mortality rates (LNMR) together make Goa 8.8 6.5 15.3
Gujarat 33.5 16.2 49.7
up the NMR.
Maharashtra 31.8 5.7 37.5

South
Andhra Pradesh 40.3 13.2 53.5
Karnataka 28.9 14.3 43.2
Kerala 11.5 3.8 15.3
Tamil Nadu 19.1 11.2 30.4

Common Causes of Perinatal Deaths

Figure 3.1.2: Infant mortality in India, with changes in neonatal
(black bar) and postneonatal (white bar) mortality rates per
1000 live births
Perinatal deaths include late fetal and early neonatal (first
week) deaths. Perinatal mortality rate in India is around
8.5 per 1000 live births. There is almost equal contribution
by stillbirths and early neonatal deaths. A large majority
of stillbirths are attributable to placental insufficiency due
to pregnancy-induced hypertension (PIH) and maternal
malnutrition, fetal and intranatal hypoxia, antepartum
hemorrhage and congenital malformations.
50 IAP Textbook of Pediatrics
Nearly one-half of early neonatal deaths occur
during first 24 hours of life. Neonatal mortality is
directly related to birth weight and gestational maturity
of the infant. In India it varies between 0.5 percent
among healthy term infants to about 30 percent in
preterm or infants with a birth weight of less than 2000
g. It is estimated that about 30 to 40 percent infants born
in India are LBW (<2500 g at birth), and about 85 percent
of all neonatal deaths occur among them. The neonatal
mortality of LBW babies is about 20 times of mortality
among term-AGA infants. Generally, several factors
operate in most perinatal deaths. Placental insufficiency,
premature separation of placenta and obstetrical
difficulties are important predisposing factors. Bacterial
infections and septicemia account for one-fifth of all
neonatal deaths.
3.2 Resuscitation of an Asphyxiated
Newborn Baby
Establishment of spontaneous breathing afterbirth is
most crucial for the survival of a newborn baby. Most
babies have a smooth transition from fetal to neonatal
life, and they are able to establish spontaneous breath-
ing without any active assistance. Nevertheless, 4 to 6
percent of the neonates are likely to face difficulties in
initiating spontaneous breathing at birth and they require
active resuscitation. Perinatal hypoxia and birth asphyxia
are the leading cause of perinatal mortality in our
country. Apart from high perinatal mortality, birth
asphyxia is an important cause of neuromotor disability.
In order to improve survival of newborn babies due to
perinatal hypoxia and improve the quality of life, it is
essential that every birth is considered as a medical
emergency, and labor room area is adequately provided
with infrastructure and facilities for resuscitation of
newborn babies. Effective resuscitation demands availa-
bility of at least two persons, one who is actively resusci-
tating and the other who is monitoring the condition of
the baby and assisting the resuscitator for administration
of drugs and external cardiac massage when required.
REFERENCE
1. National Family Health Survey (NFHS-3), 2005-06.
Ministry of Health and Family Welfare www.nfhsindia.
org accessed on 14th June, 2008.
BIBLIOGRAPHY
1. Singh M, Deorari AK, Khajuria RC, et al. A four-year
study on neonatal morbidity in a New Delhi hospital.
Indian J Med Res 1991;94:186-92.
2. Singh M, Deorari AK, Khajuria RC, et al. Perinatal and
neonatal mortality in a hospital. Indian J Med Res
1991;94:1-5.
3. Singh M, Deorari AK, Paul VK, et al. Primary causes of
neonatal deaths in a tertiary care hospital in Delhi—an
autopsy study of 331 cases. Ann Trop Pediatr
1990;10:151-57.
4. Singh M, Paul VK. Standard nomenclature and defini-
tions for expressing neonatal morbidity: A plea for
uniformity. Indian Pediatr 1989;26:1089-95.
Meharban Singh, Ashok K Deorari
Fetal Hypoxia
The existence of certain high-risk factors during preg-
nancy and labor may forewarn and alert the labor room
staff that they should be fully prepared to meet the
challenge of an asphyxiated baby (Table 3.2.1). All high-
risk pregnancies should be monitored for fetal growth,
TABLE 3.2.1: Conditions demanding resuscitation alert
1. Fetal distress
2. Meconium-stained liquor
3. Placental insufficiency (PIH, hypertension, postmaturity)
4. Premature onset of labor
5. Antepartum hemorrhage
6. Malpresentation, difficult and abnormal or operative
delivery
7. Cord prolapse
8. Rhesus isoimmunization
9. Multiple gestation
10. Bad obstetric history

presence of congenital malformations, adequacy of
placental function and evidences of fetal hypoxia.
Nonstress test, oxytocin challenge test and biophysical
profile score on ultrasound examination are useful to
identify early evidences of fetal hypoxia. The time
honored clinical parameters of fetal distress offer useful
guidelines to an experienced obstetrician. The asphyxia-
ted fetus initially behaves like a strangulated individual
and makes violent efforts leading to exaggerated fetal
movements which is followed by reduced or absent fetal
movements. Due to the release of catecholamines,
initially there is tachycardia followed by bradycardia and
slow, irregular heart beats. The presence of meconium
due to visceral over activity in a baby presenting as vertex
is an important and ominous sign of fetal hypoxia
specially when associated with an abnormal fetal heart
pattern.
Pathophysiology of Asphyxia
Birth asphyxia is associated with reduction in arterial
oxygen tension, accumulation of carbon dioxide and fall
in blood pH. These biochemical changes lead to right-
to-left shunt with the perpetuation of birth asphyxia.
During the early phase of birth asphyxia, the blood
glucose level is significantly elevated due to the
breakdown of glycogen to glucose, while severe and
prolonged hypoxia in preterm and growth retarded
babies is associated with hypoglycemia. Hypothermia
and hypoglycemia lead to accumulation of non-esterified
free fatty acid and glycerol. Anoxic damage to cells leads
to failure of energy-dependent sodium pump mechanism
with release of potassium and phosphates into the
extracellular fluid.
Assessment of the Infant at Birth
Despite its limitations, Apgar scoring system is conven-
tionally used for assessing the condition of a newborn
baby at one minute afterbirth (Table 3.2.2). The
respiratory effort and heart beats are the most critical
components of Apgar scoring system because muscle
tone, response to reflex stimulus and color are dependent
upon the gestational maturity and cardiorespiratory
status of the baby.
Resuscitation Kit
The resuscitation table or trolley must be available in the
same room where the mother is being delivered. Each
Newborn Care 51
TABLE 3.2.2: Apgar scoring system
Score/item 0 1 2
1. Breathing Nil Slow Crying
2. Heart rate Nil Up to 100 > 100
3. Tone Flaccid In-between Flexed
4. Reflex response Nil Grimace Cry
to catheter
5. Color Blue or pale Peripheral Pink
cyanosis
delivery room must have a well-lighted and warm
microenvironment to receive the newborn baby. The
resuscitation tray must contain a pencil handle laryngo-
scope with infant (0 and 1) blade, resuscitation bag and
mask, De Lee suction trap, gamma-irradiated disposable
endotracheal tubes with internal diameters of 2.5, 3.0,
3.5, 4.0 mm mounted with adaptors, suction catheters,
syringes and needles, 7.5 percent sodium bicarbonate
solution, epinephrine 1 in 10,000 solution, naloxone,
physiological saline and 5 percent dextrose. Electrical
points and the suction machine should be in working
order. The oxygen cylinder should be checked for its
contents. Sterile neonatal packs containing a bowl,
scissors, cotton swabs and umbilical ties should be
available for each delivery. The bassinet on which the
baby is received should be kept warm and provided with
an overhead radiant heat source and a stop clock to
accurately time the sequence of events afterbirth. It is
mandatory that the resuscitation kit must be checked by
the staff nurse of every duty shift and rechecked by the
physician before each delivery. It is desirable that the
equipment for resuscitation is maintained in a sterile
condition. Above all, the health professional attending
the delivery must be skilled and experienced in the art
of cardiopulmonary resuscitation. The art of endotracheal
intubation should be learnt by continuous practice on
stillborn and dead neonates.
Basic Care of the Baby at Birth
The umbilical cord should be clamped as soon as the
infant is completely delivered. There should be no undue
delay or unnecessary anxiety or hurry to clamp the cord.
Early and immediate clamping of the cord is indicated
in babies with severe birth asphyxia, cord around the
neck and rhesus isoimmunization.
52 IAP Textbook of Pediatrics

Routine Care
Nearly 90 percent of newborns are vigorous term babies
with no risk factors and clear amniotic fluid. These babies
do not need to be separated from their mothers to receive
initial steps. Temperature can be maintained by putting
the baby directly on the mother’s chest, drying and
covering with dry linen. Warmth is maintained by direct
skin to skin contact. Clearing of the airway can be done
by wiping the babies nose and mouth.

Assess for the Four Questions (Refer to Algorithm)

Figure 3.2.1
If answer is `No‘ to any of these questions, begin initial
steps of resuscitation. Provide initial care (refer to
alogrithm). Provide warmth, position, clear airway (as
necessary), dry, stimulate, reposition and give O2 (as
necessary).
If answer to any of four is `No’ baby needs initial
steps. In this efforts are directed to prevent hypothermia
and attention is focussed on the airways so that they are
cleared off any secretions and kept patent. The overhead
radiant warmer of the resuscitation trolley or table should
be put on 15 minutes before the birth of the baby. The
baby should be received in a prewarmed linen and dried
from top to bottom immediately afterbirth. The wet linen
should be removed and baby should be covered Figure 3.2.2
effectively with a dry and warm towel. The practice of
Figures 3.2.1 and 3.2.2: Two methods of
bathing the babies soon afterbirth is dangerous and must
tactile stimulation over the soles
be abandoned.
The baby should be placed either in a head low
position to ensure drainage of oropharyngeal secretions and the heart rate should be monitored for possible
or kept flat with 1/2 inch to 3/4 of an inch towel roll bradycardia. These steps usually take around 30 to 45
under the shoulders to maintain slight extension of the seconds and by this time most babies are vigorously
neck for ensuring patency and adequacy of airways. The crying, actively moving and pink. Centrally cyanosed
mouth should be suctioned first followed up suctioning baby requires free flow of oxygen with the help of tube
of the nose using 10 Fr catheter. The suction force should or mask. If the baby is not crying by this time and he or
be gentle and intermittent using a maximum suction she is gasping or having no breathing efforts give one or
pressure of 100 mm Hg (136 cm of water). Suctioning two flicks or slaps over the soles to stimulate breathing
should not be done for more than 5 seconds at a time, (Figs 3.2.1 and 3.2.2). Prolonged stimulation or use of
violent maneuvers like pouring cold water on the baby's
face and slapping the back are not only dangerous but
useless resulting in delay in the resuscitation of the baby.

Approach to a Meconium Stained Baby

The amniotic fluid is meconium stained in 10 to 15
percent of deliveries. When baby passes meconium in
utero, there is a chance that the meconium will be
aspirated into infant’s mouth and potentially into the

trachea and lungs. Appropriate steps must be taken
immediately after delivery to reduce the risk of serious
consequences resulting from aspiration of the meconium
(Note: Intrapartum suctioning of the mouth and nose after
delivery of the head and before delivering the shoulders is no
longer recommended). Direct endotracheal suctioning,
using the endotracheal tube as a suction catheter, should
be performed in cases of non-vigorous baby born with
meconium stained liquor. Vigorous baby (as defined by
strong respiratory effort, good muscle tone and a HR
>100/mt) do not require endotracheal suction.
Endotracheal suctioning may not be necessary the
newborn is vigorous. The infant may have to be intubated
two to three times till all traces of meconium has been
sucked out and baby has not developed bradycardia. The
meconium-stained baby should never be ventilated till
the air passages have been effectively cleared of all
possible meconium.
Bag and Mask Ventilation
If despite stimulation, the baby is still apneic or having
ineffective ventilation as evidenced by heart rate of less
than 100 per minute, he or she should be given bag and
mask ventilation. The mask should tightly fit on the face
enclosing nose and mouth of the baby. The oxygen
reservoir should be attached to the bag to increase the
concentration of oxygen delivered to the baby (Fig. 3.2.3).
The infant should be ventilated at a rate of 40 to 60 per
minute. There should be a noticeable rise and fall of the
chest during each ventilation (Fig. 3.2.4). Naloxone 0.1
ml/kg should be administered intravenously through
umbilical vein if mother had received pethidine or
morphine within 4 hours before delivery after initiating
baby and mask ventilation. During bag and mask
Figure 3.2.3: Self-inflatable resuscitation bag and mask. A
reservoir (corrugated tube or a bladder) should be attached at
the air inlet to increase the oxygen concentration delivered to
the baby
Newborn Care 53
Figure 3.2.4: The procedure of bag and mask ventilation. Mask
should enclose both nose and mouth resting snugly over the
chin and just below the eyes. There should be gentle but visible
rise and fall of chest with each inflation
ventilation, heart rate should be closely monitored after
every 20 to 30 seconds. To save time, heart rate is counted
for 6 seconds and multiplied by 10 to get the heart rate
per minute. If despite effective bag and mask ventilation,
heart rate is not coming up or it further slows down and
drops below 100 per minute, the infant should be
intubated. A large majority of asphyxiated babies can be
effectively revived and resuscitated by using bag and
mask ventilation alone and intubation is usually not
required. There is no role of dexamethasone, atropine,
calcium and respiratory stimulants like nikethamide,
lobeline, etc. in resuscitation. The Apgar scoring system
is not taken into consideration while taking management
decisions during resuscitation of a newborn baby. The
management is guided by the status of breathing, heart
rate and color of the baby. Apgar score may be recorded
at 1 minute, 5 minutes and subsequently (till it is more
than 7) to serve as a prognostic indicator of the outcome
of an asphyxiated baby.
Endotracheal Intubation
Endotracheal intubation is indicated if bag and mask
ventilation fails to maintain adequate ventilation as
evidenced by persistent bradycardia (heart rate below
100 per minute). Infants with diaphragmatic hernia and
thickly meconium stained babies are electively intuba-
ted because bag and mask ventilation is contraindicated
in these situations. The art of intubation cannot be taught
and must be learnt by practicing on stillborn babies and
neonates dying in the nursery. The appropriate sized
54 IAP Textbook of Pediatrics
Flow chart 3.2.1: Neonatal resuscitation
(4.0 mm in a term baby and 2.5 mm in a tiny baby)
endotracheal tube should be prepared by shortening it
to 13 cm and attaching a connector. It is easy to intubate
an asphyxiated baby with some practice because of lack
of resistance and hypotonia. The endotracheal tube
should be suctioned before starting positive pressure
ventilation with a bag or machine. The ventilation can
be stopped as soon as the baby establishes spontaneous
breathing and heart rate is maintained above 100 per
minute (See Flow Chart 3.2.1).
External Cardiac Massage and Medications
External cardiac massage is indicated in babies in whom
heart rate drops below 60 per minute despite effective
ventilation. The ventilation should be continued and
simultaneously heart should be massaged either by using
two fingers of one hand or encircling the chest of the
baby with both the hands and applying sternal
compressions with two thumbs (Fig. 3.2.5). Press the
lower part of the sternum to a depth of 1 to 2 cm at a rate
of 90 compressions and 30 ventilations in 1 minute (3:1
ratio) per minute. The thumbs and tips of fingers
(depending upon the method used) should remain in
contact with the sternum all the time, and they should
not be lifted off after each compression. Check the heart
rate after every 20 to 30 seconds, and chest compressions
may be stopped when heart rate goes above 60 per
minute.
If heart rate is not picking up despite effective venti-
lation and external cardiac massage, administer 0.5 to
1.0 ml of 1.10,000 solution of epinephrine through the
umbilical vein or endotracheal tube. Intracardiac route

Figure 3.2.5: Chest compressions with two-finger technique.
Bag and mask ventilation must be continued while providing
chest compressions
is dangerous and should be avoided. The dose of epi-
nephrine may be repeated after 10 minutes. If a baby is
in shock, consider the use of plasma expander (blood,
plasma, saline) in a dose of 10 ml per kg intravenously.
Sodium bicarbonate 1 to 2 ml/kg of 7.5 percent solution
(adequately diluted with equal volume of distilled water
or double volume of 5% dextrose) should be adminis-
tered intravenously slowly at a rate of 1.0 ml/minute if
effective ventilation is not established even by 10 minutes
or later (Apgar score of less than 7 at 10 minutes).
Early Care of an Asphyxiated Baby
Infants with birth asphyxia should be admitted to the
SCNU for observation and management. A stomach
wash should be done with normal saline and vitamin K
0.5 to 1.0 mg should be given intramuscularly. The infant
should be nursed in a thermoneutral environment.
Intravenous infusion with 10 percent dextrose (without
sodium and potassium) should be started immediately
to prevent any hypoglycemia. Fluid volume should be
restricted to two-thirds because of syndrome of inappro-
priate antidiuretic hormone (ADH) secretion. Infants
with prolonged birth asphyxia (infants needing bag and
mask ventilation even at 5 minutes) should be given
7.5 percent sodium bicarbonate 1 to 2 ml/kg diluted with
equal volume of distilled water or double volume of
5 percent dextrose slowly to correct any acidosis. Sodium
bicarbonate should be administered only when effective
respirations have been established, otherwise, it will lead
to further accumulation of carbon dioxide in the blood.
Hypovolemic shock should be corrected by the
Newborn Care 55
administration of 10 ml/kg of fresh blood, fresh frozen
plasma or physiological saline. A skiagram of chest
should be taken to exclude pneumothorax and congenital
malformations of the respiratory system. The infant
should be closely monitored and observed to detect any
manifestations of hypoxic damage to various organs.
Seizures should be promptly managed by correction of
any metabolic disturbances and by administration of
phenobarbitone 20 mg/kg intravenously slowly over 20
minutes. The neurological behavior of the infant should
be closely watched till he or she is able to establish self-
feeding.
Prognosis
Early neonatal mortality due to birth asphyxia is higher
in preterm babies, but later neuromotor outcome is often
better in preterm babies as compared to term babies. It is
difficult to prognosticate the future neuromotor outcome
in an individual baby. Most infants with an Apgar score
of 3 or less at 5 minutes do fairly well on follow-up. Term
infants with Apgar of 0 to 3 at 10, 15 and 20 minutes
have mortality rates of 18, 48 and 59 percent respectively;
in survivors the risk of developing cerebral palsy are 5, 9
and 57 percent respectively. Therefore, as a general rule,
a guarded rather than hopeless prognosis should be
communicated to the parents to prevent anxiety.
Relatively adverse outcome is anticipated if 15 minutes
Apgar score is less than 3, cord blood pH of less than 7.0,
hypoglycemia, occurrence of neonatal seizures or
abnormal neurological behavior for more than 7 days
and in infants with acute renal failure. Preterm infants
with evidences of intraventricular or parenchymal
hemorrhage on ultrasound examination of the brain are
likely to manifest neurological handicaps in later life.
BIBLIOGRAPHY
1. Behrman RE, James LS, Klaus M, et al. Treatment of an
asphyxiated newborn—current opinions and practices
expressed by a panel. J Pediatr 1969;79:981.
2. Cross KW. Resuscitation of asphyxiated infant. Br Med
Bull 1966;22:73.
3. Kattwinkel J. Textbook of Neonatal Resuscitation, 5th ed,
Dallas, American Heart Association, and Elk Grove
Village, Ill, American Academy of Pediatrics 2005.
4. Paul VK, Shankar V, Deorari AK, et al. Tracheal suction
in meconium stained neonates. J Pediatr 1989;144:508.
5. Singh M. Recommendations for creation of a modest level
II neonatal care facilities in India. Indian Pediatr
1992;29:891-94.
56 IAP Textbook of Pediatrics
6. Singh M. Care of normal newborn babies: Some practical
points. IAP J Pract Pediatr 1993;1:6-13.
7. Singh M. Monitoring of perinatal asphyxia in the
hospital. Indian J Pediatr 1991;58:51.
3.3 Care of a Normal Newborn Baby
Grades of Neonatal Care
Neonatal morbidity and mortality is directly related
to the birth weight and gestational maturity of the
newborn. High-risk pregnancies (which are associated
with the birth of high-risk infants) must be identified
during antenatal period and referred to an appropriate
center for skilled management. Based upon birth weight
and gestational age, a three tier system of neonatal care
is proposed for the developing countries.
Level I Care
Over 80 percent of newborn babies require minimal care
which can be provided by their mothers under the
supervision of basic health professionals. Neonates
weighing above 2000 g or having a gestational maturity
of 37 weeks or more belong to this category. The care
can be provided at home, primary health center level.
Basic care at birth, provision of warmth, maintenance of
asepsis and promotion of breastfeeding form the
mainstay of level I care.
Level II Care
Infants weighing between 1500 and 2000 g or having a
gestational maturity of 32 to 36 weeks need specialized
neonatal care supervised by trained nurses and
pediatricians. First referral units, district hospitals,
teaching institutions and nursing homes should be
equipped to provide intermediate neonatal care.
Equipment for resuscitation, maintenance of thermo-
neutral environment, intravenous infusion and gavage
feeding, phototherapy and exchange blood transfusion
should be provided. There should be no compromise on
the basic needs of adequate space, nursing staff and
maintenance of asepsis including provision for dispo-
8. Svenningsen NW, Blennoh G, Lindroth M, et al. Brain
oriented intensive care treatment in severe neonatal
asphyxia. Arch Dis Child 1982;57:176.
9. Sykes GS, Johnson P, Ashworth F, et al. Do Apgar scores
indicate asphyxia? Lancet 1982;27:494.
Meharban Singh, Ashok K Deorari
sable gamma-irradiated suction catheters, feeding tubes,
endotracheal tubes, small-vein infusion sets, etc.
Intermediate neonatal care is needed for about 10 to 15
percent of the newborn population and should be
available at all hospitals catering to 1000 to 1500 deliveries
per year.
Level III Care
Intensive neonatal care is required for babies weighing
less than 1500 g or those born before 32 weeks of
gestation. Apex institutions or regional perinatal centers
equipped with centralized oxygen and suction facilities,
servocontrolled incubators, vital sign and transcutaneous
monitors, ventilators and infusion pumps, etc. are best
suited to provide intensive neonatal care. Skilled nurses
and neonatologists especially trained in the art of
neonatal intensive care are required to organize this
service. About 3 to 5 percent of the newborn population
qualify for intensive care. Establishment of intensive care
neonatal center demands a sound infrastructure and
should be envisaged only when optimal intermediate
neonatal care facilities have already been in existence for
some time. The capital and recurring expenditure for
level III care is exhorbitant, and it is not cost-effective
unless the service is regionalized.
Care at Birth
After having ensured that the baby has established
effective breathing, it is essential that all efforts are made
to prevent the occurrence of hypothermia. The baby
should be promptly dried and effectively covered with
prewarmed clothes. The baby should be placed under a
radiant warmer or any heat source during the procedure
of resuscitation. A sterile disposable delivery kit should
be used for each baby to prevent cross-infection. The eyes

should be cleaned with sterile normal saline using one
swab for each eye. When prophylaxis against gonococcal
ophthalmia is required, it can be ensured either by
instillation of 1.0 percent silver nitrate drops or 0.5
percent tetracycline or erythromycin ophthalmic
ointment. The umbilical cord should be tied using two
ligatures or rubber band or a disposable clamp. The
clamp or ligature should be applied at least 2 to 3 cm
beyond the base of the cord to avoid inadvertent incision
of gut contained in minor exomphalos. The base and tip
of the umbilical stump should be painted with triple dye
or absolute alcohol. Vitamin K 0.5 to 1.0 mg is adminis-
tered intramuscularly to all babies weighing less than
2000 g, traumatic deliveries following difficult forceps
or vacuum extraction, preoperatively and to babies
whose mothers had received dicoumarol derivatives,
salicylates, anticonvulsants (phenytoin, phenobarbitone)
and antituberculous agents like isoniazid or isonicotinic
hydrazide (INH) and rifampicin. The baby must have
an identification tag before being transferred out of the
labor room.
Quick but thorough clinical screening is essential to
identify any life-threatening congenital anomalies and
birth injuries. The cut end of the umbilical cord should
be inspected for the number of vessels. Normally, there
are two umbilical arteries and one umbilical vein. The
presence of a single umbilical artery is associated with
internal congenital malformations in 15 to 20 percent of
the cases. The commonly associated malformations
include esophageal atresia, imperforate anus and
genitourinary anomalies. Single palmar crease (simian
crease) has increased association with additional
anomalies including Down syndrome. The face and head
should be closely observed for any asymmetry and
dysmorphic features. If while crying the angle of the
mouth and the mandible are pulled down and infant has
asymmetric crying, it is indicative of hypoplasia of the
depressor anguli oris muscle. This is a useful marker of
associated cardiovascular anomalies and congenital
dislocation of hips. The infant should be examined for
location and patency of all the orifices, because anomalies
are frequently encountered around the orifices. The oral
cavity must be examined to exclude the cleft palate. The
patency of the esophagus should be checked by passing
a stiff rubber catheter into the stomach in the following
situations:
i. Small-for-dates baby
ii. Single umbilical artery
Newborn Care 57
iii. Polyhydramnios, and
iv. Excessive drooling of saliva.
If there is no esophageal atresia and the catheter has
reached the stomach, gastric contents should be
aspirated. If gastric aspirate exceeds 20 ml in volume, it
is strongly suggestive of high intestinal obstruction due
to pyloric or duodenal atresia. The anomalies are also
concentrated over the midline areas in the front and back,
e.g. spina bifida, meningomyelocele, pilonidal sinus,
ambiguous genitalia, hypospadias, exomphalos, cleft lip,
cleft palate, etc. The abdomen should be palpated for any
masses and heart examined for its position and any
murmurs. Displacement of the heart towards the right
side in association with respiratory difficulty and
resuscitation problems, is suggestive of either diaphrag-
matic hernia or pneumothorax on the left side.
Breastfeeding
The milk of different mammals is species-specific and
human milk is most suitable to serve the physiological,
biochemical, immunological and emotional needs of the
baby. The low protein content of human milk is in
accordance with the slow rate of growth of the human
infant. The relatively high concentration of lactose and
galactolipids in breast milk is most suited to enhance the
maturation and myelination of the brain which is highly
evolved in human beings.
The preparation and motivation for breastfeeding
should begin during the antenatal period. Inverted and
cracked nipples must be managed during pregnancy so
that the baby is not faced with any mechanical difficulties
during breastfeeding. The mother is advised to put the
baby to the breast as soon as she has recovered from the
exhaustion of labor. According to baby friendly hospital
initiative guidelines breastfeeding should be started
within half an hour of normal delivery and within four
hours of cesarian section. Most babies can be put to the
breast within (half to) one hour of birth. There is no need
for any prelacteal feeds. During the first two to three days,
relatively small quantity of highly concentrated milk
known as colostrum is produced which is extremely rich
in secretory IgA and proteins. It is most suited to serve
the immediate biological needs of the baby. It is essential
that the baby receives the colostrum, and the prevalent
practice of discarding the colostrum must be condemned.
The mother should be advised to feed the baby every
two to three hours on a demand schedule. During each
58 IAP Textbook of Pediatrics
Figure 3.3.1: Burping after a feed helps to eructate swallo-
wed air and reduces the risk of regurgitation after feeds
feed, one breast should be completely emptied before
the baby is put to the other breast. The mother should sit
up comfortably and keep the baby's head slightly raised
and supported on her elbow, and she should offer
alternate breasts at each feed. The baby should not be
allowed to merely suck on the nipple, but he or she must
grasp the areola and part of the breast tissue into his or
her mouth.
After each feed the baby should be burped by holding
him/her upright against the shoulder to prevent
regurgitation of the feeds (Fig. 3.3.1). It is preferable to
put the baby in a prone position or right lateral position
with head end slightly raised to prevent regurgitation
due to gastroesophageal reflux. During the first few days,
many babies fall asleep after taking a few sucks of milk.
It is important that the mother actively interacts with
the baby during breastfeeding. Breastfeeding is not a
passive ritual, and the mother must intently look towards
the baby and gently cuddle and fiddle with the baby by
stroking and tickling behind his or her ears or on the
soles so that he or she does not lapse into sleep without
taking adequate feeds. When the mother perceives that
the baby is becoming slow in his or her sucking efforts,
she should try to gently pull her nipple out when baby
will come out of slumber and restart sucking with
renewed vigor. During the first two to three days, when
lactation is not fully established, the mother is often
anxious that her baby is not getting adequate milk. It
must be explained to her that the act of sucking enhances
lactation and whatever little colostrum the baby receives
during the first few days of life is enough to meet the
nutritional needs of a normal baby. It is absolutely
essential that bottle feeding is not instituted at this stage
with the mistaken belief that lactation is inadequate.
Sucking is the best stimulation both for the enhancement
of milk production and for the ejection of milk. The
mother should be relaxed, free from any anxiety and pain
and reassured that her baby is getting enough nutrition.
Within two to three days, this problem is resolved if
proper support and guidance is given to the mother.
During the first four to six weeks, most babies need to be
fed round-the-clock. Subsequently, one late night feed
and another in the early hours of the morning are enough
to satisfy most babies. During the first four months, the
baby should be exclusively breastfed, and there is no need
to give him or her additional water even during summer
months. This policy is the best safeguard against the
occurrence of infective diarrhea in developing countries.
Ten Steps to Successful Breastfeeding
Every facility providing maternity services and care for
newborn infants should:
1. Have a written breastfeeding policy that is routinely
communicated to all health care staff
2. Train all health care staff in skills necessary to
implement this policy
3. Inform all pregnant women about the benefits and
management of breastfeeding
4. Help mothers initiate breastfeeding within half-hour
of birth
5. Show mothers how to breastfeed, and how to
maintain lactation even if they should be separated
from their infants
6. Give newborn infants no food or drink other than
breast milk, unless medically indicated
7. Practise rooming-in to allow mothers and infants
to remain together throughout 24 hours a day
8. Encourage breastfeeding on demand
9. Give no artificial teats or pacifiers (also called
dummies or soothers) to breastfeeding infants
10. Foster the establishment of breastfeeding support
groups and refer mothers to them on discharge from
the hospital or clinic.
Maintenance of Body Temperature
Newborn babies are homeothermic but their thermore-
gulatory mechanisms are physiologically unsatisfactory.

They are very prone to develop hypothermia unless
adequate precautions are taken to protect them. The
environmental temperature that may feel relatively
uncomfortable to an adult may impose serious thermal
stress to a newborn baby. The baby must be kept dried
and effectively clothed using a cap and socks. The ritual
of bathing babies at birth must be condemned. The baby
bath should be delayed till the next day when his or her
temperature has stabilized. During winter, the linen and
clothes of the baby should be prewarmed before dressing.
The room should be kept warm in winter with the help
of a heater. The baby should be nursed in close proximity
to the mother so that the baby is kept warm by maternal
warmth. The oil massage is both culturally and
scientifically acceptable as it provides insulation against
heat loss and reduces insensible water loss. The cultural
practice of keeping the mother-baby dyed isolated for
40 days is useful and needs to be promoted. It prevents
exposure of the baby to cold and safeguards against the
occurrence of infections. In summer months, depending
upon the environmental temperature, the baby should
be dressed in loose cotton clothes and kept indoors as
far as possible. Exposure of the baby to direct sunlight
during the hot summer months can lead to serious
hyperthermia.
Skin Care
The baby should be bathed or sponged on the next day
afterbirth using unmedicated soap and lukewarm water.
Special precautions must be taken during bath to prevent
draught and chilling. It is preferable to perform the ritual
of bathing and nursing toilet of each baby by the cot-
side. This would provide the unique opportunity and
advantage for imparting health education and active
participation of the mother. The routine use of hexachlo-
rophene for skin prophylaxis is not recommended
because of its risk of toxicity to newborn babies. During
an epidemic of staphylococcal infection, hexachloro-
phene lotion or medicated soap can be used taking care
that the skin is thoroughly rinsed with water after its
application. Dip baths should be avoided till the cord
has fallen. Special attention should be paid to clean the
scalp, skin creases (neck, axillae, groins) and the diaper
area. Vigorous attempts should not be made to scrub off
the vernix caseosa which provides a protective covering
to the delicate skin of the baby. During the winter months,
Newborn Care 59
instead of bathing, the baby can be sponged daily to avoid
unnecessary exposure and risk of hypothermia. During
the procedure of bathing or sponging, the nurse should
specifically look for any superficial infections like
pyoderma, umbilical sepsis, conjunctivitis, oral thrush,
etc. and bring them to the notice of the physician.
Handwashing, barrier nursing and storing separate
articles for personal use of each baby in their individual
lockers is desirable to prevent nosocomial infections.
Care of the Umbilical Stump
The umbilical cord is an important portal of entry for
Clostridium tetani in domiciliary midwifery. Health
personnel must be told the importance of using a sterile
disposable dai-kit to prevent the occurrence of tetanus
neonatorum. The cord should be cut with a sterilized
blade. The umbilical stump must be inspected after 2 to
4 hours of clamping. Bleeding may occur at this time due
to shrinkage of cord and loosening of the ligature. The
use of a rubber band or a disposal clamp safeguards
against the hazard. Triple dye or ethyl alcohol should be
applied at the tip and around the base of the umbilical
stump every day to prevent colonization. The cord must
be left open without any dressing. The cord usually falls
after 5 to 10 days, but may take longer if it has been kept
moistened, when it is infected and in immunocompro-
mised babies. The stump should be inspected for any
discharge or infection and kept clean and dry till
complete healing takes place.
Care of the Eyes
The eyes should be cleaned at birth and once every day
using sterile cotton swabs soaked in sterile water or
normal saline. Each eye should be cleaned using a
separate swab by modified crede method (cleaning from
media) to lateral canthus by swab) saline soaked. The
cultural practice of instillation of human colostrum in
the eyes has been found to be useful in reducing the
incidence of sticky eyes. The practice of applying kajal
in the eyes is not recommended because it may transmit
infections like trachoma or may even cause lead
poisoning. If the eyes are sticky, they can either be
managed by frequent cleaning using sterile cotton swabs
soaked in normal saline or by instillation of 10 percent
sulfacetamide eyedrops every two to four hours. Some
60 IAP Textbook of Pediatrics
neonates may develop persistent epiphora due to
blockage of nasolacrimal duct by epithelial debris. The
mother should be advised to massage the nasolacrimal
duct area (by massaging the outer side of the nose
adjacent to the medial canthus) 5 to 8 times, each time
before she feeds the baby.
Weight Record
Most healthy term babies lose weight during the first 2
to 3 days of life. The weight loss is usually up to 5 to 7
percent of birth weight. The weight remains stationary
during the next one to two days and birth weight is
regained by the end of first week. The factors contributing
to physiological weight loss include removal of vernix
caseosa, mucus and blood from skin, passage of
meconium and reduction of extracellular blood volume.
Delayed feeding and unsatisfactory feeding schedule is
associated with excessive weight loss. There is no need
to monitor early weight changes in a healthy newborn
baby, because it can cause unnecessary anxiety to the
mother and may lead to lactation failure. Babies who are
adequately fed are contented, playful, have good sleep
and are satisfied for at least two to three hours after a
feed. The adequately fed baby passes urine at least 5 to 6
times in a day, while many babies may pass urine (even
stools) after each feed during the first 3 months of life.
The average daily weight gain in term babies is around
30 g, 20 g and 10 g during the first, second, third, fourth-
month periods respectively. Most infants double their
birth weight by 4 to 5 months of age, and triple it by
their first birthday.
Immunization
It is recommended to give the Bacille Calmette-Guérin
(BCG) and a first dose of oral polio vaccine (OPV) as
early as possible preferably within the first week of
life. It should be explained to the mother that the child
must receive all the vaccinations at the proper time
as recommended in the National Immunization
Schedule (Chapter 9, Table 9.1.1). Hepatitis B vaccine
can be administered in 3 doses at birth, 6 weeks and
14 weeks.
Early Identification of Disease
Most mothers do observe their babies carefully and are
often worried by minor physical peculiarities and
problems which are of no serious consequence. She must
be adequately informed and appropriately advised
regarding minor problems to prevent undue anxiety,
concern and worry. The baby-mother dyed should be
approached twice a day to enquire about any feeding
problems, vomiting, bowel disorders and to identify any
problems and relieve the anxiety of the mother regarding
various developmental peculiarities and minor physical
problems which may be bothering her. The onset and
intensity of jaundice should be watched in good natural
daylight. The infant should be closely watched for
following danger signs which should be brought to the
attention of the physician for prompt management:
bleeding from any site, appearance of jaundice within
24 hours of age or yellow staining of palms or soles,
failure to pass meconium within 24 hours or urine within
48 hours, persistent vomiting or diarrhea, poor feeding,
undue lethargy or excessive crying, drooling of saliva or
choking during feeding, respiratory difficulty, apneic
attacks or cyanosis, sudden rise or fall in body tempera-
ture, seizures and evidences of superficial infections such
as conjunctivitis, pustules, umbilical sepsis, oral thrush,
etc.
Follow-up
Each baby should be followed up in the well baby clinic
for assessment of growth and development, early diag-
nosis and management of illnesses and health education
of parents. It is preferable that every baby is seen and
assessed by a health worker at least once every month
for 3 months and subsequently 3 monthly till 1 year of
age.
BIBLIOGRAPHY
1. Davies PA, Robinson RJ, Scopes JW et al: Routine care of
the normal term baby. Medical Care of Newborn Babies
1972;44/45:73.
2. Singh M. Care of the normal baby, Care of the Newborn
(4th edn) Sagar Publications, New Delhi; 1991.
3. Singh M. Care of normal newborn babies—some practical
points. IAP J Pract Pediatr 1993;1:6-13.

3.4 Common Developmental and Physiological
Problems in Newborn Babies
Most mothers observe their babies carefully and are often
worried by minor physical or physiological peculiarities
which are of no consequence. It is important that her
complaints are listened to carefully, and they are not
ignored lightly without doing proper evaluation of the
baby. She must be given reassurance and advice
regarding the minor problems and difficulties that may
be bothering her. Adequate explanation and reassurance
is necessary to allay her anxiety which may lead to lacta-
tion failure.
Regurgitation of Feeds and Vomiting
Most normal newborn infants regurgitate some amount
of milk soon after feeds. Babies swallow air (aerophagy)
while sucking and as the air is expelled, part of the feed,
looking like curd, also comes out. Unlike vomiting, the
expulsion of stomach contents is without force and
nonprojectile. All mothers must be given proper advice
regarding the technique of feeding and burping after each
feed. The baby must be held upright against the shoulder
or made to sit up in the lap for at least 5 to 10 minutes to
eructate the air swallowed during the feeding before he
or she is put back to the cot. Most babies enjoy being
placed in the prone position which is associated with
less risk of regurgitation, and it relieves abdominal
distention and colic. When vomiting is persistent,
projectile or bile-stained and associated with failure to
pass meconium during the first 24 hours and/or abdo-
minal distention, the baby should be investigated for
intestinal obstruction.
Bowel Disorders
The baby may pass meconium in utero or soon afterbirth,
but all healthy newborn babies must evacuate within 24
hours of birth. During the first two to three days, the
baby passes black, tarry meconium stools which is
followed by greenish (transitional) stools for the next one
or two days. The breastfed baby usually passes 4 to 8
semisolid sticky golden-yellow stools everyday. Some
Newborn Care 61
Meharban Singh, Vinod K Paul
babies may pass stools after each feed due to the
exaggerated gastrocolic reflex. The stools are often very
small (at times like droppings of the birds) with normal
consistency. The babies continue to gain weight. The
family should be reassured and advised against any
medication as this physiological problem will settle in
due course of time. The breastfed babies may develop
increased frequency of stools if the mother is taking
ampicillin, cephalexin and certain laxatives. Milk of
magnesia, bulk laxatives and a glycerine suppository are
safe for a nursing mother. The administration of glucose
water or honey to the baby may cause osmotic diarrhea
and can lead to infective gastroenteritis due to contami-
nation. When the baby is exclusively breastfed, he or she
is unlikely to develop infective diarrhea. A sudden
change in the baby's established bowel pattern leading
to greater frequency and change in the character of stools
should be taken seriously. Infective diarrhea occurs in
top-fed babies. The stools are often watery with mucus
and plenty of pus cells. Neonatal diarrhea may also occur
in association with septicemia, necrotizing enterocolitis
(NEC), Hirschsprung's disease and phototherapy.
Maternal drug addiction, congenital thyrotoxicosis and
metabolic disorders, such as the salt-losing variety of
congenital adrenal hyperplasia and disaccharidase and
enterokinase deficiency are rare causes of diarrhea in
neonates.
Babies fed on cow's milk are often constipated due to
hard casein curds. Constipation may also occur due to
inadequate feeding or gastrointestinal obstruction.
Infants with congenital hypothyroidism, Hirschsprung's
disease and anal stenosis are often constipated. Mild
constipation in the absence of any underlying disease
process often needs no treatment. Insertion of a glycerine
suppository is often followed by a motion if constipation
is significant. At times offering sugar water, honey or
orange juice for a day or so may be advised. For infants
who are on top-milk, addition of sugar to the feed will
often take care of the problem. The use of laxatives should
be avoided in newborn babies.
62 IAP Textbook of Pediatrics

Delayed Passage of Urine should be suspected if there is history of gonorrhea in

the mother or conjunctivitis characterized by abundant
Most newborn babies pass urine during the first day of
purulent discharge and chemosis of eyelids. It should be
life, but all must void within first 48 hours of birth. If a
confirmed by microscopic examination of a Gram stained
baby has not passed urine by 48 hours, he or she should
preparation of purulent discharge. It is best treated by
be examined to rule out renal agenesis and obstructive
parenteral and topical administration of crystalline
uropathy. However, the most common cause of the
penicillin and frequent cleaning of eyes. Nongonococcal
alleged nonpassage of the urine is that the baby has
purulent conjunctivitis is usually caused by staphy-
actually passed urine but it has been overlooked by the
lococci, but other pathogens may be responsible
mother. The normal frequency of micturition in a
depending upon the microbial ecology of the environ-
newborn baby varies between (5-10 times per day). Some
ment. It is best treated with local instillation of
babies may cry before passing urine due to discomfort
chloramphenicol or gentamicin eyedrops hourly. After
of a full bladder, they become quiet and dazed while
24 hours intervals between local medications can be
passing urine and start crying again after having passed
gradually increased. The chlamydial conjunctivitis
urine due to wet napkins. This should not be considered
characteristically manifests as purulent blenorrhea, often
as an evidence of urinary tract infection or obstructive
unilateral, during the second week of life. It is managed
uropathy. The narrow stream of urine, straining and
by oral erythromycin therapy (40 mg per kg per day, in
crying during the act of micturition, dribbling in the end
four divided doses) for 2 weeks. In addition, topical
and presence of palpable urinary bladder or enlarged
instillation of 10 percent sulfacetamide eyedrops or 0.5
kidneys are suggestive of obstructive uropathy.
percent erythromycin ophthalmic ointment should be
Physiological Jaundice advised. The eyes should be cleansed with sterile wet
cotton swabs prior to the instillation of eyedrops by using
About 60 to 70 percent of newborn babies develop one swab for each eye.
jaundice on the second or third day of life. The icterus is
detectable on the face and the trunk, sparing the palms Pyoderma
and the soles. The serum bilirubin level does not cross
Pyoderma manifests as multiple pustules especially over
15 mg/dl. Jaundice disappears within 7 to 10 days.
the scalp, neck, axillae and groins. The infection is usually
Physiological jaundice does not need any treatment, and
transmitted by the hands of personnel and is caused by
the mother should be reassured that it will disappear
staphylococci. The large pustules can be punctured with
spontaneously. It is not indicative of any infection and
a sterile needle to drain the pus. The skin should be
does not require administration of extra water. The
washed with soap and water. The skin lesions should be
occurrence of jaundice within the first 24 hours of life or
painted with triple dye or an antibiotic cream two to three
when it is deep and intensely staining the trunk, causing
times a day. When despite this therapy the skin lesions
yellow discoloration of the palms and the soles or if it
are increasing in size or number, oral administration of
persists beyond 2 weeks need investigations and
erythromycin or cloxacillin is recommended. Close
management.
observation for signs of septicemia should be maintained.
Jitteriness
Umbilical Sepsis
Many normal babies are jittery or tremulous on touch Umbilical sepsis manifests as redness and edema at the
and handling. They are easily startled by loud noise or
base of the cord and a foul smelling purulent discharge.
rough handling. When jitteriness is excessive and persists
The presence of mucoid discharge on the stump and even
even during feeding, it is important to exclude hypogly- isolation of bacteria are not indicative of umbilical sepsis
cemia and hypocalcemia.
unless there are clinical evidences of periumbilical
inflammation or there are pus cells in the exudate. The
Superficial Infections
umbilical stump should be cleaned with spirit and treated
Sticky red eyes or purulent conjunctivitis are common with local application of triple dye or antibiotic lotion. If
during the newborn period. Gonococcal ophthalmia periumbilical inflammation is spreading or the infant is

showing evidences of systemic spread of infection as
evidenced by fever, lethargy, poor feedings, etc. he or
she should be managed with parenteral antibiotics as in
a case of neonatal septicemia.
Oral Thrush
Oral thrush manifests as white patches with erythe-
matous margins distributed over the tongue and buccal
mucosa. Unlike milk curds, the patches of thrush are
adherent and they often bleed when attempts are made
to remove them. Local application of 0.5 percent aqueous
solution of gentian violent or nystatin or ketoconazole
after each feed is followed by prompt recovery. The
mother should be examined for vaginal and mammary
candidiasis and given appropriate treatment.
Dehydration Fever
During the summer months, when the environmental
temperature approaches 40oC, some healthy newborn
babies may develop transitory fever during the second
or third day of life. The fever is usually moderate in
intensity (up to 38.5oC) and the child is active and keen
to feed. The condition is transient and is best managed
by lowering the environmental temperature. Once the
lactation is established and adequate feeding is ensured,
the infant becomes afebrile.
Excessive Crying
During the first few weeks most newborn babies sleep
during the day and they are awake, playful and
troublesome during the night. This behavior is probably
due to continuation of their in utero pattern of activity.
During pregnancy when the mother is up and about
during daytime, the baby is rocked in the pool of amniotic
fluid and sleeps. During the night when mother is resting,
the fetus is active and playful. Moreover, during the
solitude of night even the normal cry of a baby sounds
too loud and disturbing, both to the mother and the
neighbors. This pattern of activity or behavior sponta-
neously disappears after 4 to 6 weeks of age. Most babies
usually cry when they are either hungry or are having
discomfort. The cry may be a signal of unpleasant
sensation of a full bladder before passing urine, painful
evacuation of hard stools or discomfort of wet napkins.
At times insect bites, nose block and inapparent trauma
are the reasons for cry. The experienced mother and
physician are able to differentiate between the cry used
as a signal for feed and the cry of discomfort. An infant
Newborn Care 63
with abdominal colic would have audible gurgling
sounds in the abdomen and usually feels comfortable
when placed in a prone position which facilitates the
expulsion of gas. The presence of excessive inconsolable
crying or a high-pitched cry is always indicative of
serious disorder like meningitis or a painful inflam-
matory condition.
Excessive Sleepiness
During the first few days of life, many infants keep their
eyes closed most of the time, and they readily go to sleep
after taking only a few sucks at the breast. This excessive
sleepiness may be aggravated by heavy maternal
sedation during labor. Barbiturates and opium deriva-
tives when taken by the nursing mother may cause
sleepiness in her suckling infant. Infants with Down
syndrome and hypothyroidism are often lazy and lack
activity due to generalized hypotonia. The sudden
appearance of lethargy or lack of interest in feeding, in a
baby who had been feeding adequately in the past, is
often ominous and may be the only manifestation of a
serious illness like septicemia or a metabolic disorder.
Cephalhematoma
It is a subperiosteal collection of blood secondary to injury
during vaginal delivery. It may occur both following an
obstructed or a precipitate delivery. The swelling is not
present at birth and it manifests after a couple of hours
when sufficient amount of blood has extravasated. It is
characterized by a fluctuant swelling which is limited
by suture lines. It gradually resolves over a period of
several days or weeks depending upon the size of the
swelling. Incision or aspiration is contraindicated unless
it gets infected or is associated with critical hyperbili-
rubinemia.
Cephalhematoma should be differentiated from
caput succedaneum which manifests as a boggy, pitting
edema of the scalp on the presenting part. It is a non-
fluctuant swelling and is not limited by the suture lines.
The caput succedaneum is present right at birth and
rapidly disappears during the next 24 to 48 hours.
Umbilical Granuloma
It manifests as a slightly red flesh-like nodule at the base
of the umbilical cord with persistent nonpurulent
discharge after the cord has fallen. This can be managed
by cautery with silver nitrate or application of common
salt for 2 to 3 days.
64 IAP Textbook of Pediatrics
Napkin Rash
The perineal skin may become red, indurated and exco-
riated due to ammoniacal dermatitis if the infant is not
promptly cleaned and dried after the passage of urine or
stools. Occurrence of diarrhea and the use of nylon or
watertight plastic napkins aggravate the condition. The
bottom should be kept dried and exposed to air or
sunlight. Application of coconut oil or a bland ointment
is promptly followed by recovery. The causative factors
should be identified and eliminated. In resistant cases,
infection of the skin by Candida albicans should be ruled
out and appropriately managed with a topical lotion.
Sneezing and Nose Block
Sneezing is common in healthy newborn babies due to
irritation of the nose by amniotic fluid, meconium, blood,
or debris, etc. It should not be considered as a sign of a
common cold. The nostrils should be cleaned with sterile
cotton buds if sneezing is excessive.
Nose block is another common problem. Often there
is no obvious nasal discharge. The infant may be in
discomfort because he or she is an obligatory nose
breather. Severe nose block may even cause respiratory
distress. Nose block is managed by instilling one or two
drops of normal saline into the nostrils 15 minutes before
feeds. Medicated nasal drops are contraindicated in
neonates.
Hiccups
Most newborn babies develop hiccups especially after
the feeds. This is normal. The distention of stomach
causes irritation of the diaphragm which leads to hiccups.
They do not indicate any disease process in a newborn
baby, and the mother should be reassured regarding the
benign nature of the hiccups.
Disorders due to Transplacental
Passage of Hormones
Term babies of both sexes may develop engorgement of
the breasts on the third or fourth day due to effect of
transplacentally transferred progesterone and estrogens.
The hypertrophy of the breast may last for a few days to
several weeks, but it disappears spontaneously. Local
massage, fomentation and temptation to express the milk
may lead to complications.
Vaginal Bleeding
About 20 to 25 percent female babies may develop
menstruation like withdrawal vaginal bleeding after 4
to 5 days of birth. The bleeding is usually mild and lasts
for 2 to 4 days. It does not need any specific therapy apart
from local aseptic cleaning of genitals.
Mucoid Vaginal Secretions
Most female babies have copious grayish white slimy
mucoid vaginal secretions due to female sex hormones.
This should not be confused with purulent vaginal
discharge.
Minor Developmental Peculiarities
Toxic Erythema (Urticaria Neonatorum)
About one-third healthy term newborn babies may
develop an erythematous rash with a central pale papule
on the second or third day of life. The rash usually starts
on the face and spreads to the trunk and extremities in
about 24 hours. The rash disappears spontaneously after
two to three days without any specific treatment. The
exact cause is not known, but it is considered as an early
marker of atopy. The scrappings from the skin lesions
often show increased number of eosinophils. The rash
should be differentiated from pyoderma and skin lesions
of congenital syphilis.
Tongue Tie
A thin frenulum under the tongue is normal and does
not need any treatment. A thick and tight fibrous
frenulum producing a notch at the tip of the tongue is
abnormal and may have to be snipped at the age of three
months. Tongue-tie seldom interferes with sucking or
speech development of the child.
Nonretractable Prepuce
The prepuce is normally nonretractable in all male
newborn babies, and it should not be diagnosed as
phimosis. The mother should be advised against forci-
ble retraction of the foreskin.
Mongolian Blue Spots
Almost all newborn babies of African and Asian origin
have irregular blue patches of skin pigmentation espe-

cially over the sacral area and buttocks. These patches
have no relationship with Down syndrome, and they
invariably disappear by the age of 6 to 18 months.
Congenital Teeth
Some newborn babies may be born with one or two lower
incisor teeth. They do not interfere with feeding, but
cause considerable anxiety among the parents and
relatives due to the mistaken cultural belief that they are
a bad omen. The loose teeth may be extracted as a
safeguard against the risk of aspiration.
Milia
Yellow white pinhead-sized papules on the nose are seen
in practically all babies. They occur due to the retention
of sebum and disappear spontaneously.
Excessive Scales and Peeling of Skin
Dry scaly skin with peeling and increased transverse skin
creases is seen in post-term and some term small-for-
3.5 Management of Low Birth Weight Babies
Vinod K Paul, Ashok K Deorari, Meharban Singh
INTRODUCTION
The average birth weight of a newborn baby in our
country is around 2800 to 3000 g. A neonate who weighs
less than 2500 g at birth is a low birth weight baby (LBW).
In India, over 30 percent infants are born LBW.
Nearly 80 percent of neonatal deaths and 50 percent
of infant deaths occur among the LBW neonates. Even
after recovering from neonatal complications, some LBW
babies are prone to develop malnutrition, recurrent
infections, and neurodevelopmental handicaps. There is
emerging evidence that LBW or growth-retarded
neonates are more prone to manifest diabetes mellitus,
hypertension and coronary artery disease in later life.
Therefore, LBW is a key risk factor for adverse outcome
in life.
The newborn baby may be LBW because of prema-
turity or intrauterine growth retardation (IUGR). A baby
born before 37 weeks of gestation is called a preterm baby.
Newborn Care 65
date babies. Dryness of skin occurs due to the paucity of
amniotic fluid. Application of an emollient cream or oil
provides relief.
Subconjunctival Hemorrhage
In some babies semilunar spots of subconjunctival
hemorrhage may be seen over the outer canthus of the
eye. They are seen in babies born by vaginal delivery
following vertex presentation. The hemorrhage gets
resorbed after a few days.
Prominent Xiphisternum
The spear-shaped xiphisternal cartilage may stand out
prominently in some babies, and it is not indicative of
any disease process.
BIBLIOGRAPHY
1. Singh M. Common neonatal problems and their
management. Indian Practitioner 1970;23:65.
2. Singh M, Krishnamoorthy KS, Sinclair S, et al. Some
developmental characteristics in the newborn. Indian
Pediatr 1970;7:378.
Fetal size and weight are directly linked to gestation.
Therefore, it is obvious that if the delivery takes place
prematurely, the baby is likely to be small. Approxi-
mately one-third of LBW neonates in our country are
preterm. The second situation that leads to LBW is IUGR.
The gestation may be full term or preterm, but the baby
is undernourished, undersized and, therefore, LBW. Such
a baby is also called a small-for-date (SFD) baby. Two-
thirds of our LBW neonates fall in this category. At times,
an LBW neonate may be both preterm as well as SFD.
Etiology
Poor nutritional status of the mother and frequent
pregnancies are the major causes of IUGR. Mothers with
a weight of less than 40 kg and a height of less than
145 cm often give birth to SFD babies. Insufficient
nutritional intake during pregnancy also has an adverse
effect on fetal growth. Maternal hypertension,
66 IAP Textbook of Pediatrics
preeclampsia, postmaturity, frequent pregnancies,
multiple pregnancy, anemia, malaria and tobacco use are
other causes of IUGR. Chronic maternal diseases of heart,
kidneys, lungs or liver may also lead to IUGR.
Preterm labor occurs in teenage mothers and in the
setting of low maternal weight, cervical incompetence,
antepartum hemorrhage, previous fetal loss, previous
preterm delivery. Sometimes, preterm labor is medically
induced for the sake of the baby as in the case of Rh-
isoimmunization or maternal diabetes mellitus. The
cause of a majority of preterm deliveries, however,
remains unknown.
How to recognize Two Types of LBW Neonates?
It is desirable and of practical relevance to make clinical
distinction between the two types of LBW babies. A
preterm baby is diagnosed on the basis of the period of
gestation calculated from the last menstrual cycle of the
mother. If it is less than 37 completed weeks, the baby is
designated as preterm. Preterm babies also have distinct
physical and neurological features which help in their
recognition. The deep skin creases over the soles are
present only over the anterior one-third. The external ear
or the pinna is soft and devoid of cartilage, and it does
not recoil back promptly on being folded. In males, the
scrotum does not have rugae and testes may not be
descended into the scrotum. In female infants, the labia
are widely separated and do not cover the labia minora,
resulting in the prominent appearance of the clitoris. The
back of the preterm babies has abundant growth of fine
hair called lanugo.
Small-for-dates neonates have an emaciated look and
loose folds of skin because of lack of subcutaneous tissue.
These are particularly prominent over the buttocks and
the thighs. They look alert and often plethoric. In SFD
babies, the head circumference exceeds the chest
circumference by more than 3 cm. The SFD babies are
often full term or borderline term in gestation. When their
birth weight is plotted on the intrauterine growth chart,
it falls below the tenth centile.
Problems of LBW Neonates
Preterm Babies
The basic underlying feature of the preterm LBW infant
is immaturity of their organ systems. They may not
establish respiration satisfactorily at birth and develop
asphyxia necessitating expert resuscitation. All newborn
babies keep themselves warm by active metabolism in
the brown fat. The preterm babies lack adequate stores
of brown fat and are, therefore, vulnerable to become
hypothermic at the usual ambient temperatures unless
specific measures are taken to keep them warm. Preterm
neonates less than 34 weeks of gestation do not have
coordinated sucking and swallowing movements.
Therefore, they are unable to suck at the breast and are
liable to get choked. Preterm infants, especially those less
than 30 weeks of gestation may not tolerate enteral feeds
initially because of immaturity of gut. Infants born before
34 weeks of gestation have immature lungs which do
not expand well afterbirth and are, therefore, unable to
perform the function of gas exchange. They develop
respiratory distress syndrome (RDS) characterized by
rapid and labored respirations, indrawing of the chest,
grunting and cyanosis. Because of the immature respi-
ratory control mechanisms, these babies also have a
tendency to manifest apneic spells. These infants have
immature vascular beds around the cerebral ventricles.
The delicate vessels may rupture and cause intraventri-
cular hemorrhage (IVH). Immature metabolic pathways
of preterm infants predispose them to the development
hypoglycemia, metabolic acidosis, and hyperbilirubi-
nemia. Infection is another major problem among
preterm babies and indeed an important cause of
mortality. These babies do not have efficient humoral,
cellular and mucosal immune mechanisms to protect
themselves against infections. Besides, interventions such
as needle pricks and intravenous lines, especially in the
setting of a contaminated environment, predispose them
to develop potentially fatal bacterial infections. Preterm
infants may develop blindness due to retinopathy of pre-
maturity (ROP) as a result of hyperoxia due to unmoni-
tored oxygen therapy.
Small-for-date (SFD) Babies
The neonatal complications in SFD babies occur due to
in utero undernutrition and hypoxia. The stress of labor
may lead to fetal distress, meconium passage in utero and
birth asphyxia. Respiratory distress may occur due to
meconium aspiration syndrome. Due to chronic fetal
malnutrition, they also lack adequate brown fat stores.
This predisposes them to develop hypothermia. They are
also prone to develop hypoglycemia because of
insufficient glycogen stores. Like preterm babies, they
are also vulnerable to develop neonatal sepsis. SFD
infants are more likely to have congenital malformations
as compared to their normal counterparts.

Management
Delivery of LBW Babies
Ideally, the delivery of an anticipated LBW baby should
be conducted in a hospital. Premature labor as well as
IUGR are indications for referral of the pregnant mother
to a center with well-equipped facilities. The in utero
transfer of a low weight fetus is far more desirable, con-
venient and safe than the transport of a LBW baby
afterbirth. Delivery should be conducted by trained
health professionals, at least one of them should be well-
versed with the art of neonatal resuscitation. Resusci-
tation equipment like suction catheters, bag and mask,
oxygen cylinder, laryngoscope, etc. should be kept ready
beforehand. Baby must be provided warmth from a heat
source like a heater, or a lamp with 200 W bulb to prevent
hypothermia.
The Place of Care
An LBW newborn with a birth weight of 1800 g or above,
or a gestation of 34 weeks or more can be managed at
home by the mother and the family under the supervision
of a health worker or a family physician. The following
infants should be hospitalized for care:
i. birth weight of less than 1800 g
ii. gestation of less than 34 weeks
iii. neonate who is not able to take feeds from the breast
or by katori-spoon (irrespective of birth weight and
gestation)
iv. a sick neonate (irrespective of the birth weight or
gestation).
Keeping the LBW Babies Warm
Provision of warmth to prevent hypothermia is one of
the cardinal principles of newborn care. A baby under
cold stress wastes energy and oxygen in trying to main-
tain temperature. Hypothermia can lead to hypogly-
cemia, bleeding diathesis, pulmonary hemorrhage,
acidosis, apnea, respiratory failure, shock and even death.
All this is entirely preventable through the following
simple measures.
First and foremost, the mother herself is a source of
warmth for the baby. It is of immense help to nurse the
baby next to the mother, in between the breasts over the
chest, in Kangaroo positioin, day and night. Further, the
room where an LBW baby is nursed should be kept warm
(temperature between 28oC to 30oC in all weathers). This
Newborn Care 67
temperature is slightly uncomfortable for adults, but this
discomfort should be accepted for the sake of the baby.
While in summer months no extra effort is required to
maintain this temperature, in winter a room heater or
any other warming device may have to be used. The baby
should be clothed well. Two or three layers of clothes
are generally required. If the room is not warm enough,
woollen sweater should also be put on. Feet should be
covered with socks, hands with mittens and head with a
cap. Besides, a blanket should be used to cover the baby.
The temperature regulation of the baby is satisfactory
when the trunk feels warm to touch, while the soles and
the palms are pink and warm. In early stages of
hypothermia, the trunk is warm, but the soles and palms
are cold to touch. This is not normal and baby requires
additional warmth immediately to prevent cold stress
and its adverse consequences.
In the hospital apart from the above methods,
overhead radiant warmer or incubator may be used to
keep the baby warm. Regular monitoring of axillary or
skin temperature with a low-reading thermometer (30oC-
40oC) should be carried out in all the hospitalized babies.
Nutrition and Fluids
Birth weight, gestation, presence or absence of sickness
and individual feeding effort of the baby determine the
decision as to how a LBW neonate be provided with
fluids and nutrition (Table 3.5.1). Ultimate goal is to meet
both these needs from direct and exclusive breastfeeding.
Neonates weighing less than 1200 g or a gestation of
less than 30 weeks, or those having sickness should
receive IV fluids initially. Enteral feeds should be intro-
duced gradually by gavage as the baby’s acute problems
begin to settle. In due course, the baby is shifted to katori-
spoon feeds, and then the direct breastfeeds.
Infants weighing 1200 to 1800 g (or 30–34 weeks
gestation) and not having any significant illness should
be put on gavage feeds initially. In a couple of days, it
should be possible to shift them to katori-spoon feeds, and
then gradually to breastfeeds.
In order to promote lactation and enable the baby to
learn sucking, all babies on gavage or katori-spoon feeds
should be put on the breast before each feed for 5 to 10
minutes. With improvement in their overall condition,
the infants would start meeting a part and, later on all of
their nutritional needs from direct breastfeeding. Breast
milk is the best milk for a LBW baby.
68 IAP Textbook of Pediatrics

TABLE 3.5.1: Guidelines for the modes to provide fluids and until breast milk feeding can be ensured. Any formula
nutrients to LBW babies providing (per dl) about 2 g protein (whey-dominant),
Age Categories of neonates 4.0 g fat (containing polyunsaturated fatty acids and
medium chain triglycerides), and 10 to 12 g of carbo-
Birth weight <1200 gm 1200-1800 >1800
hydrate (as lactose and maltodextrins) and 70 to 80
Gestation <30 weeks 30-34 weeks > 34 weeks
kilocalories is quite suitable. If it is not possible to afford
Initial Intravenous Gavage a formula milk, any milk obtained for household use may
fluids. Try Breast- be fed to the baby without dilution.
gavage feeds feeding.
if not sick If unsatis-
It is emphasized that the decision to feed a substitute
factory give milk other than breast milk is a very major decision and
katori-spoon must not be taken lightly. Only when all avenues for
feeds obtaining breast milk are exhausted, should one resort
After 1–3 days Gavage Katori-spoon Breast to this choice as an interim and unavoidable choice.
Later (2–4 weeks) Katori-spoon Breast Breast
Amount and Frequency of Enteral Feeds
After some more Breast Breast Breast
time (4–6 weeks) For infants on gavage or katori-spoon feeds, total daily
Note: requirements can be estimated from the table on the fluid
1. For gavage and katori-spoon feeds, use expressed breast requirements (Table 3.5.2). In a stable, growing LBW baby
milk only. Start with small volume, and gradually build- daily intake of feeds should be gradually built up to 180
up. to 200 ml/kg. LBW babies should be fed every 2 hours
2. When the baby is on gavage or katori-spoon feeds, it is
starting at 2 hours of age. Two hourly feeds are also
important that he is put on the breast before every feed.
Although the baby may not obtain much milk, it will help applicable to LBW receiving direct breastfeeding. LBW
promote lactation and enable the baby to learn how to babies may take longer on the breast as compared to their
suck. normal weight counterparts.
3. When shifting a baby from one mode of feeding to
another, be very careful. Introduce the new mode for only
TABLE 3.5.2: Fluid requirements of neonates
some of the feeds to begin with and then build-up
(ml per kg body weight)
gradually.
4. The feeding of every baby should be individualized. The Day of life Birth weight
above recommendations should only serve as broad
>1500 g 1000 to 1500 g <1000 g
guidelines.
1 60 80 100
2 75 95 115
Most LBW babies weighing more than 1800 g or over
3 90 110 130
34 weeks of gestation are able to feed directly from the
4 105 125 145
breast. However, some of them may not be able to do so
satisfactorily during the first few days of life. During this 5 120 140 160
period, the feeds may be provided with a katori-spoon. 6 135 155 175
Breast milk is the ideal food for a LBW baby. It is 7 onwards 150 170 190
well to remember that the breast milk of the mother of Note:
the LBW baby contains appropriately higher content of 1. On the first day the fluid requirements range from 60 to
protein and calories and is uniquely suited to provide 100 ml/kg, (the difference between the three categories
near optimum nutrition to her LBW baby. The milk is being 20 ml/kg each).
2. The daily increment in all groups is around 15 ml per kg till
thus not only species specific, it is baby specific. If lact-
day 7.
ation is inadequate in spite of best efforts, the baby should 3. Extra 20 to 30 ml/kg fluid should be added for infants
be carefully evaluated for supplementary feeding with nursed under a radiant warmer. For those receiving
top milk. Feeding with a substitute milk other than breast phototherapy add extra 10 to 15 ml/kg fluid.
milk should be reserved essentially for the hospitalized 4. These are general guidelines, fluid therapy of every baby
babies and resorted to for the minimum necessary period should be individualized.

Technique of Feeding
Gavage feeds For gavage feeding, Fr 5 polythene feeding
catheter is used for nasogastric or orogastric placement.
For nasogastric insertion, the catheter is measured from
the external nares to the tragus of the ear, and from there
to the ansiform cartilage, and marked. This length of the
tube should be inserted through the nose. For the
orogastric catheter the distance between angle of the
mouth to tragus and then to the ansiform cartilage is used
for insertion. During nasogastric or orogastric insertion,
the head is slightly raised and a wet (not lubricated)
catheter is gently passed through the nose (nasogastric)
or mouth (orogastric) down through the esophagus to
the stomach. Its position is verified by aspirating the
gastric contents, and by injecting air and auscultating
over the epigastric region. At the time of feeding, the
outer end of the tube is attached to a 10 or 20 ml syringe
(without plunger) and milk is allowed to trickle by
gravity. At the end, about 2 ml of sterile water should be
injected to rinse the tube. The baby should be placed in
the right lateral position for 15 to 20 minutes to avoid
regurgitation. There is no need to burp a gavage-fed baby.
The polythene nasogastric or orogastric tube may be
inserted before every feed or left in situ for 2 to 3 days.
While pulling out a feeding tube, it must be kept pinched
and pulled out gently while applying constant negative
pressure with a syringe to avoid trickling of gastric
contents into the trachea.
Gavage feeding may be risky in very small babies.
They have a small capacity of stomach and the gut may
not be ready to tolerate feeds. Stasis may also result from
paralytic ileus due to autonomic immaturity. Thus,
gavage-fed preterm babies are candidates for regurgi-
tation, aspiration and necrotizing enterocolitis (NEC).
Before every feed, the abdominal girth (just above the
umbilical stump) should be measured. If the abdominal
girth increases by more than 2 cm from the baseline, the
baby should be evaluated carefully for any illness. The
enteral feeds may have to be suspended till the
abdominal distention improves.
Katori-spoon feeds Feeding with a spoon (or a similar
device such as paladai') and katori (or any other recep-
tacle such as a cup) has been found to be safe in LBW
babies. This mode of feeding is a bridge between gavage
feeding and direct breastfeeding. It is based on the
premise that neonates with a gestation of 30 to 32 weeks
or more are in a position to swallow the feeds satis-
Newborn Care 69
factorily even though they may not have coordinated
sucking efforts. The required amount of expressed breast
milk is taken in a katori. The baby is placed in a semi-
upright posture with a napkin around the neck to mop
up the spillage. The spoon is filled with milk, a little short
of the brim, placed at the lips of the baby in the corner of
mouth. The baby will actively swallow the milk. The
process is repeated till the required amount has been fed.
With paladai the tapering snout is placed at the angle of
the mouth and milk is allowed to be trickled gradually
as the baby swallows it.
If the baby does not actively accept and swallow the
feed, try to arouse the baby with a gentle stimulation. If
he or she is still sluggish, do not insist on this method. It
is better to switch back to gavage feeds till the baby is
better prepared.
Breastfeeding The method of breastfeeding is essentially
the same as for the normal weight babies. LBW babies
may be slow in sucking and take longer time to feed.
Assessment of Adequacy of Nutrition
The key measure of optimal feeding is the weight pattern
of the baby. A LBW baby loses up to 1 to 2 percent weight
everyday amounting to 10 to 15 percent cumulative
weight loss during the first week of life. Birth weight is
regained between 10th and 14th day. All babies start
gaining weight by the second week of life at a rate of
about 15 to 20 g per day (1–2% of birth weight). It is
important to note that the SFD-LBW babies who are
otherwise healthy should not have any appreciable
weight loss at all, and they should start gaining weight
early. It is desirable to weigh all LBW babies at the
postnatal age of 2 weeks (to check regaining of the birth
weight), 4 weeks (to ascertain a weight gain of at least
200–300 g) and then every month. Hospitalized LBW
babies should be weighed everyday on an accurate
weighing scale.
Excessive weight loss, delay in regaining birth weight
and poor weight gain are suggestive of inadequate
feeding, cold stress, excessive insensible water loss or
systemic illness (like anemia, sepsis, late metabolic
acidosis, etc.).
Nutritional Supplements
All LBW babies should receive intramuscular vitamin K
1.0 mg at birth. Vitamin A and D are required in doses of
1000 IU and 400 IU everyday, respectively, from 2 weeks
70 IAP Textbook of Pediatrics

of age. At 8 weeks of age, iron supplements should be
started in a dose of 2 mg/kg/day. Very low birth babies
(<1500 g, <32-wk gestation) need vitamin E, calcium and
phosphorus supplementation till 37 weeks.
Early Detection of Sickness and
Management of Complications
The cornerstone of care of the newborn infants, more so
for the LBW babies, is anticipation and early detection
of complications. This is achieved by careful monitoring
of the babies. Clinical monitoring is the most important
and practical method. It involves periodic evaluation for
signs of illness. These include lethargy, refusal to feed,
hypothermia, respiratory distress, grunt, apnea,
abnormal weight gain pattern, jaundice over soles and
palms, abdominal distention, feed intolerance, cyanosis,
pallor, sclerema, seizures and bleeding. A baby who
shows anyone or more of the above signs/symptoms
should be immediately referred for hospitalization for
prompt management of the specific complications by a
neonatologist.
written note covering the antenatal, intranatal and
neonatal details along with the baby.
Prognosis
Mortality of LBW babies is inversely related to the
gestation and birth weight, and directly to the severity
of illness and complications. Because of functional
immaturity of various body organs, the preterm babies
do rather poorly than the corresponding weight SFD
babies in the immediate neonatal period. Adequacy of
management at birth also makes a major difference. The
LBW who experiences significant birth asphyxia or
develops hypothermia soon afterbirth is seriously
compromised, no matter what heroic measures are insti-
tuted later on.
Long-term outcome of LBW infant depends upon ges-
tation, birth weight and nature and severity of compli-
cations. In general, over 90 percent of LBW babies who
survive the newborn period have no neurodevelop-
mental handicaps. Optimal and effective care of the LBW
neonates is thus a highly rewarding experience.

Vaccination of LBW Babies BIBLIOGRAPHY

If the LBW baby is not sick, the vaccination schedule is 1.
the same as for the normal babies. BCG, OPV and HBV
should be given at the time of discharge.
2.
Transport of a Sick LBW Baby 3.
It is essential to provide warmth during transport to
prevent cold injury. The baby should be clothed and 4.
placed in a prewarmed basket or box, but a transport
incubator is ideal. Hot water rubber bottles may be used
as heat source. However, make sure to cap them tightly 5.
and wrap 2 layers of towel to avoid direct contact with
the baby. Mother of the baby should also be transferred
6.
to the hospital along with the baby as far as possible.
This will allay her anxiety and ensure breast milk feeding
of the baby. Placing the baby next to mother's body 7.
during transport will provide the necessary warmth to
the child during the journey. 8.
The infant should be stabilized before transport as 9.
far as possible. A doctor or nurse should accompany the
baby, if possible. The referring doctor should send a
American Academy of Pediatrics. Committee on
Nutrition. Nutritional needs of low birth weight infants.
Pediatrics 1985;75:76.
American Academy of Pediatrics. Pediatric Nutrition
Handbook 1993.
Arora NK, Paul VK, Singh M. Morbidity and mortality
in term infants with intrauterine growth retardation. J
Trop Pediatr 1987;33:186.
Jeeva Sankar M, Agarwal R, Mishra S, Deorari AK, Paul
VK. Feeding of low birth weight infants. Indian J Ped
2008;75:459-69.
Singh M. Disorders of weight and gestation. Care of
the Newborn. Sagar Publications: New Delhi 1991;112-
25.
Singh S, Singh M: Birth weight to birth weight—
postnatal weight pattern of preterm infants. Indian J
Pediatr 1979;46:223.
Tsang RC, Lucas A, Uauy R, et al. Nutrition Needs of
the Preterm Infant Williams and Williams: London 1993.
Tsang RC, Nichols BL. Nutrition During Infancy Hanley
and Belfus: St Louis 1997.
World Health Organization. Kangaroo mother care: a
practical guide, Department of reproductive Health and
Research, WHO, Geneva 2003.

3.6 Common Diseases of Newborn Babies
Meharban Singh, Vinod K Paul, Ashok K Deorari
A large majority of newborn babies do not develop any
serious difficulties and they need level I or minimal
newborn care which can be provided by the mother
under the supervision of a nurse. High-risk mothers are
likely to give birth to preterm or low birth weight (LBW)
babies which are prone to suffer from a number of
disorders. Common causes of morbidity in newborn
babies include respiratory distress syndrome (RDS),
septicemia and hyperbilirubinemia. These disorders
affect 10 to 12 percent of neonates in our institution. Most
neonatal disorders and deaths are limited to preterm and
LBW babies.
Respiratory Distress Syndrome
Respiratory difficulties are encountered in 5 to 7 percent
of newborn babies, while pulmonary pathology is the
most frequent autopsy finding in the neonates. The
clinical diagnosis of respiratory distress is suspected
when the respiratory rate is more than 60 per minute in
a quiet resting baby, and there are either inspiratory costal
recessions or expiratory grunt.
Causes
The common causes of RDS in newborn babies include
pneumonia, meconium aspiration syndrome, transient
tachypnea of the newborn, hyaline membrane disease
(HMD) and congenital malformations of respiratory and
cardiovascular systems. The infant should be assessed
for degree of distress, severity of intercostal recessions,
cyanosis, activity or alertness, nature of cry, feeding
behavior and status of peripheral circulation.
Meconium Aspiration Syndrome (MAS)
Meconium is passed in utero by 10 to 15 percent of infants,
and it suggests that the fetus may have suffered from an
asphyxial episode. The baby may be asphyxiated at birth
and may be covered with meconium. The yellow staining
of the cord, skin and nails suggests that the baby had
been soaked in meconium for several hours. The presence
of thick particulate matter (pea-souped appearance of
amniotic fluid) is associated with increased risk of MAS.
Newborn Care 71
When management of the meconium-stained baby
is unsatisfactory at birth, there is a potential risk of
development of MAS. The baby is often asphyxiated at
birth and develops progressive respiratory distress soon
afterbirth. There is marked inspiratory intercostal
recessions and expiratory grunt. The chest may be over-
inflated or barrel-shaped due to obstructive emphysema.
The chest radiogaph shows bilateral coarse, irregular
densities with patches of obstructive emphysema. The
management is mostly supportive by maintaining
thermoneutral environment, adequate hydration and
oxygenation. There is no therapeutic utility of either
routine antibiotics or corticosteroids. All efforts should
be made to prevent morbidity due to MAS by avoiding
delay in the delivery of such babies and by ensuring
prompt and effective endotracheal suction of nonvigrous
baby at birth.
Transient Tachypnea of the Newborn (TTNB)
Transient tachypnea of the newborn (TTNB) is charac-
terized by the development of rapid shallow breathing
in a baby at birth or few hours later. The condition is
more common in term babies born by cesarean section.
The respiratory rate may vary from 60 to 100 per minute
while intercostal recessions are either absent or minimal.
The baby remains alert and active and maintains good
color. The condition occurs due to failure of drainage of
amniotic fluid through the lymphatics leading to reduced
lung compliance. A skiagram of the chest shows linear
streakings at both hila due to dilated lymphatics and
presence of fluid in the interlobar fissure. The condition
resolves spontaneously without any specific therapy
within two to three days of life. Some infants may require
administration of 40 percent oxygen to maintain good
color.
Hyaline Membrane Disease
(Idiopathic Respiratory Distress Syndrome)
Hyaline membrane disease (HMD) is the most common
cause of respiratory morbidity in preterm babies. It affects
10 to 15 percent of preterm babies in India though its
72 IAP Textbook of Pediatrics
incidence is relatively higher in the West. The condition
occurs due to a lack of pulmonary surfactant because of
the immaturity of the lungs. When surface-active
material is deficient in the alveoli, there is alveolar
collapse during expiration. Apart from prematurity, the
production of surfactant may be compromised by
damage to type II alveolar cells due to birth asphyxia,
acidosis, hypothermia, antepartum hemorrhage and
shock. Infants delivered by emergency cesarean section
are predisposed to develop HMD due to greater chances
of perinatal hypoxia.
The pulmonary immaturity of the fetal lungs can be
assessed by determination of lecithin/sphingomyelin
ratio in the amniotic fluid. Lecithin/sphingomyelin
(L/S) ratio of 2 or more is suggestive of adequate lung
maturity, while a ratio of less than 1.5 is often associated
with HMD. Amniotic fluid “shake test” is a simple
bedside test for assessment of lung maturity. Estimation
of phosphotidyl glycerol is a more specific indicator of
lung maturity (especially in diabetic mothers), and its
absence is invariably associated with development of
HMD.
Clinical Features
Hyaline membrane disease is characterized by a triad of
tachypnea, expiratory grunt and inspiratory retractions
in a prematurely born asphyxiated infant. The symptoms
may begin at birth or within 6 hours of delivery. There is
gradual worsening of retractions, grunting and cyanosis.
During the next 24 to 48 hours, the course of disease is
relentlessly progressive and may be complicated by
patent ductus arteriosus (PDA). A gastric aspirate shake
test is usually negative. The skiagram of the chest shows
the air bronchogram extending beyond the left cardiac
border followed by diffuse opaque appearance due to
solid lungs.
Management
Premature labor should be arrested by appropriate
tocolytic therapy to gain pulmonary maturity. The
induction of labor should be delayed as far as possible
till pulmonary maturity is confirmed by the results of
amniotic fluid L/S ratio or level of phosphatidyl glycerol.
When premature labor below 34 weeks of gestation is
unavoidable, the mother should be administered
betamethasone 12 mg IM every 24 hours for two doses
or dexamethasone 6 mg intramuscularly four doses at
an interval of every 12 hours.
The infant should be nursed in a thermoneutral
environment and administered oxygen through a head
box. An intravenous line should be established to
maintain fluid and electrolyte balance, for the correction
of acidosis and administration of drugs. Intratracheal
administration of synthetic surfactant is associated with
improved survival and reduced risk of complications.
Arterial oxygen saturation should be monitored with the
help of a pulse oximeter. When arterial oxygen saturation
cannot be maintained above 90 percent despite provi-
ding oxygen in the head box at a concentration of
40 percent, the infant should be provided continuous
positive airway pressure (CPAP) through silastic nasal
prongs. When CPAP is also ineffective to maintain
adequate oxygenation, the baby is managed by inter-
mittent positive-pressure ventilation (IPPV). The acid-
base parameters and blood gases should be monitored
frequently to correct acidosis and hypoxia or hyperoxia.
Unmonitored high concentrations of oxygen in preterm
babies may lead to retinopathy of prematurity (ROP) due
to oxygen toxicity. Antibiotics are administered
whenever there is suspicion of superadded bacterial
infection. The management of HMD demands excellent
supportive care by trained nurses and the availability of
high technology to monitor and manage the hypoxia due
to ineffective ventilation. The case fatality rate due to
HMD is related to the quality of neonatal care and varies
between 25 and 50 percent.
Congenital Malformations
Respiratory distress in the newborn may occur due to a
number of congenital malformations of pulmonary
system or due to congestive heart failure because of
congenital heart disease. The common respiratory
malformations include choanal atresia, Pierre Robin
syndrome, esophageal atresia with tracheoesophageal
fistula, diaphragmatic hernia and vascular rings.
Congenital and postnatal pneumonia is an important
cause of RDS and is discussed under neonatal sepsis.
Neonatal Sepsis
(Septicemia, Pneumonia and Meningitis)
Systemic bacterial infections of newborn infants are
termed neonatal sepsis. This is a generic term which
incorporates neonatal septicemia, pneumonia, meningitis
and urinary tract infections which may manifest clinically
in isolation or in different combinations. They are the
most common cause of neonatal deaths in India. Low

birth weight is an important underlying condition. In
neonatal septicemia, the infant has overwhelming
bacteremia with poor localization of infection into any
particular organ system. The clinical manifestations are
characteristic albeit nonspecific. Pneumonia manifests as
respiratory distress. Meningitis is often silent clinically
with a clinical picture dominated by manifestations of
associated septicemia. Appearance of excessive high-
pitched crying, fever, seizures, blank look and bulging
anterior fontanelle are suggestive of meningitis.
Neonatal sepsis can be divided into two subtypes
depending upon whether the onset of symptoms is
during the first 72 hours of life or later. Early-onset infec-
tions are caused by organisms prevalent in the genital
tract or in the labor room and maternity operation theater.
It often manifests as pneumonia causing respiratory
distress. The predisposing factors for early-onset sepsis/
pneumonia include prolonged premature rupture of
membranes (PPROM), foul smelling liquor, multiple per
vaginal examinations, maternal fever, difficult or
prolonged labor and aspiration of meconium.
Late-onset septicemia is caused by the organisms
thriving in the external environments of homes or
hospitals. The infection is often transmitted through the
hands of the care providers. The onset of symptoms is
usually delayed beyond 72 hours afterbirth and the
presentation is that of septicemia, pneumonia or
meningitis. The predisposing causes of late-onset sepsis
include: lack of breast milk feeds, superficial infections
(pyoderma, umbilical sepsis), aspiration of feeds,
disruption of skin integrity with needle pricks and use
of intravenous fluids. These factors enhance the chances
of entry of organisms into the body systems of neonates
who are much less immunocompetent as compared to
older children and adults. The common organisms
responsible for neonatal septicemia and pneumonia
include Escherichia coli and Staphylococcus epidermidis and
S. aureus. In hospitals Klebsiella pneumoniae is an important
etiological agent.
Clinical Features
The newborn baby has a limited ability to respond to a
number of insults resulting in identical stereotyped
manifestations due to a variety of conditions. The mani-
festations of neonatal septicemia are often vague and
nonspecific demanding high index of suspicion for its
early diagnosis. Any alteration in the established feeding
behavior is the most characteristic early feature. The baby
Newborn Care 73
who had been active and sucking normally, gradually
or suddenly becomes lethargic, inactive, unresponsive
and refuses to suck. The infant may appear pale with
grayish circumoral cyanosis and a vacant look. Hypo-
thermia is a common manifestation of septicemia in
preterm babies, while term babies may manifest with
fever, especially in association with gram-positive infec-
tions and meningitis. Diarrhea, vomiting and abdominal
distention may occur. Jaundice and hepatosplenomegaly
may be present. Episodes of apneic spells with cyanosis
may be the sole manifestation of septicemia in preterm
babies.
The additional localizing features may appear depen-
ding upon the spread of infection to different systems
and organs of the baby. The clinical manifestations of
pneumonia include tachypnea, chest retractions, grunt-
ing, cyanosis and apneic spells in addition to inactivity
and poor feeding. Cough is unusual. Findings on auscul-
tation of chest are nonspecific and noncontributory.
Diagnosis
Septic screening should be done to support the clinical
suspicion of infection before the institution of specific
antibacterial therapy. The reliable markers of neonatal
septicemia include leukopenia (less than 5000 per cu
mm), elevated band neutrophils (more than 20%), raised
micro-ESR (more than 15 mm) and positive C-reactive
protein (more than 8 mg per ml). Blood culture and CSF
examination are mandatory before initiating specific
antibacterial therapy. A skiagram of the chest should be
taken in all cases. It may show scattered or localized
opacities suggestive of patchy consolidation. Blood
should be examined for glucose, bilirubin, urea and
electrolytes. In all infants born following PPROM (more
than 24 hours) or those developing respiratory distress
soon after-birth, gastric aspirate should be collected in a
heparinized tube and examined under the microscope
after staining with Leishman's stain. The presence of
more than 5 neutrophils per high power field or when
their number exceeds three times the number of the
epithelial cells, is suggestive of intrauterine or congenital
pneumonia. A bacterial culture should be obtained from
liquor amnii (or cervical swab), gastric aspirate, throat,
umbilical stump and blood.
Management
The infant should be managed in a thermoneutral
environment and started on intravenous infusion.
74 IAP Textbook of Pediatrics
Hypoglycemia, anemia and shock should be appro-
priately managed. Fresh blood or fresh frozen plasma is
useful to improve defense mechanisms by providing
opsonins, complement and polymorphonuclear leuko-
cytes. Specific antibacterial therapy should be instituted
through intravenous route. The choice of antibiotics
depends upon the prevalence of bacterial flora and their
sensitivity pattern against available antibiotics. In a
community-acquired neonatal septicemia, a combination
of ampicillin or benzyl penicillin with gentamicin is
appropriate. In hospital-acquired neonatal septicemia,
the logical initial choice would be a combination of
cloxacillin with aminoglycoside such as gentamicin or
amikacin. When response to this antibiotic combination
is unsatisfactory or there is an associated meningitis,
ampicillin is substituted by a third generation cephalo-
sporin such as cefotaxime. When the etiologic agent is
identified, the antibacterial therapy can be made highly
specific. For instance, septicemia due to Pseudomonas
aeruginosa is best managed by ceftazidime or piperacillin
and in resistant staphylococcal infection, amoxycillin
with clavulinic acid or vancomycin may be considered.
Listeriosis is best managed with ampicillin.
Exchange blood transfusion is recommended in
critically sick neonates having sclerema, disseminated
intravascular coagulopathy (DIC) or hyperbilirubinemia.
There is no role of intravenous immunoglobulins in
neonatal sepsis. The prognosis depends upon the weight
and maturity of the infant, nature of the etiologic agent
and quality of specific and supportive therapy. The
presence of underlying congenital malformations like
meningomyelocele, tracheoesophageal fistula and
surgical procedure adversely affect the outcome. The
reported case fatality rates due to neonatal septicemia in
various studies from India range between 15 and 20
percent. Therefore, it is essential that all efforts should
be made to prevent the occurrence of bacterial infections
in newborn babies by adopting strict aseptic rituals and
routines.
Prevention of Infections
Newborn babies especially those prematurely born are
at an increased risk of developing bacterial infections and
despite aggressive management septicemia has a high
case fatality rate. It is far more cost-effective to prevent
nosocomial infections rather than to treat them with
expensive antibiotics and high quality supportive care.
The following protocols for prevention of infections
should be strictly followed in the nursery.
1. Handwashing and thorough scrubbing with soap and
water up to elbows for at least 2 minutes, gowning
and change of shoes are mandatory before entry to
the nursery. Rings, bangles and wristwatch should
be removed before hand-washing. Strict and
obsessive handwashing (for 20 seconds) and use of
antiseptic lotion in-between handling of babies
should be ensured. The hands should be dried with
either a disposable paper napkin (or reusable
autoclaved minitowel) or hand dryer.
2. Babies should be fed early and exclusively with
expressed breast milk (or breastfeed) without any
prelacteal feeds. Careful attention should be paid to
the hygiene of the katori and spoon. The use of a
feeding bottle and pacifier are condemned.
3. The umbilical stump should be left open. Local
application of triple dye or spirit reduces coloniza-
tion.
4. All procedures in the nursery should be performed
after wearing mask and gloves. Unnecessary invasive
interventions such as needle pricks and setting up of
intravenous lines should be kept to the barest
minimum. The use of stock solution of heparinized
saline for rinsing of intravenous lines is a dangerous
practice and should be replaced by flushing with a
single-use normal saline ampule. There should be no
compromise in the use of disposables. Barrier nursing
should be ensured.
5. Strict housekeeping routines for washing, dis-
infection, cleaning of cots/incubators, etc. should be
ensured, and these policy guidelines should be
available in the form of a manual in the nursery.
6. The use of prophylactic antibiotics for prevention of
nosocomial infections is strongly condemned. They
are not only useless but dangerous due to the
potential risk of emergence of resistant strains of
bacteria.
Neonatal Jaundice
Jaundice is a relatively common physical abnormality in
a newborn baby during the first week of life. Clinical
jaundice manifests as yellowness of the skin of the face
when the serum bilirubin level exceeds 5 mg/dl. As the
degree of jaundice increases, there is a cephalopedal
progression of yellowness of the skin. When the trunk of
the baby is distinctly yellow stained, the serum bilirubin
level is likely to range between 10 and 15 mg/dl. The
yellow staining of the palms and soles is ominous and
indicates that the serum bilirubin level has exceeded

TABLE 3.6.1: Causes of pathological jaundice
1. Idiopathic
2. Prematurity
3. ABO-incompatibility (ABO-HDN*)
4. Rh-isoimmunization (Rh-HDN*)
5. G-6-PD deficiency
6. Septicemia
7. Breast milk jaundice
8. Hypothyroidism
9. Neonatal hepatitis (intrauterine infections)
10. Metabolic disorders
* HDN—Hemolytic disease of the newborn
15 mg/dl. All newborn babies must be examined twice
a day during the first week of life to assess the onset,
severity and age of disappearance of jaundice.
Causes of Jaundice
The important causes of pathological jaundice in
newborn babies are given in Table 3.6.1. About 5 per-
cent of newborn babies develop pathological jaundice
or hyperbilirubinemia. The onset of jaundice within 24
hours of age, its marked intensity as evidenced by yellow
staining of the palms and soles and its persistence beyond
two weeks of age are suggestive of pathological jaundice.
Investigations should be performed to identify possible
cause of pathological jaundice and appropriately
managed.
Physiological Jaundice
About 60 to 70 percent of healthy newborn babies are
likely to develop physiological jaundice which may cause
undue anxiety to the parents. Physiological jaundice
appears between 24 and 72 hours of age, its maximum
intensity is seen on the 4th to 5th days of life, and the
peak serum bilirubin level does not exceed 15 mg/dl.
This type of jaundice usually disappears before 14 days
of life and does not need any specific therapy. In preterm
babies, the peak of physiological jaundice is seen a little
later, and peak bilirubin level may be higher and jaundice
takes relatively longer time to disappear. The diagnosis
of physiological jaundice cannot be made by examining
the baby at one point of time because it depends upon a
characteristic time table of jaundice, taking into
consideration the time of onset of jaundice, maximal
Newborn Care 75
limits of intensity and age of disappearance besides the
exclusion of pathologic causes. Physiological jaundice
occurs due to relative polycythemia with reduced
lifespan of neonatal red blood cells, hepatic immaturity
(regarding uptake, conjugation and excretion of bilirubin)
and exaggerated enterohepatic circulation of bilirubin.
The mother must be reassured regarding the benign
nature of physiological jaundice and her fears regarding
infection or hepatitis should be allayed. She should be
advised to breastfeed the baby frequently, but there is
no need to advise extra glucose water.
Hemolytic Disease of the Newborn (HDN)
Hemolytic disease of the newborn (HDN) due to blood
group incompatibility between the mother and fetus is
the most common cause of hyperbilirubinemia in the
newborn baby. The incompatibility may exist among
Rhesus, ABO or minor blood group systems.
Rhesus Hemolytic Disease of
the Newborn (Rh-HDN)
When an Rh-negative mother is carrying an Rh-positive
fetus, the passage of fetal red blood cells into the maternal
circulation may invoke an antibody response by the
maternal immunological system. Enough anti-D
antibodies are not produced during the first pregnancy,
but each subsequent pregnancy with Rh-positive fetus
leads to increasing antibody production. The Rh-
sensitization of the other may also occur by amnio-
centesis, external version, abortion and stillbirths. The
anti-D antibodies being IgG in type, they readily
crossover to the fetus through the placenta and destroy
D-positive fetal red blood cells. The Rh isoimmunization
can be suspected during antenatal period by identifying
the blood group of the mother and estimating the titer of
anti-D antibodies by indirect Coombs’ test.
There is a wide spectrum of clinical manifestations
of erythroblastosis due to Rh-HDN, ranging from a
normal baby to a stillborn baby with hydrops fetalis.
There is increasing severity of the disease with each
subsequent pregnancy. The newborn baby may be
anemic at birth and has hepatosplenomegaly. Jaundice
usually appears within 24 hours of age and rapidly
increases in intensity. In a severely affected baby, the
clinical picture is characterized by severe anemia, gross
hepatosplenomegaly and generalized anasarca (hydrops
fetalis), and the baby may die in utero.
76 IAP Textbook of Pediatrics
If the mother is Rh-negative, cord blood should be
collected for Rh and ABO typing, direct Coombs’ test,
hemoglobin, reticulocyte count, peripheral blood smear
and serum bilirubin. The positive direct Coombs’ test in
a Rh-positive baby clinches the diagnosis of Rh-HDN.
In the affected baby, the serum bilirubin should be
monitored every 6 to 12 hours depending upon the rate
of rise of bilirubin.
Rhesus isoimmunization can be effectively pre-
vented by prophylactic administration of anti-D imm-
unoglobulins in an unsensitized Rh-negative woman
within 72 hours of delivery in the following situations:
1. Delivery of an Rh-positive baby
2. Abortion or stillbirth of Rh-positive conception
3. Following procedures having increased risk of
fetomaternal hemorrhage such as amniocentesis and
external version.
The dose of anti-D immunoglobulin varies. The anti-
D immunoglobulin should only be given to the mother
whose indirect Coombs' test is negative.
ABO Hemolytic Disease of the Newborn (ABO-HDN)
The ABO hemolytic disease of the newborn usually
occurs when mother is O group and her baby is either A
or B group. Fetomaternal ABO incompatibility exists in
about 25 percent of pregnancies, but the hemolytic
disease develops in only 10 percent of these incompa-
tible neonates. Unlike Rh-HDN, the history of increasing
severity of disease in subsequent pregnancies is generally
not present in ABO-HDN.
The diagnosis of ABO-HDN is suspected by early
onset of jaundice in A or B group baby of an O group
mother. The ABO-HDN is a relatively milder disease as
compared to Rh-HDN. The anemia is usually absent or
mild, and there may be mild hepatosplenomegaly. The
direct Coombs’ test is usually negative or weakly positive.
Blood examination may show reticulocytosis, micro-
spherocytosis and increased fragility of red blood cells.
The diagnosis is confirmed by the demonstration of high
titer of IgG hemolysins in maternal blood against the
baby's blood group.
Septicemia
Jaundice is an important manifestation of bacterial infec-
tion in newborn babies and occurs due to hemolysis and
hepatitis. The clinical picture is usually dominated by
systemic features of septicemia and the occurrence of
jaundice after the age of three days. The direct reacting
or conjugated bilirubin is often elevated to 2.0 mg/dl or
more, and jaundice often persists beyond 14 days of life.
Glucose-6-PhosphateDehydrogenase Deficiency
The incidence of G-6-PD deficiency varies between 5 and
20 percent among different ethnic groups in India.
Deficiency is limited to male babies as the condition is
inherited as X-linked recessive. The hemolysis may occur
spontaneously or following exposure to certain drugs
and infections. The clinical picture is characterized by
the sudden and dramatic appearance of unconjugated
hyperbilirubinemia requiring exchange blood trans-
fusion.
Persistent Neonatal Jaundice
Neonatal jaundice whether physiological or pathological,
usually disappears by 2 weeks of age. The important
causes of persistent neonatal jaundice are illustrated in
Table 3.6.2. Hyperbilirubinemia may be predominantly
unconjugated or there may be significant elevation of
direct reacting or conjugated bilirubin. The elevation of
conjugated bilirubin is usually characterized by clay
colored stools, and high colored urine staining the
napkins. It must be remembered that most conditions
producing hyperbilirubinemia during the first week of
life are associated with the elevation of unconjugated
bilirubin. Despite deep jaundice, the urine in such babies
is normal colored and does not contain any bile pigments
or urobilin.
TABLE 3.6.2: Causes of persistent neonatal jaundice
Unconjugated hyperbilirubinemia
1. Breast milk jaundice
2. Hypothyroidism
3. Crigler-Najjar syndrome
4. Intestinal obstruction or stasis
5. Ongoing hemolysis (Rh, ABO)
Conjugated hyperbilirubinemia (cholestasis)
1. Neonatal hepatitis
2. Extrahepatic biliary atresia
3. Inborn errors of metabolism
4. Total parenteral nutrition
 Newborn Care 77

Pathogenesis of Kernicterus preparation of vitamin K in high doses is known to

aggravate hemolysis and may predispose to the
Jaundice in a newborn baby is a serious condition because
development of kernicterus. Administration of pheno-
unconjugated hyperbilirubinemia may cause bilirubin
barbitone during the last week of pregnancy in an Rh-
encephalopathy or kernicterus. The occurrence of
isoimmunized mother or during first three days of life
kernicterus is related to complex interaction between the
in any infant suspected to have Rh-HDN and cephal-
level of unconjugated bilirubin which is lipid soluble,
hematoma may reduce the severity of jaundice by
gestational maturity of the infant and integrity of the
enhancing maturation of hepatic microsomal enzymes
blood-brain barrier. It is generally believed that
like Y-acceptor proteins and glucuronyl transferase in
unconjugated bilirubin level of more than 20 mg/dl due
the liver. Its therapeutic utility, howerver, is limited
to any cause may lead to kernicterus in a newborn baby.
especially in preterm babies. High dose intravenous
However, it is well-known that a preterm infant may
immunoglobulin (0.5-1.0 gm/kg) in Rh-iso-immunized
develop brain damage at a relatively lower serum
babies is known to decrease need of exchange blood
bilirubin level, while some term babies may tolerate
transfusion and duration of phototherapy.
serum bilirubin concentration of up to 30 mg/dl without
any kernicterus. Adequate levels of serum proteins are
Phototherapy
essential for effective binding of bilirubin to prevent its
leakage into the interstitial and intracellular compart- Phototherapy or exposure to light is known to cause
ments. When bilirubin binding sites in the albumin are photoisomerization of bilirubin to more polar, water-
blocked by other anions like hydrogen (acidosis), free soluble, harmless compounds which are readily excreted
fatty acids, (hypoglycemia and hypothermia) and certain in the bile, feces and urine. Phototherapy units with blue
drugs like salicylates, sulfonamides and sodium or white tubes or halogen lamps are useful for preventing
benzoate, kernicterus may occur at lower serum bilirubin rapid rise in serum bilirubin levels (Fig. 3.6.1). The naked
levels. Perinatal distress factors such as hypoxia, infant is exposed under phototherapy unit which is kept
hypothermia, hypoglycemia, acidosis, birth injury and at a distance of about 45 cm from the baby's skin. During
septicemia may damage the integrity of the blood-brain exposure to light, the eyes must be effectively shielded
barrier, and predispose the infant to develop bilirubin to prevent retinal damage. The position of the infant
encephalopathy at a relatively lower serum bilirubin should be changed frequently so that the maximal area
levels. of the skin is exposed to light. The infant is kept under
the light round-the-clock and taken out only for feeding
Management
Hyperbilirubinemia should be considered as a medical
emergency, and all attempts must be made to ensure that
serum bilirubin levels are kept within safe limits.
Exchange blood transfusion remains the most effective
and reliable method of lowering serum bilirubin when
it approaches critical levels. Other supportive measures
are useful to prevent excessive rise of serum bilirubin.

Supportive Measures
Early feeding and the maintenance of adequate hydration
are useful to prevent hyperbilirubinemia. Hypoxia,
hypothermia, hypoglycemia and acidosis should be
prevented and if they occur they should be promptly
managed. Septicemia should be treated with appropriate
Figure 3.6.1: Compact fluorescent light phototherapy units (top
antibiotics. When cephalhematoma is associated with both sides) and fibreoptic cold light below the baby for giving
critical hyperbilirubinemia, it should be aspirated or intense phototherapy for jaundice. Note eyes are effectively
drained. The administration of a water-soluble covered to prevent retinal damage
78 IAP Textbook of Pediatrics
or change of wet napkins. Most preterm babies are placed
under phototherapy when their serum bilirubin
approaches 10 to 12 mg/dl, and term babies are given
phototherapy when their serum bilirubin approaches
15 mg/dl. Appropriate charts are available which are
based on serum bilirubin levels, postnatal age of the
infant and birth weight of the child, to provide more
reliable indications for phototherapy and exchange blood
transfusion. During phototherapy the infant should be
closely watched for hydration status, temperature, degree
of jaundice and anemia by frequent blood examination.
Phototherapy is by and large safe but may produce loose
greenish stools, dehydration, hypothermia, or hyper-
thermia, and skin rash. During phototherapy, the clinical
evaluation of the severity of jaundice becomes unreliable
because the infant's skin gets bleached under light.
Exchange Blood Transfusion
If despite phototherapy and other supportive measures,
the bilirubin level is approaching 20 mg/dl, exchange
blood transfusion is mandatory to prevent brain damage.
The indications for exchange blood transfusion are listed
in Table 3.6.3. However, in an individual infant, the
decision for exchange blood transfusion should not be
based merely on the level of unconjugated serum
bilirubin but other important factors like gestational
maturity, postnatal age, presence or absence of perinatal
distress factors, and cause of jaundice should also be
taken into consideration. Double volume (160 ml/kg
blood) exchange blood transfusion is performed through
umbilical vein.
BIBLIOGRAPHY
1. Arya LS, Singh M. Gastric aspirate shake test as a
predictor of hyaline membrane disease. Indian J Med Res
1979;70:444.
2. Deorari AK, Chellani H, Carlin JB, Greenwood P, Prasad
MS, Satyavani A, et al. Clinico-epidemiological profile
and predictors of severe illness in young infants
(<60 days) reporting to a hospital in North India. Indian
Pediatrics 2007;44:739-48.
TABLE 3.6.3: Indications for exchange
blood transfusion
Early indications in infants with Rh-HDN
1. Cord hemoglobin of 10 g/dl or less
2. Cord bilirubin of 5 mg/dl or more
3. Unconjugated serum bilirubin of more than 10 mg/dl
within 24 hours or rate of rise of more than 0.5 mg/dl
per hour
Jaundice due to any cause
1. Exchange at lower bilirubin levels in the presence of
perinatal distress factors (Asphyxia, respiratory distress,
sepsis, hypothermia, etc.)
2. Unconjugated serum bilirubin of 20 mg/dl or more in a
term baby
3. In preterm babies, serum bilirubin of more than 1.0 mg/
100 g weight of the infant (i.e., 10 mg/dl for 1000 g and
15 mg/dl for 1500 g and so on)
3. Diamond I. Kernicterus. Revised concepts of patho-
genesis and management. Pediatrics 1966;38:539.
4. Gluck L, Kulovich HV, Borer RC, et al. Diagnosis of the
respiratory distress syndrome by amniocentesis. Am J
Obstet Gynecol 1997;109:440.
5. Gottstein R, Cooke RW. Systematic review of intravenous
immunoglobulin in hemolytic disease of the newborn.
Arch Dis Child Fetal Neonatal 2003;88:F6-F10.
6. Jeeva Sankar M, Agarwal R, Deorari AK, Paul VK. Sepsis
in the newborn. Indian J of Pediatrics 2008;76:261-66.
7. Kishore K, Deorari AK, Singh M, et al. Early-onset neo-
natal sepsis: Vertical transmission from maternal genital
tract. Indian Pediatr 1987;24:45.
8. Mishra S, Agarwal R, Deorari AK, Paul VK. Jaundice in
the newborns. Indian J of Pediatr 2008;75:157-63.
9. Newman TB, Maisels MJ. Bilirubin and brain damage:
what do we do now? Pediatrics 1989;83:1062.
10. Paul VK, Singh M. Diagnosis and treatment of neonatal
sepsis. Indian Pediatr 1986;23:1023.
11. Singh M. Some practical aspects of neonatal jaundice.
Indian J Pediatr 1977;44:220.
12. Starr SE. Antimicrobial therapy of bacterial sepsis in the
newborn. J Pediatr 1985;106:1043.
4.1 Growth and Development: Basic Concepts: AB Desai, Dilip Mukherjee ......................................................................................... 80
4.2 Growth—Birth to Puberty: KN Agarwal, DK Agarwal, SK Upadhyay ................................................................................................. 83
4.3 Physical Growth and Sexual Development in Adolescence: KN Agarwal, DK Agarwal, SK Upadhyay ....................................... 96
4.4 Development: KN Agarwal, DK Agarwal, SK Upadhyay ..................................................................................................................... 105
4.5 Failure to Thrive: Madhulika Kabra, PSN Menon ................................................................................................................................ 111
80 IAP Textbook of Pediatrics
4.1 Growth and Development: Basic Concepts
Growth and development begin at conception and end
at maturity. They are unique characteristics of children
and any obstacle in this process at any stage can possibly
result in aberration of growth and/or development.
Frequently, the terms growth and development are used
together. In the normal child they progress together, and
are interdependent. Growth is defined as an increase in
the size of an individual due to increase in number and
size of the cells, resulting in an overall increase. This
increase can be seen, appreciated and measured
accurately.
ASSESSMENT OF GROWTH
Growth can be measured in terms of:
i. Nutritional anthropometry (weight, height, circum-
ference of head, chest, abdomen and pelvis)
ii. Assessment of tissue growth (skin fold thickness and
measurement of muscle mass)
iii. Bone age (radiological by appearance and fusion
of the various epiphyseal centers)
iv. Dental age
v. Biochemical and histological means.
For day-to-day work anthropometry is the simplest
tool.
Nutritional Anthropometry
This is the technique of measuring somatic growth.
Length
Until 24 or 36 months of age, length in recumbency is
measured using an infantometer (See Chapter 2.2 on
Physical Examination for details). The length is recorded
in centimeters upto one decimal point.
Height
After the age of 2 years, standing height is recorded by a
stadiometer. The details have been provided in the
Chapter 2.2 on Physical Examination. Detecto weighing
scales fixed with anthropometric rods are in common
use. For community survey, portable type of anthropo-
metric rods are also used. For recording stature (height),
AB Desai, Dilip Mukherjee
the subject should remove his/her socks and shoes and
stand perfectly straight with arms relaxed by his/her sides
and ankles and knees together. Before measurement starts,
a gentle pressure may be applied over the spine with one
hand while other hand holds the anthropometric rod. The
subject’s head is positioned in Frankfort plane.
Sitting Height
For recording sitting height, the subject is made to sit on
a table or other convenient hard surface so that his/her
head lies in Frankfort plane. The back should be straight,
thighs horizontal and comfortably positioned. The feet
should be supported on the foot board and hands should
rest comfortably on the subject’s lap. To ensure that the
subject's back is fully extended, the observer may run
his/her index finger up the spine applying pressure to
the lumbar and sacral regions, causing the subject to sit
up a reflex action. The head board should be lowered
and made to touch the head of the subject and reading
should be recorded to the nearest completed unit.
Body Proportions
The total body length is divided in two segments. The
upper segment is from head to pubic symphysis and
lower segment from pubic symphysis to the toes. The
U/L segment ratio is 1.7:1 at birth. By 6 to 7 years, it
reaches 1:1. If the ratio is infantile after 1 year of age, it
suggests short limb dwarfism due to bone disorders such
as rickets and hypothyroidism.
Weight
It is the commonest and important anthropometric
measurement. The weighing scales best suited are those
which are designed on balance arm principle. The details
of measurement have been provided in Chapter 2.2 on
Physical Examination. Accuracy up to 0.1 kg is quite
acceptable. For smaller babies, machines of more
accuracy are required as 0.1 kg forms a higher percen-
tage of total body weight. More recently, many electronic
weighing scales giving accuracy up to 0.01 kg have been
made available.

The weighing scales should be checked for
accuracy using known weight from time to time. The
beam scales are better instruments for all purposes rather
than spring weighing scales, i.e. bathroom scales, as the
spring may get expanded due to repeated use, may get
rusted and variation of temperature may give false
reading.
In Japan special type of weighing scales are devised
which in addition to the weight of an individual also note
Body Mass Index and amount of subcutaneous fat.
Head Circumference
The details of measuring head circumference has been
given in Chapter 2.2 on Physical Examination. It should
be recorded to the nearest 0.1cm.
Midarm Circumference (MAC)
The details have been provided in the Chapter 2 on
Physical Examination. It should be kept in mind, that
upper arm circumference can be measured both in flexed
and extended positions and also either at the maximum
circumference of biceps muscle or mid-point, as the
difference between the two is negligible.
Chest Circumference
The chest circumference for boys, prepubertal girls and
men can be recorded at the level of xiphisternal junction
during normal breathing. It is recorded to the nearest
0.1 cm.
Age Independent Anthropometry
Midarm Circumference (MAC)
As the midarm circumference is relatively constant
between 16.5 cm to 17.5 cm in 1 to 5 years of age, this
measurement may be considered as an age independent
variable up to 5 years of age. Any child whose MAC is
less than 12.5 cm up to 5 years of age, is considered
malnourished. Shakir’s tape also measures the MAC. A
bangle of 4 cm in diameter, used in field studies is not a
reliable method (Bangle test).
Weight for Height
The degree of wasting can be measured by comparing the
child’s weight with expected weight for a healthy child of
the same height. Combinations of these measurements
have been used to distinguish different types of
malnutrition. Waterlow suggested that weight for height
Growth and Development 81
can be used to distinguish between malnutrition of recent
origin, i.e. wasting and malnutrition due to a considerable
period of months. In chronic malnutrition the child is
stunted with the weight for age and height for age being
low. In acute malnutrition, height for age is normal but
weight for age is low (wasting). Thus, the weight and height
measurements together are useful in understanding the
dynamics of malnutrition. In nutritional short stature the
weight/height is equal; the child may pass off as a normal
child of lower age if the chronological age is not known.
These have been discussed in the chapter on ‘Protein-energy
malnutrition’.
Quackstick
Quaker’s midarm circumference measuring stick is a
height measuring rod, calibrated in MAC rather than
height; values of 80 percent MAC for height are marked
on the stick at corresponding height levels. If a child is
found taller than his/her arm circumference level on the
stick, he/she is considered malnourished. The quackstick
was devised in Mexico and has since been adapted in
Africa and India.
Midarm/Head Circumference Ratio
It is a simple and useful criterion for detection of
malnutrition. A ratio 0.280 to 0.314 indicates early mal-
nutrition, 0.250 to 0.279 moderate, and less than 0.249
denotes severe malnutrition.
Quetlet’s Index
It is based on the relationship between weight and height
and is expressed as weight (kg)/Height (cm) × 100.
Normal value varies from 0.14 to 0.16. In gross
malnutrition, it is less than 0.14. It is a quite reliable ratio
for assessing malnutrition.
Mid-upper Arm/Height Ratio
It is also a very good indicator of nutritional status. A
ratio of less than 0.29 indicates gross malnutrition, while
the normal value ranges from 0.32 to 0.33.
Body Mass Index (BMI)
Weight (kg)
BMI = _________________
Height2(m2)
82 IAP Textbook of Pediatrics
This is similar to Quetlet’s index except that the values
are in SI units. BMI values can be used to draw standar-
dized percentile curves in children and adolescents. It is
specially useful for defining obesity. BMI values above
95th percentile for age are usually used to define obesity.
Ponderal Index (PI)
Height (cm)
PI = ______________________________________
Cube root of body weight (kg)
This is another index similar to BMI and is often used
in defining newborn with intrauterine growth retarda-
tion (IUGR).
Tissue Growth
This measurement is done for special purposes and is
not used in routine clinical practice. It is measured with
a special caliper.
Triceps Skinfold Thickness
The skinfold is picked up over the posterior surface of
the triceps muscle, 1 cm above the mark on a vertical
line passing upward between bony point identified for
taking measurement, maintaining a pressure of 10 g/
mm2 on the caliper and freeing the skinfold from the
underlying muscle with left hand between thumb, index
and middle finger and holding caliper with the other
hand. The reading is recorded to the nearest 0.1 mm.
Subscapular Skinfold Thickness
The subject stands as for the triceps skinfold with
shoulder and arm relaxed. The inferior angle of scapula
is located by running finger on medial border of scapula
downward, till inferior angle is reached. The skin is
pinched up immediately below the inferior angle either
in vertical line or slightly downward and reading is
recorded to the nearest 0.1 mm maintaining pressure of
caliper as before.
Biceps Skinfold Thickness
For recording biceps, the child is made to stand erect,
facing observer with arm on side and palm facing
forward. The skinfold is picked up over the belly of biceps
and 1 cm above the line marked for the upper arm
circumference and triceps skinfold on a vertical line
joining antecubital fossa to the head of humerus. The
caliper is applied at the marked level and reading is
recorded to 0.1 mm.
Bone Age or Skeletal Maturity
Appearance and fusion of various epiphyseal centers
follow a definite sequence related to chronologic age from
birth to maturity. Radiological examination of left wrist
and elbow is usually considered for bone age assessment.
X-ray of the lower end of femur, and talus is used for the
assessment of maturity of new-born babies. The details
of appearance and fusion of various centers is given in
subsequent sections.
Dental Development
Eruption of teeth follow a definite sequence. Eruption of
temporary or deciduous teeth begins at about
6 months with eruption of upper or lower central incisors,
followed by lateral incisor. By one year of age 4 to 8 teeth
are present. The permanent teeth begin to erupt at 6 years.
Details of dental development are provided in
subsequent chapters.
GROWTH STUDIES AND PERCENTILES
While discussing growth, various terms which are used
must also be understood.
Cross-sectional Study
This is a very convenient, easy, less time consuming and
economical method to study growth. For example,
children of each age group in large number are collec-
ted, their weights are recorded and an average is found
out. These groups of children are studied just once.
Linear or Longitudinal Study
In this type of study, the same child is measured from
birth to maturity at yearly or previously decided regular
intervals. It is difficult to study very large number of
children in this fashion and hence, the linear studies have
comparatively less subjects in number. The longitudinal
study helps us to determine the growth velocity.
Concept of Percentiles
While making various calculations, the use of terms like
mean or average and standard deviation (SD) is well
known. While expressing the growth the term percentile
or centile is often used. This may be explained in a simple

way, e.g. the height of 100, one year old normal children is
not exactly the same. They are arranged in such a way
that the shortest is number one and the tallest is number
100. Rows of children are thus made. The mean of each
number is worked out. The child at number 1 is one
percentile, number 10 is 10th centile, number 50 is 50th
centile and so on. The child on 10th centile on height
chart means that 9 children are less in height and 90
children are more in height. The 50th centile is the median
value and is also termed the standard value. Accepted
range for normal is between 3rd and 97th percentiles.
The standard deviation (SD) charts are based on
distribution of data above and below a mean value. The
average normal range falls above and below 2 SD,
expressed as 2 SD. + 1 SD is equal to 84 centile and-1 SD
is equal to 16th centile. + 2 SD corresponds to 97th centile
and - 2 SD corresponds to 3rd centile. The mean ± SD
curves are useful for quantifying the degree of retardation
exactly.
Growth Charts
Growth chart is the most important tool in assessment
of growth of an individual child. A standard chart
contains weight for age, height for age and weight for
height. The head circumference is included for first 3
years of life. They depict mean, ± standard deviation (SD)
or percentile values at each age.
World Health Organization (WHO) has accepted
National Center for Health Statistics (NCHS) USA, charts
as the international standard for growth for the first 3
years of life. The growth of the healthy and well-
nourished children is represented in these charts. The
4.2 Growth—Birth to Puberty
DEFINITION
Growth and development in human beings at the moment
of conception and are continuous processes, until the
epiphyses (growing ends of bones) fuse and growth in
height ceases. The term growth denotes increase in size or
body mass; and development is the emerging and expanding
capacities of an individual to provide progressively greater
Growth and Development 83
charts are separate for boys and girls. The recently
developed Indian standards are provided in subsequent
sections.
Velocity Growth Charts
These charts are developed by long-term longitudinal
studies and are known as incremental charts. They show
the rate of change which could be due to chronic illness
or growth hormone deficiency. Different countries may
use their own growth charts. In Great Britain, Tanner's
growth charts are used. In India, Agarwal et al have
prepared the charts based on studies on affluent Indian
children.
BIBLIOGRAPHY
1. Agarwal DK, Agarwal KN, Upadhyay SK, Mittal R,
Prakash R, Rai S. Physical and sexual growth pattern of
affluent Indian children from 5 to 18 years of age. Indian
Pediar 1992;29:1203–83.
2. Agarwal KN. Physical growth in Indian affluent
children (Birth to 6 years). Indian Pediatr 1994;31: 377–
413.
3. Falknar F, Tanner JM (Eds). Human Growth, 2nd edn, 3
vol. New York: Planum. 1986.
4. Mukherjee D, Nair MKC. Growth and development.
Growth and Development 1st edn. IAP, 1997.
5. Tanner JM. Growth at Adolescence, 2nd edn. Oxford:
Blackwell Scientific Publication 1962.
6. Tanner JM. Physical growth and development. In :Forfar
JO, Arneil GC (Eds): Textbook of Pediatrics, 2nd edn.
London : Churchill Livingstone 1978;249–303.
7. Tanner JM, Whitehouse RH, Camerson N et al. Assess-
ment of Skeletal Maturity and Prediction of Adult Height,
2nd edn. London: Academic Press. 1983.
KN Agarwal, DK Agarwal, SK Upadhyay
faculties in functions, i.e. acquisition of a variety of
competencies for optimal functioning in a social milieu.
The growth, measures show how body grows, i.e.
length (growth in stature), skull circumference (brain
growth) and weight (bone and muscle mass) increase
rapidly in early childhood-first three years of life( the
most active growth period). Therefore, regular measure-
ments of length (best indicator of physical growth) and
84 IAP Textbook of Pediatrics

TABLE 4.2.1: Growth pattern in infant and skull circumference (indicator of brain growth) are
early childhood important to detect growth failure (Figs 4.2.1 and 4.2.2;
Length gain being the best indicator of growth Table 4.2.1).

Length gain Measurement at age Postnatal growth, i.e. increase in length/height, skull
circumference and weight, stretches from i) Conception:
At birth 50 cm
Intrauterine growth period to infancy (the most rapid
Birth to 3 months 3.5 cm/month 3 months 60 cm
3–6 months 2.0 cm/month 9 months 70 cm growth period. Brain growth is very rapid from 20 weeks
6–9 months 1.5 cm/month 12 months 74-75 cm of gestation, and continues until 20 months of age, It is
9–12 months 1.3 cm/month 24 months 86-87 cm around 67%, of the adult size at birth and 90%, on the
first birthday (Fig 4.2.3; Tables 4.2.1 and 4.2.6). These
By 3rd year (36th month length is 93 cm). At 4th year approaches
100 cm. cerebellum (meaning “Little Brain” in Latin, it plays a big
part in the integration of sensory perception and motor output)
Weight reaches adult size by 18 months of age.
Weight at birth 3.0–3.5 kg, there is loss of around 8–10 percent
in first 8–10 days by 12–15th days it approaches the birth weight.
Growth in Preschool and School Years
Weight gain Measurement at age
This rapid early childhood growth is followed by a long
2 weeks to 3 25 g/day Doubles birth weight phase of slow juvenile growth the height gain is: in early
months by 5–6 months school Years, by 3-5 years of age the height increment is 6-
3–6 months 20 g/day Trebles (3 times) at 1 year of
8 cm/year and weight gain is 2 kg / year. Later in school
age
6–9 months 15 g/day Quadruples (four times) at age 6 to 10 years in girls and 6- 12 years in boys
2 years of age. Five time by (Prepubescent) 5-6 cm per year and weight 3-3.5 kg per
3 years of age and 6 times by year, until pubescence sets in (Table 4.2.2 and Figs 4.2.4
5 years of age and 4.2.5).
9–12 months 12 g/day

By the time infant wt. doubles birth weight~ 5-6 months; fat in Growth in Adolescence
body trebles (25% of the total body weight) thus almost 1.5 kg The morphological and physiological changes during
body weight at 6 months is fat, while during 6-12 months-fat
“Adolescent Growth Spurt” involve nearly all organs of
deposit is 500 g, only.
the body. These changes do not begin at the same age
Skull—(Head Circumference): Indicates Brain Growth point or take the same length of time in all individuals to
Growth in head circumference (cm): In normal full term child reach completion. During “Puberty” somatic as well as
skeletal growth is related to sexual development (sexual
Age Head circumference
maturity rating by Tanner 1962), as adolescent growth is
At birth 34-35 initiated and controlled by the sex hormones. Thus for
3 months 40 assessment of their growth means for height, weight,
6 months 42-43 BMI, skin fold thickness etc. in relation to sexual maturity
9 months 44-45
are more relevant than those obtained for chronological
12 months 46-47
2 years 48 age (Agarwal et al Indian Pediatrics, 2001).
5 years 50.3 Around 10-12 years in girls and 12-15 years in boys
12 years 52 cm there is initiation of puberty- adolescent growth spurt
lasting for 2.5 to 3.0 years. In this phase girls gain 25-26
Increment is 2 cm/mo in first 3 mo; 1 cm/mo between 3 to 6 mo;
0.5 cm/mo between 9-12 mo. Thereafter gain in head circum- cm and boys 28-30 cm in height (Tables 4.2.2, 4.2.3 and
ference is very slow, only 5 cm after first birth day to 12 years of Fig. 4.2.4 and 4.2.5). The muscles, heart, liver, and kidney
age. follow the same growth pattern. The lymphoid tissue
achieves peak growth in prepubertal period 6 to 9 years
Head Circumference (HC) in Preterm
with a steady decline thereafter. The reproductive organs
Gestation weeks 26 27 30 32 34 36 show the most rapid growth in size and function along
HC cm 24.0 25.6 27.6 29.6 31.6 33.0 with body growth (somatic) with onset of puberty.
 Growth and Development 85

Figure 4.2.1: Height, weight and head circumference for boys from 0-36 months (Percentiles)
(Redesigned by Agarwal KN, Agarwal DK, Bansal AK for the Indian Academy of Pediatrics. From-Agarwal DK, Agarwal KN.
Physical growth in Indian affluent children (Birth—6 years). Indian Pediatr 1994;31:377-413
86 IAP Textbook of Pediatrics

Figure 4.2.2: Height, weight for girls from 0-36 months (Percentiles)
(Redesigned by Agarwal KN, Agarwal DK, Bansal AK for the Indian Academy of Pediatrics. From-Agarwal DK, Agarwal KN.
Upadhyay SK, Mittal R, Prakash R, Rai S. Physical and social growth pattern of affluent Indian children from 5-18 years of age.
Indian Pediatr 1992,29:1203-1282 (Birth—6 years). Indian Pediatr 1992

Figure 4.2.3: Increase in head circumference in late gestation
and first 2 years of life. The period of maximum brain growth is
also plotted
Adult Stature
Individual child’s growth potential for height is related to
the mid parental height (MPH) the calculations are as
follows
Father’s height-13 + Mother’s height
MPH for boys (cm)= ___________________________________________________
2 Growth Curves
Or = average of parents height – 6.5 cm
Mother’s height + 13 + Father’s height
MPH for boys (cm) = ___________________________________________________
2
Or = average of parents + 6.5 cm
Growth Monitoring- Why?
• Growth is a fundamental characteristic of childhood
• Despite being influenced by many factors, it remains
remarkably predictable
• Normal growth is an indicator of optimum health
• Deviation from the normal pattern is indicative of a
pathological process
• Periodic assessment facilitates early detection of
growth faltering which may be the first manifestation
of an infection/disease.
There were several growth standards to measure
children, e.g.
• Staurt Meredith Charts 1940 (Harvard standard
1929-39). Used in Indian Academy Pediatrics
Growth and Development 87
classification of malnutrition since mid 1970s (50th
percentile taken as 100%).
• NCHS—1963-1974. CDC growth charts. (International
growth reference on American children)
• British children- Tanner et al 1966
• Dutch-V an-Wieringen 1964-66.
• Other European Growth standards: Czechoslovakia;
Denmark; Hungary; Norway and Sweden.
• Asian—China, Japan, Hongkong, Thailand, Taiwan
and India (These growth curves are very similar).
• Infact every country has national growth standard.
Although world’s children appear to follow a similar
growth pattern, still there are variations due to ethnic,
geographical, and regional factors giving differences in
velocity of growth and adult stature. Therefore, Indian
Academy of Pediatrics (IAP) “Growth Monitoring
Guidelines consensus committee in Sept 2006,
recommended to use affluent children data collected by
Agarwal et al 1992 and 1994 see Indian Pediatr March
2007 pp 187-197 as standard for Indian children’s growth
assessment”. To identify children: with growth deviation,
i.e., under nutrition and over nutrition and with conditions
that manifest through abnormal growth.
Distance growth curves (Percentile growth curves)- the
term refers to the position of an individual child on a
given reference distribution. The percentiles are
calculated for 3rd, l0th, 25th, 50th, 75th and 97th etc
values. The observations between 3rd and 97th
percentiles include 94% children; this also represents
children with mean: + 2 SD. The 50th percentile (median
value) is similar to mean, if there is Gaussian distribution.
For any age 50th percentile indicates that for the given
parameter 50% children are taller and 50% shorter than
the boy/girl under measurement.
As recommended by the lAP growth curves and
tables with percentile distributions for height, weight and
skull circumference are given for boys as well as girls for
birth to 3 years of life (Figs 4.2.1 and 4.2.2), and height
and weight for 2-18 years for boys and 2-17 years for
girls (Figs 4.2.4 and 4.2.5 and Tables 4.2.2 and 4.2.3).
Measure child’s height/weight or skull circumference
then put your scale or pencil on the age of the child and
mark this parameter on the curve and note in which
percentile the measured parameters fall.
88 IAP Textbook of Pediatrics

TABLE 4.2.2: Height or length percentile (in cm) for Boys and Girls:
Birth to 18 years of age (Indian affluent and NCHS data)
Indian affluent Age NCHS
percentiles percentiles
Boys Girls Boys Girls

3rd 50th 97th 3rd 50th 97th 3rd 50th 97th 3rd 50th 97th

47.6 50.4 53.2 47.5 50.3 53.1 Birth 46.2 50.5 54.8 45.8 49.9 53.9
56.3 59.4 63.8 55.8 59.1 62.9 3 56.1 61.1 66.1 54.9 59.5 64.2
62.5 65.9 70.8 61.6 65.5 69.7 6 62.8 67.8 72.9 61.0 65.9 70.9
66.8 70.6 75.4 65.6 70.0 74.5 9 67.4 72.3 77.3 65.3 70.4 75.6
70.1 74.3 78.8 68.6 73.5 78.0 12 71.0 76.1 81.2 69.0 74.3 79.6
75.6 80.7 84.9 73.8 79.8 84.4 18 76.7 82.4 88.1 75.1 80.9 86.7
80.1 86.0 90.5 78.2 85.0 90.2 24 81.3 87.6 94.0 80.3 86.5 92.6
84.0 90.5 95.9 82.0 89.9 95.3 30 85.8 92.3 98.7 84.9 91.3 97.7
87.3 94.4 100.8 85.3 93.3 99.9 36 89.9 96.5 103.2 88.8 95.6 102.3
90.2 97.7 105.2 88.3 96.7 104.0 42 91.5 99.1 106.7 90.6 97.9 105.3
92.8 100.8 109.3 91.2 99.8 107.6 48 94.9 102.9 111.0 94.0 101.6 109.2
95.3 103.7 113.1 94.1 102.9 110.9 54 98.2 106.6 114.9 97.2 105.1 113.0
97.9 106.2 116.4 97.2 106.0 113.8 60 101.3 109.9 118.6 10..1 108.4 116.7
100.7 110.0 119.5 100.6 109.3 116.4 66 104.2 113.1 122.0 102.8 111.6 120.3
103.9 113.6 122.2 104.5 113.1 118.7 72 107.0 116.1 125.2 105.4 114.6 123.9
106.1 117.3 128.4 104.5 114.5 126.0 6.5 109.6 119.0 128.3 107.9 117.6 127.4
108.5 119.7 130.8 107.1 117.4 129.3 7.0 112.1 121.7 131.3 110.3 120.6 130.9
110.8 121.6 133.2 109.7 120.3 132.8 7.5 114.1 124.4 134.2 112.6 123.5 134.3
113.3 123.6 135.8 112.3 123.2 136.4 8.0 116.9 127.0 137.0 115.0 126.4 137.7
115.6 125.7 138.5 115.0 126.2 139.8 8.5 119.2 129.6 139.9 117.5 129.3 141.1
118.0 128.2 141.4 117.8 129.2 143.1 9.0 121.5 132.2 142.8 120.0 132.2 144.5
120.3 130.8 144.5 120.6 132.3 146.2 9.5 123.7 134.8 145.9 122.6 135.2 147.8
122.7 133.6 147.7 123.4 135.2 149.0 10.0 126.0 137.5 149.0 125.4 138.3 151.2
125.1 136.6 151.0 126.1 138.1 151.7 10.5 128.3 140.3 152.3 128.5 141.5 154.5
127.5 139.6 154.3 128.8 140.9 154.2 11.0 130.6 143.3 155.9 131.7 144.8 157.8
129.9 142.7 157.5 131.4 143.5 156.5 11.5 133.0 146.4 154.7 135.2 148.2 161.2
132.4 145.8 160.8 133.9 146.0 158.5 12.0 135.5 149.7 163.8 138.7 151.5 164.4
134. 148.9 163.9 136.3 148.3 160.4 12.5 138.1 153.0 167.9 141.9 154.6 167.2
137.4 152.0 166.9 138.5 150.4 162.1 13.0 140.9 156.5 172.0 144.6 157.1 169.7
140.0 154.9 169.7 140.6 152.2 163.5 13.5 143.8 159.9 175.9 146.5 159.0 171.6
142.6 157.6 172.3 142.4 153.8 164.7 14.0 147.0 163.1 179.2 147.8 160.4 172.6
145.2 160.2 174.7 144.1 155.1 165.8 14.5 150.4 166.2 182.0 148.6 161.2 173.9
148.0 162.5 176.8 145.5 156.0 166.5 15.0 153.8 169.0 184.2 149.1 161.8 174.5
150.8 164.6 178.5 146.6 156.6 167.1 15.5 157.1 171.5 185.8 149.5 162.1 174.8
153.6 166.3 179.8 147.5 156.8 167.4 16.0 160.0 173.5 187.1 149.9 162.4 175.0
156.6 167.7 180.7 148.0 156.5 167.6 16.5 162.3 175.2 188.0 150.4 162.4 175.0
159.6 168.7 181.2 148.3 157.0 168.0 17.0 163.9 176.2 188.6 151.1 163.1 175.0
162.7 169.3 181.1 17.5 164.5 176.7 189.0
161.0 169.8 181.6 18.0 164.4 176.8 189.2

(Source: Data from (1) Agarwal DK et al. Physical and sexual growth pattern of affluent Indian children from 5 to 18 years of age.
Indian Pediatr 29:1203–82, 1992, (2) Agarwal DK et al. Physical growth in Indian affluent children (Birth to 6 years). Indian Pediatr
21:377–413, 1994. and (3) Hamill PVV et al. NCHS growth curves for children Birth–18 years. National Center for Health Statistics,
Publ. No. DHS 878–1650, 1977. Hyattsville MD,USA)
 Growth and Development 89

Figure 4.2.4: Percentiles for height (cm) and weight (kg) (Boys 2-18 years)
Data source Agarwal et al. Indian Pediatrics 1992 and 1994
90 IAP Textbook of Pediatrics

Figure 4.2.5: IAP growth curve: Percentiles for height (cm) and weight (kg) (Girls 2-17 years)
Data Agarwal et al. Indian Pediatrics, 1992 and 1994
 Growth and Development 91

TABLE 4.2.3: Weight (kg) Percentiles of Boys and Girls : Birth to 18 years (Indian affluent and NCHS data)

Indian affluent Age NCHS

percentiles percentiles
Boys Girls Boys Girls

3rd 50th 97th 3rd 50th 97th 3rd 50th 97th 3rd 50th 97th
2.5 3.1 4.0 2.5 3.2 3.9 Birth 2.5 3.3 4.2 2.3 3.2 3.9
4.8 5.7 6.7 4.5 5.4 6.6 3 4.2 6.0 7.6 4.0 5.4 6.9
6.2 7.4 8.6 5.9 7.0 8.4 6 6.0 7.8 9.7 5.6 7.2 8.9
7.2 8.5 10.1 6.8 8.1 9.6 9 7.4 9.2 11.1 6.7 8.6 10.4
7.8 9.3 11.2 7.5 9.0 10.5 12 8.2 10.2 12.2 7.6 9.5 11.5
8.9 10.7 13.1 8.6 10.4 12.2 18 9.3 11.5 13.8 8.6 10.8 13.0
9.8 11.9 14.7 9.4 11.6 13.7 24 10.1 12.6 15.0 9.6 11.9 14.3
10.6 12.9 16.0 10.1 12.6 15.2 30 10.9 13.7 16.2 10.5 12.9 15.7
11.3 13.8 17.2 10.8 13.5 16.7 36 11.8 14.7 17.5 11.3 13.9 17.0
11.9 14.6 18.3 11.3 14.3 18.0 42 12.4 15.7 19.3 12.1 15.1 19.1
12.5 15.4 19.3 11.9 15.1 19.4 48 13.1 16.7 20.5 12.8 16.0 20.4
13.1 16.2 20.3 12.6 15.9 20.6 54 13.9 17.7 21.8 13.4 16.8 21.6
13.8 17.1 21.5 13.4 16.8 21.9 60 14.7 18.7 23.2 14.0 17.7 22.9
14.5 18.1 22.7 14.4 17.8 23.1 66 15.5 19.7 24.7 14.6 18.6 24.3
15.3 19.2 24.2 15.7 18.9 24.3 72 16.3 20.7 26.2 15.3 19.5 25.8
15.7 20.0 27.7 14.4 18.3 25.4 6.5 17.1 21.7 27.9 15.9 20.6 27.6
16.2 21.0 29.7 14.8 19.0 27.5 7.0 17.9 22.9 29.8 16.7 21.8 29.7
16.8 22.0 31.6 15.3 19.9 29.8 7.5 18.7 24.0 31.8 17.4 23.3 32.2
17.5 22.6 33.5 15.9 20.8 32.3 8.0 19.5 25.3 34.1 18.3 24.8 35.0
18.2 23.5 35.5 16.4 22.0 34.9 8.5 20.2 26.7 36.5 19.2 26.6 38.0
19.2 24.4 37.7 17.1 23.5 37.7 9.0 21.0 28.1 39.2 20.2 28.5 41.3
19.9 25.6 40.1 18.3 25.1 40.5 9.5 21.8 29.7 42.1 21.3 30.5 44.7
20.9 27.0 42.7 19.5 26.9 43.4 10.0 22.7 31.4 45.2 22.5 32.5 48.2
21.9 28.7 45.4 20.9 28.9 46.4 10.5 23.7 33.3 48.4 23.8 34.7 51.8
22.9 30.6 48.2 22.3 30.9 49.3 11.0 24.8 35.3 51.7 25.2 37.0 55.3
24.1 32.7 51.1 23.7 32.9 52.2 11.5 26.1 37.5 51.1 26.7 39.2 58.7
25.3 34.8 54.1 25.1 35.0 55.1 12.0 27.6 39.8 58.7 28.3 41.5 62.0
26.7 37.1 57.1 26.5 37.1 57.9 12.5 29.3 42.3 62.3 30.0 43.8 65.1
28.1 39.4 60.0 27.9 39.1 60.7 13.0 31.2 45.0 65.9 31.7 46.1 68.0
29.6 41.8 63.0 29.3 41.0 63.2 13.5 33.4 47.8 69.5 33.5 48.3 70.7
31.2 44.1 65.9 30.7 42.7 65.7 14.0 35.9 50.8 73.2 35.2 50.3 73.0
32.9 46.3 68.7 32.1 44.3 67.9 14.5 38.4 53.8 76.7 36.8 52.1 75.1
34.6 48.6 71.4 33.4 45.7 70.0 15.0 40.9 56.7 80.1 38.3 53.7 76.8
36.5 50.5 73.9 34.6 46.8 71.8 15.5 43.4 59.5 83.4 39.7 55.0 78.2
38.5 52.4 76.3 35.7 47.7 73.3 16.0 45.7 62.1 86.4 40.8 55.9 79.1
40.6 54.0 78.5 36.7 48.2 74.3 16.5 47.8 64.4 89.2 41.6 56.4 79.7
42.8 55.5 80.5 37.6 48.4 75.6 17.0 49.6 66.3 91.6 42.3 56.7 80.0
45.2 57.2 82.2 17.5 51.0 67.8 93.7
47.6 58.6 83.6 18.0 52.0 68.9 95.3

(Source: Data from (1) Agarwal DK et al. Physical and sexual growth pattern of affluent Indian children from 5 to 18 years of age.
Indian Pediatr 29:1203–82, 1992, (2) Agarwal DK et al. Physical growth in Indian affluent children (Birth to 6 years). Indian Pediatr
21:377–413, 1994. and (3) Hamill PVV et al. NCHS growth curves for children Birth–18 years. National Center for Health Statistics,
Publ. No. DHS 878–1650, 1977. Hyattsville MD,USA)
92 IAP Textbook of Pediatrics

TABLE 4.2.4: BMI (Mean +SD) and Percentiles for Indian Boys

Age (Years) N Mean SD Percentiles

5 10 25 50 75 85 95
5 97 14.4 1.31 12.4 12.8 13.5 14.4 15.0 15.6 17.0
6 358 14.8 1.34 13.0 13.4 13.9 14.7 15.4 15.9 17.8
7 501 15.0 1.57 13.0 13.5 14.0 14.8 15.7 16.4 18.8
8 585 15.2 1.83 12.9 13.3 14.0 14.8 15.9 17.0 19.7
9 701 15.6 2.09 12.9 13.4 14.2 15.1 16.4 17.3 21.0
10 1135 16.1 2.42 13.2 13.6 14.5 15.4 17.0 18.5 22.1
11 1476 16.6 2.71 13.3 13.8 14.7 15.8 17.6 19.1 23.4
12 1652 17.1 2.72 13.6 14.2 15.2 16.4 18.3 19.8 23.8
13 1591 17.7 3.03 14.0 14.5 15.5 17.1 19.0 20.4 25.3
14 1433 18.2 2.90 14.5 15.1 16.3 17.7 19.6 21.1 25.3
15 1093 19.2 3.12 15.4 15.9 16.9 18.4 20.5 22.0 27.3
16 771 19.7 3.09 15.8 16.5 17.4 19.1 21.1 22.7 27.6
17 361 20.1 2.83 16.3 16.9 17.8 19.7 21.5 24.4 26.8
18 87 20.4 3.36 15.7 16.8 17.8 20.0 22.5 23.6 28.0

N = Number of children.

TABLE 4.2.5: BMI mean (+ SD) and percentiles for Indian Girls
Age (Years) N Mean SD Percentiles

5 10 25 50 75 85 95

5 254 14.4 1.5 12.3 12.7 13.5 14.3 15.2 15.7 18.3
6 449 14.5 1.7 12.4 12.9 13.5 14.3 15.3 16.0 18.8
7 596 15.0 1.9 12.5 12.9 13.5 14.6 15.7 16.6 19.7
8 640 15.7 2.32 12.8 13.2 13.9 14.9 16.5 18.0 21.4
9 784 15.7 2.5 12.5 13.1 14.0 15.1 16.8 18.0 21.7
10 933 16.7 6.6 13.0 13.6 14.6 16.1 18.2 19.9 23.2
11 906 17.5 3.1 13.5 14.1 15.2 16.9 19.0 20.6 24.5
12 893 18.4 3.2 13.9 14.6 15.9 17.8 20.1 21.9 25.7
13 782 19.2 3.6 14.6 15.3 16.7 18.6 21.0 22.6 27.1
14 627 19.7 3.2 15.4 16.0 17.3 19.0 21.4 23.0 27.4
15 383 20.0 3.3 15.9 16.5 17.7 19.3 22.0 23.6 27.7
16 27 20.5 3.2 15.9 16.6 18.1 20.0 22.4 23.1 27.4
17 119 20.3 3.1 16.6 16.9 18.3 20.1 22.0 23.0 25.9
18 27 20.9 3.2 16.9 11.9 18.3 20.0 23.0 23.2 —

N = Number of children.

Methods to measure height, weight and skull circumference
are discussed in other chapters.
The human growth velocity is measured as gains in
length, skull circumference and weight this is most rapid
during 3 months (3rd trimester) of gestation and 4-5
months after birth, than at any other age. Deceleration
in growth continues throughout childhood. In mid
childhood particularly in boys there is growth spurt term
adenarche this is related to androgens released from the
adrenal cortex. By the onset of puberty girls average 140
cm and boys around 150 cm (due to 2 extra years of
growth before the pubertal growth).
Growth velocity (the height velocity) is the rate
growth over a fixed time interval. The velocity must
oscillate closer to the 50th centile (if < 3rd percentile slow
growth; if> 90th percentile rapid growth- both are
 Growth and Development 93

Figure 4.2.6: IAP growth curve: Percentiles for body mass index (BMI) (boys 2-18 years)
Prepared from Indian Pediatrics 1994;p-377 and 2001;p-1217 (DK Agarwal, AK Bansal and KN Agarwal)
94 IAP Textbook of Pediatrics

Figure 4.2.7: IAP growth curve: Percentiles for body mass index (BMI) (girls 2-17 years)
Prepared from Indian Pediatrics 1994;p-377 and 2001;p-1217 (DK Agarwal, AK Bansal and KN Agarwal)

abnormal). The velocity change is the earliest evidence of
alteration in growth rate as compared to “distance growth
curve”. Thus a doctor can suspect disease/nutrition
deprivation/behavioral problem if the velocity falls.
Body growth: The growth is cephalocaudal in direction-
head→neck→arms→trunk and legs. It is also distoproxi-
mal, i.e. trunk-arms become functional before-hands -
fingers (pincer grasp).
Body Mass Index (BMI; kg/m2) the ratio of weight in kg to
the square of height in meters is a good indicator of
energy reserves and diagnoses obesity and under
nutrition (Tables 4.2.4 and 4.2.5; Figs 4.2.6 and 4.2.7 for
 Growth and Development 95

TABLE 4.2.6: Percentile for Head, Chest and Midarm

circumferences in (cm) of Boys and Girls between birth-72
months of age
Boys Age (month) Girls
3rd 50th 97th 3rd 50th 97th
Head
;
33.2 34.8 36.7 Birth 33.0 34.6 36.5
38.0 39.8 41.9 3 37.6 39.5 41.1
40.8 42.8 44.9 6 40.3 42.4 44.0
42.4 44.4 46.5 9 41.8 44.1 45.6
43.3 45.3 47.4 12 42.7 45.0 46.5
44.6 46.6 48.7 18 43.8 46.2 48.0
45.5 47.6 49.7 24 44.6 47.2 49.1
46.2 48.4 50.5 30 45.2 47.8 50.0
46.6 49.0 51.1 36 45.6 48.2 50.8
46.9 49.4 51.6 42 45.8 48.5 51.4
47.0 49.7 52.1 48 46.0 48.7 51.9
47.2 50.0 52.6 54 46.2 49.1 52.5
47.4 50.3 53.1 60 46.5 49.5 53.0
47.6 50.7 53.8 66 47.0 50.2 53.7
48.1 51.2 54.6 72 47.8 51.2 54.6
Chest

30.9 32.6 34.8 Birth 30.3 32.4 34.8

36.2 38.4 42.1 3 35.7 38.0 41.3
39.4 42.0 46.5 6 38.9 41.6 45.2
41.3 44.1 48.9 9 40.8 43.7 47.4
42.4 45.4 50.2 12 41.8 45.0 48.7
44.1 47.4 52.2 18 43.3 46.9 50.7
45.4 49.0 53.7 24 44.4 48.4 52.4
46.3 50.2 55.0 30 45.1 49.4 53.5
47.0 51.1 55.9 36 45.7 50.2 54.4
47.5 51.8 56.7 42 46.1 50.9 55.9
48.0 52.4 57.7 48 46.6 51.4 56.8
48.5 53.1 58.3 54 47.1 52.1 57.7
49.2 53.8 59.1 60 47.8 52.9 58.6
50.1 54.7 60.2 66 48.8 54.0 59.5
51.4 55.9 61.6 72 50.3 55.4 60.6
Midarm circumferences

8.9 9.8 1.3 Birth 8.4 9.9 11.1

10.0 12.3 14.2 3 9.5 12.2 13.7 Figure 4.2.8: Surface area nomogram modified from the data
10.8 13.7 15.7 6 10.4 13.5 15.2 of E Boyd by CD West (Source: Nelson’s Textbook of
11.4 14.3 16.4 9 11.1 14.1 15.9 Paediatrics, 12th edition 1983. WB Saunders and Co.)
11.9 14.5 16.6 12 11.7 14.3 16.2
12.6 14.8 17.0 18 12.6 14.7 16.7
13.2 15.0 17.2 24 13.2 15.0 17.1
13.6 15.2 17.5 30 13.5 15.2 17.4
13.9 15.4 17.8 36 13.6 15.4 17.8
14.0 15.6 18.1 42 13.6 15.7 18.1 affluent Indian children). Children with BMI >95th
14.1 15.8 18.4 48 13.6 15.8 18.3 percentile for age and sex are obese and those <5 th
14.2 16.0 18.7 54 13.7 16.0 18.6 percentile are thin. BMI is sex and age specific in children
14.2 16.2 19.0 60 13.8 16.2 18.8 and changes as they grow older.
14.3 16.5 19.4 66 14.2 16.4 18.9
14.4 16.7 19.8 72 14.8 16.7 19.1 Ponderal Index: (kg/m3) the main clinical application is
(Source: Agarwal DK, Agarwal KN. Indian Pediatrics 31:377: in the new born period. PI< 2.0 suggests symmetrical
413,1994) IUGR (retarded fetal growth).
96 IAP Textbook of Pediatrics
Body Proportions
The body proportion can be assessed by measuring lower
body segment (L) by taking length from symphysis pubis
to the floor. The upper segment is obtained by subtracting
lower segment from height of the child. The ratio of upper
to lower segment is 1.7 at birth; 1.3 at 3 year of age and
1.0 at 7 years of age. Higher U/L ratio may indicate short-
limbed dwarfism or bone disorders such as rickets.
There are racial differences in body proportions:
a. Africans have longer legs and arms, narrower hips
as compared to shoulders.
b. Chinese have longer arms to legs and broader hips.
c. Japanese have larger trunk to legs.
d. Indians and Europeans are similar.
e. In spite of similar environment, Afro-Americans are
taller than Americans but Asians are shorter than
Europeans.
Mid-arm circumference: Measured mid way between
acromian and olecranon processes (left upper arm). It
increases from 9.8 at birth to 14.5 cm at 1 year of age.
Between 1-5 years there is increase from 14.8 to 16.2 cm
(Table 4.2.6). For this age period of 1-5 years >13.5 cm is
taken as normal children with 12.5-13.4 cm are having
mild to moderate undernutrition and those <12.4 as
severe under nutrition.
4.3 Physical Growth and
Sexual Development in Adolescence
The morphological and physiological changes during
“Adolescent Growth Spurt” involve nearly all organs of
the body. These changes do not begin at the same age
point or take the same length of time in all individuals to
reach completion. During “Puberty” somatic as well as
skeletal growth is related to sexual development (Sexual
maturity rating by Tanner, 1962 and Marshall and Tanner
1985), as adolescent growth is initiated and controlled
by the sex hormones. Thus for assessment of their growth
means for height, weight (Tables 4.3.1 and 4.3.2), BMI
(Table 4.3.3) skin fold thickness etc in relation to sexual
Chest circumference: It can be recorded at the level of nipples.
It overtakes head circumference by 8-10 months of age
(Table 4.2.6).
Body surface area: In pediatric practice, the growth
parameters of height and weight are used to calculate
“Body surface area” useful in calculating fluids and drug
doses (Fig. 4.2.8).
BIBLIOGRAPHY
1. Agarwal DK, Agarwal KN, Upadhyay SK et al. Physical
and sexual growth pattern of affluent Indian children
from 5 to 18 years of age. Indian Pediatr 1992;29:1203–
82.
2. Agarwal DK, Agarwal KN. Physical growth in Indian
affluent children (Birth–6 years). Indian Pediatr 1994;
31:377–413.
3. Agarwal KN, Saxena A, Bansal AK, Agarwal DK. Physical
growth in adolescence. Indian Pediatr 2001; 38:1217-35.
4. Hamill PVV, Johnson CL, Red RV et al. NCHS growth
curves for children, Birth–18 years. Hyattsville MD,
National Center for Health Statistics. Publication number
DHS 1997;878–1650.
5. Khadilkar VV, Khadilkar AV, Choudhury P, Agarwal
KN, Ugra D, Shah NK. IAP Growth monitoring
guidelines for children from birth to 18 years. Indian
Pediatr 2007; 44:187-97.
KN Agarwal, DK Agarwal, SK Upadhyay
maturity are more relevant than those obtained for
chronological age (Figs 4.3.1 and 4.3.2).
This chapter discusses pattern of physical growth and
sexual development during adolescent growth spurt. The
reasons for earlier initiation of “Puberty” and completion
of adolescent growth in girls as compared to boys are
discussed. It also presents the growth tables relevant in
assessment of growth during pre adolescence (as
initiation of puberty has big age range) and adolescence
based on Indian affluent children growth data by
Agarwal et al 1992, 1994, 2001 and 2007.
 Growth and Development 97

TABLE 4.3.1: Showing weight and height percentiles in relation to genital development and age in boys
Age (yrs) 3 10 25 50 75 90 97 Number
Genital development stage (SMR)
10 Wt. 23.0 25.3 27.5 31.1 35.3 40.8 48.2 259
Ht. 128.2 130.8 135.5 139.7 144.6 148.5 151.3
11 Wt. 24.5 27.0 29.4 32.6 37.0 42.9 51.0 480
Ht. 130.7 134.7 138.5 142.4 146.8 151.0 155.3
12 Wt. 26.1 28.1 31.0 34.9 39.9 46.3 55.8 518
Ht. 133.8 137.3 141.7 145.5 150.0 154.5 159.3
13 Wt. 28.2 30.2 32.5 36.5 41.5 52.2 61.2 287
Ht. 136.5 141.0 145.0 149.0 152.2 156.0 160.6
14 Wt. 31.4 32.2 35.0 38.9 42.5 49.0 62.1 91
Ht. 142.4 145.7 148.6 153.4 156.6 159.9 166.6
Genital development stage (SMR)
10 Wt. 23.8 26.2 28.9 34.7 40.2 45.4 49.1 64
Ht. 127.8 134.6 137.8 145.6 151.8 155.1 159.1
11 Wt. 28.4 29.7 32.8 36.4 41.8 46.7 50.9 165
Ht. 134.2 139.6 143.6 148.0 153.1 158.5 163.0
12 Wt. 28.7 32.4 35.4 39.0 44.2 50.6 59.4 366
Ht. 139.6 143.4 148.2 152.2 156.4 160.5 163.0
13 Wt. 30.4 32.7 35.8 39.9 45.6 51.7 61.9 467
Ht. 141.5 142.2 149.5 154.1 158.5 162.1 166.9
14 Wt. 32.8 34.7 38.2 42.8 48.6 54.4 64.8 311
Ht. 145.7 149.3 153.5 157.8 161.8 165.6 169.1
15 Wt. 37.2 38.0 42.0 46.1 51.3 61.6 77.0 116
Ht. 152.5 152.5 156.1 161.1 166.0 169.3 172.7
16 Wt. 39.6 41.8 44.1 50.2 55.3 63.7 71.9 45
Ht. 154.6 157.0 157.4 162.0 165.6 172.8 179.6
Genital development stage (SMR)
11 Wt. 27.9 35.8 39.7 43.2 49.0 54.3 58.6 28
Ht. 138.8 147.4 150.9 156.4 161.3 163.0 166.0
12 Wt. 32.1 35.1 38.4 43.0 47.7 54.1 61.0 156
Ht. 143.0 148.4 153.1 157.9 162.5 167.0 168.9
13. Wt. 33.8 36.8 41.1 45.6 51.1 59.4 71.1 430
Ht. 147.0 151.5 156.0 160.2 165.0 168.5 172.6
14 Wt. 34.8 38.5 42.5 47.7 52.7 58.9 68.6 555
Ht. 148.5 154.0 158.0 162.6 167.5 171.2 174.8
15 Wt. 39.2 41.7 45.2 50.8 56.5 65.7 75.2 407
Ht. 154.0 157.0 161.0 165.5 169.3 172.8 176.3
16 Wt. 41.8 43.5 47.8 52.6 60.2 69.5 76.6 210
Ht. 156.7 159.0 162.5 166.5 171.5 175.0 178.9
17 Wt. 43.9 45.7 48.4 55.1 62.9 68.6 76.2 68
Ht. 160.3 161.0 164.1 167.8 173.7 177.5 184.3
Genital development stage (SMR)
13 Wt. 39.3 41.3 45.8 50.5 57.2 65.7 71.3 80
Ht. 152.9 157.6 160.5 164.9 169.1 173.0 177.4
14 Wt. 40.5 42.9 46.8 52.0 57.7 65.8 77.3 316
Ht. 153.7 158.0 162.0 166.0 170.7 174.1 178.2
15 Wt. 41.6 44.0 47.3 52.3 59.6 69.2 77.9 461
Ht. 156.5 159.2 163.5 167.0 171.5 174.5 179.4
16 Wt. 42.5 45.4 50.0 55.0 62.5 70.5 82.3 420
Ht. 157.9 160.2 164.7 168.9 173.5 177.2 181.5
17 Wt. 44.8 47.1 52.3 57.1 63.1 70.9 80.6 259
Ht. 160.3 162.0 165.4 169.3 173.3 176.5 181.0
18 Wt. 43.9 46.5 51.7 58.3 64.5 74.7 84.9 75
Ht. 157.5 163.8 166.5 170.0 173.0 177.9 183.2

(Source: Indian Pediatrics 2001;38:1217-35)

98 IAP Textbook of Pediatrics

TABLE 4.3.2: Showing weight and height percentiles in relation to breast development and age in girls percentiles

Age (yrs) 3 10 25 50 75 90 97 Number

Breast development stage (SMR)

10 Wt. 23.0 26.4 29.3 32.3 36.5 42.3 49.9 383
Ht. 127.7 131.5 135.4 139.4 143.9 147.3 151.0
11 Wt. 24.5 26.7 29.0 32.2 36.8 42.1 50.6 353
Ht. 131.1 134.3 137.7 142.5 146.2 149.7 154.7
12 Wt. 25.8 27.2 29.9 33.2 37.4 43.0 48.7 195
Ht. 134.9 137.6 140.0 144.5 149.1 152.6 157.7
13 Wt. 27.0 29.1 30.7 36.1 41.0 46.8 50.9 53
Ht. 139.9 141.3 144.9 149.5 153.7 161.0 165.2

Breast development stage (SMR)

10 Wt. 29.0 31.2 33.1 37.6 43.0 48.9 53.0 131
Ht. 134.9 138.5 141.0 144.3 147.5 150.5 153.7
11 Wt. 30.1 32.4 34.8 38.8 43.5 48.3 56.2 316
Ht. 138.0 140.0 143.2 147.0 150.5 154.5 157.1
12 Wt. 30.9 33.6 35.9 39.4 44.5 51.2 57.2 330
Ht. 140.0 143.5 146.0 150.2 153.5 157.3 162.0
13 Wt. 32.0 33.5 36.3 40.0 45.0 50.6 60.6 242
Ht. 141.5 145.0 148.0 151.9 156.7 160.1 163.3
14 Wt. 32.4 34.2 38.8 42.9 47.0 52.1 58.3 143
Ht. 144.0 145.8 150.0 154.2 157.0 161.7 164.5
15 Wt. 34.8 37.8 39.1 43.0 46.5 48.2 53.2 71
Ht. 146.5 149.0 150.6 155.0 157.3 162.7 164.9
16 Wt. 36.2 37.2 38.2 43.0 46.8 52.6 55.2 34
Ht. 147.1 148.9 152.0 155.2 158.4 163.5 168.3

Breast development stage (SMR)

11 Wt. 29.9 35.5 39.3 43.6 49.6 54.9 58.7 115
Ht. 138.2 142.7 147.0 150.3 154.5 156.3 161.7
12 Wt. 34.4 37.8 40.2 44.5 49.3 53.9 59.1 244
Ht. 142.7 145.3 148.5 152.0 156.0 159.3 161.9
13. Wt. 33.4 37.6 40.5 44.3 49.6 55.3 64.3 304
Ht. 144.0 146.2 150.1 153.3 157.1 160.6 164.2
14 Wt. 35.7 38.0 40.9 44.4 50.3 55.3 63.6 264
Ht. 145.1 146.5 150.5 154.5 157.7 161.6 167.0
15 Wt. 35.7 38.7 42.3 45.8 50.4 56.0 64.5 142
Ht. 146.2 148.2 152.0 155.0 159.0 161.7 167.7
16 Wt. 38.2 39.5 43.5 48.0 53.3 57.3 66.4 89
Ht. 147.1 148.7 152.7 156.0 159.9 163.0 167.1
17 Wt. 37.4 39.7 43.0 47.7 51.5 54.2 59.3 33
Ht. 148.0 149.3 152.0 155.5 159.0 165.0 166.8

Breast development stage (SMR)

12 Wt. 39.0 42.7 47.3 52.8 58.6 63.3 66.1 88
Ht. 142.8 147.5 149.8 152.6 156.8 161.1 163.2
13 Wt. 39.4 42.0 45.7 51.8 59.3 66.2 71.5 178
Ht. 143.0 147.5 150.5 155.1 160.5 163.8 167.8
14 Wt. 37.1 41.5 45.4 51.4 57.3 65.0 73.2 189
Ht. 145.6 147.8 151.5 155.0 159.5 162.2 165.6
15 Wt. 36.5 41.5 44.9 49.9 58.5 66.2 72.4 187
Ht. 146.2 148.1 151.5 156.0 160.8 164.5 168.0
16 Wt. 38.4 41.8 46.4 50.5 58.0 64.8 75.2 148
Ht. 147.1 148.2 152.8 156.6 159.9 163.0 166.9
17 Wt. 41.2 43.4 48.0 53.2 57.7 62.8 77.0 60

(Source: Indian Pediatrics 2001;38:1217-35)

 Growth and Development 99

TABLE 4.3.3: Showing Body Mass Index (BMI) in adolescents in relation to sexual development and age

Age BMI percentiles kg/m2

yrs
5 15 50 85 90 95 5 15 50 85 90 95

SMR. 2 SMR. 3
9 G 13.4 14.2 16.5 20.1 20.7 21.7 — — — — —
B 13.0 13.7 15.4 17.6 17.9 18.7

10 G 13.7 14.6 16.7 20.2 21.0 22.6 14.7 15.6 18.0 21.5 22.6 23.8
B 13.5 14.3 15.9 18.7 20.0 21.5 13.7 14.7 16.1 18.9 19.4 20.1

11 G 13.3 14.2 15.8 18.9 20.2 22.5 14.9 15.8 18.0 1.2 22.2 24.1
B 13.5 14.4 15.9 19.1 20.2 21.6 14.1 15.0 16.6 19.0 19.8 21.3
12 G 13.4 14.2 15.8 18.9 19.5 20.8 14.7 15.6 17.6 20.8 21.9 24.3
B 13.6 14.4 16.2 19.5 20.8 22.4 14.2 15.2 16.7 19.8 20.9 23.5

13 G 13.3 14.2 15.4 18.3 19.6 21.4 14.5 15.3 17.4 20.1 21.4 23.3
B 14.0 14.7 16.4 21.1 22.3 24.5 14.0 14.9 16.8 20.2 20.7 23.2

14 G — — — — — — 15.1 15.7 17.9 21.0 21.8 23.2

B
SMR-4 SMR-5

11 G 16.1 16.7 19.0 23.0 23.6 24.9 – – – – – –

B – – – – – –
12 G 15.1 16.9 19.2 22.1 23.0 24.3 17.0 19.2 22.5 25.7 26.9 27.8
B 14.5 15.6 17.0 19.8 20.9 22.3 – – – – – –

13 G 15.6 16.6 18.9 21.8 22.6 24.9 17.0 18.6 21.6 25.2 26.3 27.8
B 14.9 15.7 17.8 21.1 21.9 44.4 15.5 16.9 18.7 21.7 22.6 23.7

14 G 15.5 16.5 18.8 21.9 23.0 24.3 16.8 18.4 21.2 24.5 26.2 27.7
B 14.7 15.8 17.7 20.8 21.7 23.8 15.4 16.4 18.6 22.3 23.5 25.2
15 G 16.0 16.9 19.0 22.3 23.5 25.2 16.5 17.8 20.7 25.1 25.8 26.7
B 15.4 16.4 18.4 22.0 23.7 25.7 15.5 16.5 18.9 22.3 23.9 25.8

16 G 16.1 17.2 19.6 23.1 24.5 25.9 16.5 17.5 21.2 24.9 26.7 28.1
B 15.9 16.9 18.9 22.7 23.9 25.3 15.8 17.1 19.3 22.7 23.8 26.0

17 G 16.5 17.1 19.5 21.6 22.1 23.2 16.7 18.2 21.3 24.2 25.3 26.3
B 16.2 17.1 19.3 22.3 23.4 25.5 16.2 17.3 20.1 23.0 23.9 26.2

SMR = Sexual maturity rating; G = Girls and B = Boys.

Indian Pediatr 2001;38:1217.35.

STAGES OF PUBERTAL DEVELOPMENT Puberty Encompasses

Clinically identifiable stage in development of secondary
sexual characteristics for girls and boys are summarized
below. The values in parentheses give mean age of
appearance or % of adolescents (Indian affluent data)
having appearance in that stage.
These features in girls and boys help to rate the sexual
maturity, once this is done it is easier to assess growth of
the individual adolescent in relation to SMR and age.
Somatic Growth and Sexual Development
1. Adolescent growth spurt
2. Development of secondary sexual characteristics.
3. Attainment of fertility.
4. Establishment of individual sexual identity.
Timing for Puberty onset has wide variability Girls—
8-12 years and Boys—9-14 years of age.
100 IAP Textbook of Pediatrics

A. Development of Breast and Pubic Hair in Girls

Sexual maturity Breast Pubic hair (Mean age = 13.6 yr)

Stages (SMR)

1. Preadolescent Preadolescent
2. Bud stage and papilla elevated Sparse lightly pigmented straight
as small mould (10.2 yr) around medial border of labia (22%)
3. Areola enlarged no contour separation (11.6 yr) Darker, more and curl + (92%)
4. Areola and papilla form secondary mound (13.6 yr) Coarse curly abundant (98.8%)
5. Mature nipple projects, areola part Adult feminine triangle spread
of general breast contour( 15.6 yr) to medial surface of thigh (100%)

B. Development of Genitals and Pubic Hair in Boys

SMR Penis Scrotum and testes Pubic hair

1. Preadolescent Testes <4 ml None

2. Slight or no pigmented
enlargement (11.3 yr)
3. Longer (12.8 yr)
4. Larger, glans +
breadth increased (14.1 yr)
5. Adult size (16.4 yr)
Enlarged darker scrotum Scanty long slightly (60%)
Pigmented
Testes 6-8 ml Dark, small, curling + (97%)
Testes 10-12 ml Resemble adult type but less in
scrotum dark quantity and curls (99%)
Testes 12 ml Spread to medial surface of thigh,
Facial hair- 14.8 yr.

Puberty Growth Spurt -related to
Adrenal Steroids
There is increase in general growth rate of skeleton, muscle
mass and viscera.
During adolescent growth spurt—this growth in girls
is evident shortly before the appearance of mammary
budding. The budding of breast (Thelarche) is due to
secretion of ovarian estradiol. Estradiol stimulates
growth hormone secretion; the growth velocity is
doubled (Peak Height Velocity). The adrenal androgens
initiate pubic/axillary hair growth and the onset of
apocrine sweat production, though facilitated by the
estrogen. The peak height velocity (maximum body
growth—9-10 cm/year) is at Tanner stages II and III of
mammary gland development. It is at this level of sexual
maturity in girls the menarche is attained. The growth
in the post menarchial period is limited as girls can gain
5-6 cm in linear growth, only. Thus the maximum gain
in height is pre-menarchial in Tanner stages II-III.
In boys the first evidence of adolescent growth spurt
is noted with increase in testicular volume over 4 ml. The
peak height velocity (10.5 cm/year) approaches at the
testicular volumes of 10-12 ml (Tanner stages III and IV).
Testosterone is poor stimulator of the growth hormone
(both are synergistic); large quantity of testosterone must
collect to initiate growth hormone secretion. Therefore in
boys growth spurt and sexual development is delayed by
2 years. This gives advantage to boys for extra period for
growth. Testosterone is converted to Dihydrotestosterone
by 5 α reductase. Both hormones induce growth of the
external genitals and pubic hair.
Achievements in Physical Growth during Puberty
a. Average duration of growth is 2.5 to 3 years.
b. Total gain in height: Boys average = 27-29 cm;
Girls = 24-26 cm.
At 10.5 years—Boys and girls have similar height.
11.0-12.5 years—Girls have higher mean height by 2
cm.
14.0 years—Boys are taller by 5 cm
16.0 years—Boys are taller by 12 cm.
c. Average “Peak height velocity (PHV)”: is observed
in SMR-2 (breast stage-2); while in boys it is observed
in SMR-3. Boys have PHV of 10.5 cm/year around
G-3 to G-4 stages of sexual development. In Girls PHV
is comparatively lower 9.0 cm/year in B-2 to B-3 stage
of SMR. There is no relationship in normal boys and

Figure 4.3.1
girls between PHV and final height. Finally early and
late maturing end Up at exactly the same height. Total
weight gain during adolescence is around 1/4 of the
adult weight (around 25 to 30 kg). Peak weight
velocity is preceded by PHV. Early maturing are more
fatty and muscular, the late matures fattier.
d. Those undernourished also gain same height in
adolescence but do not show any PHV. During
adolescence early life stunting is not corrected. The
growth pattern in an undernourished adolescent is
summarized below (Agarwal 1986-92; ICMR report):
• Height gain was similar to affluent Indian children
in adolescent growth spurt.
• No age period could be identified for peak height
velocity.
Growth and Development 101
• Weight gain was 38% of the affluent Indian.
• Deficit of early life in height was not corrected”
during adolescent growth spurt
• Rapid growth of undernourished adolescents has
been associated with hypertension.
• Boys had delayed maturation of genitals by 1.54
yr.; pubic hair by 0.82-yr and axially hair by 0.65-
yr testicular vol was similar.
• Girls had delayed breast development by
2.19 years.
• Menarche was delayed by 0.82 year.
Growth is accelerated in obese children, generally they are
tall, and bone age is advanced but commensurate with
height age.
102 IAP Textbook of Pediatrics

Figures 4.3.1 and 4.3.2: Shows genital development according to Tanner (Tanner 1962, Growth at adolescence 2nd Ed. Blackwell
Oxford). The height and weight data for affluent Indian children (Indian Pediatr 29:1203-82, 1992) in relation to genital development
are presented graphically, M = Mean, represents mean of all the children measured at a particular age; 2 to 5 lines, correspond
to means of children measured in the genital development stage for that age. To find the average height of a boy 14 years of age
in genital development stage 3, the value is 156.5 cm, but for stage 4 for the same age the value will be 161.5 cm. Therefore,
during the adolescent period growth is to be correlated with sexual development rather than age

Sexual Dimorphism Boys as well as girls both start puberty with similar fat
and lean body mass content. The gain in lean body mass
The growth and body composition is regulated by the sex
is almost twice in boys as compared to the girls. Therefore
hormones. Shoulder growth is more in boys while girls have
girls have more fat; finally it approaches around 25% of
more hip growth (wide hip). Boys have more growth for all
total body weight as compared to 18% in boys. Boys who
other measurements except for hip width as compared to
are more active in sports also need more oxygen. Therefore
girls.

they have more ‘Red Blood Cell’ mass (higher hemoglobin
as compared to girls) in order to provide oxygen.
Bone growth: Bone growth (bone mineral density): 50% of
the bone growth completes during first month of life to
puberty onset. b) 30% in puberty and remaining 20% in
late adolescence to adulthood. Therefore almost 50% of
the bone growth occurs during adolescence (period 2.5 to
3 years).
Brain growth: MRI studies show that the “Maximum brain
growth related to organization and planning occurs in
older children in the rear of the brain- linked more to
language learning and spatial understanding. Thus brain
development continues.
Metabolic changes: Onset of puberty immediately raises
the demand on nutritional needs. During peak periods
of growth nutritional requirements are increased. These
correlate with sexual maturity rating (SMR) being highest
in SMR 2 and 3. The heart rate slows down and settles at
adult rate of 62-82/min. The blood pressure increases
and normal level 110-120 systolic and 60 to 80 diastolic
is achieved. The basal metabolic rate is high. The rate,
depth and type of respiration settle at 15-20/min. The
tidal volume increases to 1000 to 1500 ml/day.
Hematological values match the adult values.
Dietary requirements for adolescent growth: Energy-around
136500 Kcal as total cost of adolescent growth spurt. Peak
need in girls with budding of breast (SMR II and III) in
boys with testicular enlargement (SMR-III and IV) 2200
and 3000 Kcal respectively/day.
Protein 12-14% of energy—For Boys 0.34 g/cm of height
and girls 0.28 g/cm of height.
Fat < 30% of the total energy need. 7% saturated, 10%
polysaturated and 10% mono saturated fat. Cholesterol
ideally <200 mg/day.
During adolescence the early life lesions of
Atherosclerosis begin to accelerate —400 μg of Folic acid
is recommended. Other B complex vitamins are
important to maintain cellular energy metabolism.
Vitamin D for Calcium absorption, etc.
Adolescent Behavior—Implications for
Growth and Health
a. Extremes of nutrition intake:
i. Overeating resulting in overweight and obesity;
Growth and Development 103
ii. for social pressure to reach cultural ideals of
thinness—excessive dieting, e.g. anorexia ner-
vosa—1% (more in girls) and bulimia-can lead to
renal failure, irregular heart rate, bone marrow
hypoplasia, osteoporosis and dental erosion.
b. Intensive physical training alters hypothalamic-
pituitary axis in adolescent girls—menstrual
functions and reduced bone density.
Over Weight and Obese Diagnosis in
Indian Adolescents (Table 4.3.4)
The BMI values for Indian children 5-18 yr boys and girls
(Indian Pediatrics 200 IP 1220) are lower than the
NCHS—WHO reference data WHO 1995 Physical Status
p 475. The supporting data also do not have sufficient
follow-up in India to show that those at extremes have
similar later life health consequences as seen in USA. It
was observed that BMI was closely similar for different
ages in the same sexual maturity rating. Thus suggesting
that during adolescence SMR related BMI will be a better
index to assess thinness (<5th centile); overweight and
obesity (> 85% and >95% centile, respectively).
The percentage of such children likely to be higher
in adolescence, if the sex maturity related criteria (SMR) of
diagnosis are used (use of BMI tables in relation to SMR).
Besides weight for age and sex and BMI the other
useful measurements are waist/ hip ration and skin fold
measurements.
TABLE 4.3.4: Showing BMI kg/m2 cut off for overweight
and obesity in relation to sexual maturity (SMR) for boys
(B) and girls (G) (Developed from the data in Indian
Pediatrics 2001; by Agarwal et al)
SMR Overweight (>85%) Obese (>95%)
2 B 19 22
G 19 21
3 B 19 20
G 21 23
4 B 22 25
G 22 24
5 B 22 26
G 25 27
104 IAP Textbook of Pediatrics

TABLE 4.3.5: Age of appearance and fusion of ossification TABLE 4.3.6: Eruption and maturation of deciduous and
centers. The following table gives the age of appearance permanent dentition
of ossification centers. The figures in the main head are
in years and indicates maximum age at which centers are Eruption Root completed
expected to appear. Figure in parenthesis indicate mean Deciduous Teeth
age in months of appearance of these centers (Courtesy
Dr SK Bhargava and G Mehrotra) Maxillary
Central Incisors 7½ months 1 month
Bone Appearance Fusion
Lateral Incisors 9 months 2 years
Males Females Males Females
Canine 18 months 8 years
Carpal bones First Molar 14 months 2 years
Capitate 0.5 (2 m) 1.0 (2 m) Second Molar 24 months 5 years
Hamate 1.0 (2 m) 1.0 (2 m) Mandibular
Triquetral 4.0 (30 m) 3.0 (21 m) Central Incisors 6 months 1 year
Lunate 6.0 (42 m) 5.0 (34 m) Lateral Incisors 7 months 1 year
Scaphoid 8.0 (66 m) 5.0 (51 m) Canine 10 months 8 years
First Molar 12 months 2 years
Trapezium 7.0 (67 m) 6.6 (47 m)
Second Molar 20 months 3 years
Trapezoid 7.1 (69 m) 6.6 (49 m)
Pisiform 13.0 10.0 Permanent Dentition
Metacarpals
Maxillary
2nd 1.7 (18 m) 1.6 (12 m) 17.0 14.9 Central Incisor 7 to 8 years 10 years
3rd 1.7 (20 m) 1.6 (13 m) 17.0 14.8 Lateral Incisor 8 to 9 years 11 years
4th 1.7 (23 m) 1.6 (15 m) 16.4 14.9 Canine 11 to 12 years 13 to 15 years
5th 1.7 (26 m) 1.6 (16 m) 16.4 14.9 I Premolar 10 to 11 years 12 to 13 years
1st 4.1 (32 m) 2.0 (18 m) 17.0 14.9 II Premolar 11 to 12 years 11 to 13 years
Wrist I Molar 6 to 7 years 10 to 11 years
Radius 1.7 3.5 17.4 16.4 II Molar 6 to 12 years 12 to 14 years
III Molar 17 to 21 years 18 to 25 years
Ulna 7.4 6.5 17.4 15.8
Shoulders Mandibular
Central Incisor 6 to 7 years 9 years
Coracoid 5.6 13.0 18.0 17.0
Lateral Incisor 7 to 8 years 10 years
Acromion 14.0 12.0 18.0 17.6
Canine 9 to 10 years 12 to 14 years
Elbow I Premolar 10 to 12 years 12 to 13 years
Radius 6.2 3.5 16.2 14.5 II Premolar 11 to 12 years 13 to 14 years
Medial epicondyle 7.4 5.6 16.2 14.3 I Molar 6 to 7 years 9 to 10 years
Lateral epicondyle 6.2 7.5 16.0 13.0 II Molar 11 to 13 years 14 to 15 years
Trochlea 7.9 7.6 16.0 13.0 III Molar 17 to 21 years 18 to 25 years
Capitulum 0.5 0.5 16.0 13.0
Ulna 10.4 8.6 16.4 14.0 BONE AGE
Hip and Knee
Bone age is better correlated with onset of secondary sex
Distal end of femur at birth at birth 16.0 15.0
characters in children, with delayed puberty than
Proximal tibia at birth at birth 17.0 16.0
chronological age. It is closely correlated with menar-
Femur head 1.0 (4 m) 1.0 (4 m) 20.0 20.0
che. Skeletal maturation is more advanced in girls than
Greater trochanter 2.0
boys of same chronological age. Table 4.3.5 gives the age
Lesser trochanter 12.0
of appearance and fusion of various ossification centers.
Patella 5.0(46 m) 3.0 (29 m),
IIiac crest 16.0 16.0
Bone Age Assessment
Shoulder
Clavicles 17.0 17.0 25.0 25.0 1. In full-term at birth, following classification centers
(medial end) are present as evidenced by X-rays of feet and knee:
Humerus-upper end 0.5 0.5 06.0 05.0 i. Distal end of femur
Greater tuberosity 3.5 2.9 17.5 16.5 ii. Proximal end of tibia
iii. Head of humerus

iv. Calcaneus
v. Talus
vi. Cuboid
2. By first birth day (X-ray hand and wrist)
i. Humerus upper end around 6 months (Age 3 to 9
months on X-ray of shoulder)
ii. Carpal centers usually appear by 2 months of age:
Two carpal centers are present at one year of age.
One additional center appears each year. Thus, 7
carpal centers are usually present at 6 years of age.
3. Third year of life: Metacarpals and phalangeal epi-
physeal centers are radiologically demonstrable.
4. 8 to 12 years: Distal ulnar epiphysis appears in most
girls by 8 to 9 years and in boys by 10 to 12 years.
5. 12 to 16 years (X-ray of elbow and hip)
Elbow: Distal end of ulna
Lesser trochanter 12 years
Hip : Iliac crest 16 years
DENTAL AGE
At birth neither the maxillary nor the mandibular
alveolar process is well developed. Occasionally, a natal
tooth is present although the first primary teeth normally
do not erupt until approximately 6 months of age. The
natal tooth that is seen, may be prematurely erupted
normal tooth or an extra or supernumerary tooth. Dental
4.4 Development
INTRODUCTION
‘Development’ refers to qualitative and quantitative
changes and acquisition of a variety of competencies
for functioning optimally in a social milieu. Further,
development is a continuous process from birth to
maturity. It depends on maturation and myelination
of brain; unless that has occurred, no amount of
practice can make the child learn that skill. It may be
stressed that, besides 10 percent prevalence of
developmental delay, the early identification of such
problems remains difficult. Although severe disorders
can be recognized in infancy, it is unusual to diagnose
speech impairment, hyperactivity or emotional
disorders before the age of 3 or 4 years, and learning
Growth and Development 105
age, as judged by gingival eruption of teeth, is closely
correlated with skeletal age. Recently it has been shown
that the timing of tooth formation, rather than eruption,
provides a more reliable index of dental maturity.
Furthermore, eruption times are restricted to less than
30 months and after 6 years of age. Table 4.3.6 gives
reference to dental age and dental root development
(Indian Pediatrics 2003, 130 and 2004, 1031).
BIBLIOGRAPHY
1. Agarwal DK, Agarwal KN. Physical growth in affluent
Indian Children (birth-6 years). Indian Pediatr 1994;
31:377-413.
. Agarwal KN, Agarwal DK, Seth A. The Growth-infancy
to adolescence (2nd edn). CBS Publisher and Distributor,
New Delhi, 2007.
3. Agarwal KN, Agarwal DK, Upadhaya SK, Mittal R,
Prakash R, Rai S. Physical and sexual growth pattern of
affluent. Indian children from 5-18 years of age. Indian
Pediatr 1992; 29:1203-82.
4. Agarwal KN, Saxena A, Bansal AK, Agarwal DK. Physical
growth assessment in Adolescence.
5. Dentition-Indian Pediatr (2003;40:124-129 and 2004,
41:1031-1034).
6. Marshall WA, Tanner JM. Puberty. In Human Growth
(2nd edn). Falkner F, Tanner JM (Editors).
7. Tanner JM. Growth in adolescence (2nd ed). 1962.
Blackwell Scientific Publication Oxford.
KN Agarwal, DK Agarwal, SK Upadhyay
disabilities are rarely recognized before children start
their schooling. If one can diagnose developmental
delay in early stages of growth, the intervention can
reduce long-term sequel.
Developmental delay is said to exist, if the child does
not reach developmental milestones at the expected age,
i.e. broad variation among normal children. Although
the delay may occur from a biological factor such as
chromosomal disorder or an environmental factor such
as maternal depression, the primary model for patho-
genesis of developmental delay is a transectional one,
with the process of development viewed as an interaction
between the child and environment, in which each can
have profound effect on other.
106 IAP Textbook of Pediatrics

BRAIN GROWTH AND DEVELOPMENT The developmental pattern from birth to first birthday
is given in Figure 4.4.1.
Brain growth is important to receive stimuli and take
body functions, the process of brain growth and
acquisition of developmental processes is summarized Developmental Surveillance
below. The first part of development is head control, which is
observed in ventral suspension, prone and supine
Process of Brain Growth position. The remaining phases of development can be
• In the ectoderm—notochord develops to form a observed either in sitting or standing position. The areas
neural groove—NEURAL tube (cavity with overlying of observation of behavior development include gross
neural crest)—18 to 24 days motor activity, fine motor and vision, hearing and speech
• Error: results in spina bifida, anencephaly, etc. and social behavior and play. Besides one has also to
• Few weeks after conception to cellular level thru observe the acquisition of sphincter control. Normal
adolescence—Brain continues to grow and myelinate development is given in Table 4.4.1 for the developmental
a. Cells inside the tube form CNS (central nervous abilities at various ages. (See Chapter 4.2 para 1).
system) and
b. Cells outside and the ectoderm—ANS (autonomic ASSESSMENT OF NORMAL DEVELOPMENT
nervous system).
The developmental history and physical findings should
Process of Myelination be compared with the achievements listed for normal
children. For preterm one must take their corrected age
• Sensory and motor areas within first month to first
into account. If one finds any ‘warning sign' take note of
year of life- training and practice is effective only after
the points in history/physical examination and define
myelination.
the type of impairment, disability or any handicap. The
• Maximum myelination, occurs by 6 years of life.
children may be observed for their activities as follows:
• Prefrontal cortex is not myelinated until close to
adolescence.
Preschool Age
Developmental Profile i. Play, climbing stairs, speech, hand (for adaptive
behavior), feeding.
1. Early brain stem and cord—Birth-light reflex, startle
ii. Posture, walking, play and manipulation with
reflex, Babinski reflex, reflex movement, reflex birth
toys (tests for vision).
cry and grasp reflex.
iii. Performance: Understanding, matching color,
2. Visual, auditory, tactile, mobility, language and
concentration, visual acuity.
manual competences
iv. Comprehension of language: To point to body
3. Brain stem and early sub cortical areas—2.5 months
parts, objects in books, to pick named toys and
4. Midbrain and sub cortical areas—7 months
accept commands appropriate to age.
5. Initial cortex—12 months
6. Early cortex—18 months
7. Primitive cortex—36 months School Age
8. Sophisticated cortex—72 months. i. Test for reading, arithmetic functions like +, –, ×,
÷, writing name, age, address, drawing a picture;
Skill Achievements
to test application, concentration and organiza-
• Gross motor tional skills.
• Fine motor ii. Test deafness, physical examination.
• Language iii. Vision by 3 to 5 years age of 6/6 (adult) capability.
• Cognitive iv. Intelligence assessment.
• Self help The various tests which can be used for develop-
• Social mental screening are outlined below:
 Growth and Development 107

Figure 4.4.1: Showing growth and development in first 2 years of life

108 IAP Textbook of Pediatrics

TABLE 4.4.1: Developmental abilities and warning signs at various ages

AREAS
Personal social Language Adaptive Gross Warning
hearings and speech motor signs
6 weeks old
Smiles, coos Stills to mother's Follows face Primitive * None is elicited
responsively voice, startles 90° stares reflexes +head *Abnormal Moro's
at sudden noice intently in line with trunk *Persistent squint
when lifted
6 to 9 months old
6 month enjoys bath, 6 month. Responds 6 to 7 months Change 6 months bears some *Slow social responses
playing boo and to own name. grasp palmar to wt on legs, rolling *Absence of
chew on items. Speaks ma, da. index. Transfers over, in prone babble
9 months show 9 month. Mama, objects hand to head up. *Persistence of
objects to mother, dada (Double syllable) mouth. wt.of hands hand Pats regard.
mirror image Understands 'No' 9 months Pincer grasp 7 months Crawls and *Abnormal
foot regard. Fixes pulls to stand voluntary hand grasp.
pellet of paper, *Persistent
follows fallen primitive
object reflexes
12 months old
Comes when called, Understands Throws objects, Shuffling gait *No tunefull babble
finds hidden some words, uses watches them fall, like a bear. *Hold objects
objects, waves bye- 'mama, dada' picks up crumbs Cruises round close to eyes.
bye, gives toys on with meaning from floor. Pincer holding on to *Immature gait
request 'No' grasp, shakes head, furniture. Walks *No sitting
Bangs two bricks one hand held,
together pivots when sitting
18 months old
Cup: Lifts-drinks-and Points to 3 Neat pincer Walks well, *Drools no words
puts down. Self spoon body parts. picking of threads Carries toys. *Absent pincer
feeding. Pulls at Obeys single pins. Scribbles Climb stairs. grasp
dirty nappy. Does commands. Says using fisted Climbs into *Does not walk
dusting, sweeping 6 words. Jargons grasp. Turns 2 or chair
echoes, speech more pages at a
time. Builds
tower of 3–4 (2.5 cm)
cubes
2 to 2½ years
Plays alone, tantrums, Phrases of 2–3 Turns one page at Pushes tricycle *No speech
demanding. Day by day, words, gives a time, Imitates a with feet, walks *Unsteady on
puts on shoes, socks name, 50 words+, straight line in downstairs 2 feet
and pants. Turns door naming games, both vertical and feet per tread,
handles. Uses spoon and Has inner horizontal and a Runs, kicks ball
fork language circle, unscrews jumps on the
lids, makes tower of spot
6–8 cubes
3 to 3½ years
Goes toilet unassisted, Gives full name, Mature pen grasp, Stands on one *No phrases
dresses/undresses with sex. Counts to copies + and 0 leg for a few * Persistent day-
minimum assistance, 10, 3–5 word Correctly matches seconds. Peddles time wetting/
Knows some nursery sentences 2 or more colors. tricycle, stairs soiling
rhymes, handles knife Threads large adult style for *clumsy
and fork, plays with beads. Makes tower of 9 ascent, jumps of
peers bottom step
Contd...
 Growth and Development 109

Contd...

AREAS
Personal social Language Adaptive Gross Warning
hearings and speech motor signs

4 to 5 years
Wipes own bottom. Gives Matches 4 colors, 4 years climbs trees *Socially iso-
Eats using knife and address/age/ Copies cross, and ladder, enjoys lated.
fork, dresses-except telephone no., square and by 5 a ball games. *Unintelligible
for tie and laces, Counts up to 10 by triangle. Draws a 5 years hops, skip or ungrammatic
imaginative play, 4 years, 20 by 5 years recognizable man jump off 3 steps, speech.
plays in groups, shares knows 3 coins, catches a ball *Unable to tell
toys, obeys rules grammatical speech name or address
asks meaning of
abstract words

Tests of General Intelligence range of developmental skills containing 125 items

i. Stanford Binet Intelligence Scale (DDST-II).
ii. Wechsler Intelligence Scale for Children
iii. Goodenough Draw a man test Bayley’s Scale of Infant Development

GeseII Development Schedule
Gesell was the pioneer in behavior development assess-
ment of children. The scale provides an estimate in 4
major areas of development, i.e. motor, adaptive,
language and personal social. In the first year of life,
development is estimated on weekly intervals starting
from 4 to 52 weeks, then every 3 monthly intervals till 2
years and at 6 monthly intervals till 5 years of age.
The scale provides an estimate of DQ (developmental
quotient) for each area separately as well as the overall
DQ.
Maturity age
DQ = ————————— × 100
Chronological age
A child having DQ below the two-thirds or three-
fourths ratio (DQ between 65–75) is considered at risk of
developmental delay.
This scale has a clinical diagnostic orientation. It is
more concerned with the diagnosis and evaluation of
abnormalities than with the measurement of attainment
of various milestones. Hence, it is more satisfactorily
applicable to handicapped children rather than some of
the other tests.
Denver Development Screening Test (DDST)
DDST has been the most extensively used screening
test. Recently, it has been revised to cover broad
This scale provides three complementary tools for asses-
sing the developmental status of children, i.e. the motor
scale, the mental scale and infant behavior record.
Phatak’s Baroda Screening Test
Test items are arranged according to age. The test has
been validated at various Indian centers such as the Child
Development Unit of KEM Hospital, Pune, Child
Development Unit, University of Baroda, and the All India
Institute of Medical Sciences, New Delhi.
Trivandrum Development Screening Chart
This test developed at Trivandrum is summarized in Table
4.4.2. This is a simplified version of the Baroda
development screeing test.
Identification of Risk Factors for
Developmental Delay
To identify child ‘at risk’ for developmental delay the
pediatricians have to listen very carefully the history given
by parents, followed by detailed physical examination
and certain screening laboratory tests for metabolic
disorders. The risk factors which could suggest for
more closer, surveillance are given in Tables 4.4.3
and 4.4.4.
110 IAP Textbook of Pediatrics

TABLE 4.4.2: Trivandrum development screening test TABLE 4.4.4: Risk factors for developmental delay that can
be identified in the physical examination
Test item 3rd 97th
Abnormal growth, e.g. height or weight <5th percentile or head
1. Social smile 0.1 2.7 circumference <5th or >90th percentile.
2. Eyes follow pen/pencil 1.1 3.9
3. Holds head steady 1.1 3.8 Major congenital anomalies, e.g. spina bifida or midline defects.
4. Rolls from back to stomach 2.7 10.0 Minor congenital anomalies, e.g. hypertelorism, hirsutism or
5. Turns head to sound to bell/rattle 3.0 5.8 micrognathia.
6. Transfers objects hand to hand 4.1 7.0
7. Raises self to sitting position 5.8 11.0 Neurocutaneous lesions, e.g. neurofibromatosis or café au lait
8. Standing up by furniture 6.3 11.0 spots.
9. Fine prehension pellet 6.7 10.9 Abnormal optical findings, e.g. esotropia, exotropia, cataracts, or
10. Pat a cake 6.7 12.7 poor visual tracking.
11. Walks with help 7.7 13.0
Abnormal findings in ears, e.g. unusual shape, placement or
12. Throws ball 9.5 16.7
recurrent acute or serious otitis.
13. Walks alone 9.9 17.9
14. Says two words 11.2 19.1 Visceral abnormalities, e.g. hepatosplenomegaly.
15. Walks backwards 11.2 19.5
Skeletal abnormalities e.g, brittle bones or dwarfism.
16. Walks upstairs with help 12.2 24.4
17. Points to parts of a doll (3 parts) 15.3 24.3 Neurologic abnormalities, e.g. lack of alertness, abnormal
reflexes, hypertonia or hypotonia or asymmetric finding.
(Nair MKC, et al. Indian Pediatrics: 1991;28:869–72)

TABLE 4.4.3: Risk factors for developmental delay that can

Disorders of Development
be identified in the history taking

Prenatal maternal factors: Acute or chronic illness (e.g., human
immunodeficiency virus infection, use of drugs or alcohol, toxemia,
previous miscarriage or stillbirth.
Perinatal factors: Obstetrical complications, prematurity, low birth
weight, multiple gestation.
Neonatal factors: Neurologic events (seizures or intraventricular
hemorrhage), sepsis or meningitis, severe hyperbilirubinemia and
hypoxia due to respiratory compromise.
Postnatal factors: Seizures, sepsis or meningitis, recurrent otitis
media, poor feeding, poor growth, exposure to lead or other toxins.
Factors in the family history: Developmental delay, deafness,
blindness, chromosomal abnormalities.
Factors in the social history: History of abuse or neglect, limited
social or financial support, teenage parent, single parent, mentally
retarded parent, stressful life full of unhappy events (e.g., divorce,
death or unemployment of parent).
1. Impairment: An abnormality of body function or
structure: Mild backwardness, delayed speech and
language, clumsiness and specific learning disabi-
lities, e.g. reading, writing, spelling.
2. Disability: Reduced ability to perform a task or func-
tion.
3. Handicap: A continuing impairment or disability of
body, intellect or personality, e.g. mental retardation,
severe learning difficulty, cerebral palsy, autism,
deafness, blindness or poor vision.
4. Presence of soft neurological signs: Poor, fine motor
coordination as assessed by finger tapping, toe
tapping, stringing beads, etc.
 Growth and Development 111

4.5 Failure to Thrive

Madhulika Kabra, PSN Menon

Failure to thrive (FTT) is a common and often perple-

xing concern for parents and pediatricians. Patho-
physiologically, FTT is a state of caloric insufficiency
without an apparent etiology. It is a descriptive term
rather than a diagnosis and is used for children whose
attained weight or rate of weight gain, is significantly
below their age and sex matched controls. Though
primarily weight is affected, linear growth and head
circumference may also get affected, if the insult is
prolonged and severe. By definition, FTT is sustained
weight loss, failure to gain weight or a persistent fall in
weight from the child's normal centile (Fig. 4.5.1). This
definition excludes transient weight loss associated with
acute illness. Figure 4.5.1: Failure to thrive: A: weight loss, B: static
There is lack of consensus about anthropometric weight, C: Fall-off in weight gain
criteria for FTT. Commonly used criteria are shown in
(Table 4.5.1) . Important points to remember are: 3. Small size alone is not an adequate criterion for
1. Label of FTT should not be given, based on a confirming FTT, as constitutional and genetic factors
single observation, i.e. failure to gain weight or weight may result in short stature.
loss should be observed over a period of time.
2. Usually children less than 3 years or maximum up to ETIOLOGY
5 years are included in this definition.
The standard classification of dividing the causes of FTT
as organic and non-organic, probably is not very appro-
TABLE 4.5.1: Definition of failure to thrive1 priate. Whether the condition is primarily organic or non-
Attained growth organic in origin, all children who fail to thrive, suffer
the physical and psychological consequences of
• Weight <3rd percentile on NCHS growth chart
malnutrition and are at a significant risk for long-term
• Weight for height <5th percentile on NCHS growth
physical and psychodevelopmental sequelae. Table 4.5.2
chart
summarizes the causes of FTT.
• Weight 20% or more below ideal weight for height.
Organic diseases are responsible for less than 20
• Triceps skinfold thickness < 5 mm
percent of cases with FTT. lt should be recognized that
Rate of growth environmental deprivation can coexist with and
• Depressed rate of weight gain
complicate organic FTT. For example, a child with
• < 20 g/d from 0 to 3 months of age
cerebral palsy, or multiple congenital malformations is
• < 15 g/d from 3 to 6 months of age
likely to be environmentally deprived due to lack of care.
• Fall-off from previously established growth curve
Organic causes of FTT are most commonly gastro-
• Downward crossing of >2 major percentiles on NCHS
intestinal or neurologic.
growth chart
• Documented weight loss DIAGNOSIS

NCHS—National Center for Health Statistics History and physical examination are the mainstay for
1Hank DA, Jeisel SH. Failure to thrive. Pediatr Clin North Am diagnosis of FTT. It should be emphasised that, extensive
1998;35:1187-1205. laboratory investigations have no role in the diagnosis
112 IAP Textbook of Pediatrics

TABLE 4.5.2: Causes of inadequate weight gain1 unless assessment suggests a probable organic cause and
localizes the pathology to a particular system.
Inadequate intake

• Poverty History
• Misperceptions about diet and feeding practices ldeally, both parents should be present during the
• Inadequate breast-milk production interview and parent-child and parent-parent interac-
• Errors in formula reconstitution tion must be critically assessed.
• Dysfunctional parent-child interaction
• Behavioral feeding problem Routine Antenatal, Natal and Perinatal History
• Neglect Apart from the details of pregnancy, delivery and peri-
• Child abuse natal details, some points need special mention.
• Mechanical problems with sucking, swallowing, feeding • Was the child born of unplanned pregnancy? Did the
• Primary neurological diseases parents consider medical termination of pregnancy?
• Chromosomal abnormality Children born of unplanned pregnancy tend to be
• Prenatal insult emotionally deprived.
• Systemic disease resulting in anorexia/food refusal
• Was it a preterm delivery? If growth parameters are
Calorie wasting not corrected for gestational age, these children may
be erroneously labelled as FTT.
• Persistent vomiting
• Intrauterine growth retardation (IUGR) is another risk
• Gastroesophageal reflux
factor for FTT. Symmetrical IUGR children have a
• Gastrointestinal obstruction
worse prognosis in this regard.
• Rumination
• History suggestive of exposure to intrauterine
• Metabolic problems
infections.
• Increased intracranial pressure
• Malabsorption and/or chronic diarrhea
Growth Data
• Primary gastrointestinal diseases
• Cystic fibrosis Evaluation of growth pattern is the most important aspect
• Infections of evaluation. Review child's present and past growth
• Endocrinopathies parameters. This is only possible if parents have maintai-
• Structural problems ned a 'Road to health' card or previous growth status is
• Renal losses known. Undocumented weight loss may not help in diag-
• Diabetes mellitus nosis. In situations where previous record is not avai-
• Renal tubular acidosis lable, it is advisable to follow the child for weight gain.
Increased caloric requirements
Dietary History
• Congenital heart disease
A detailed dietary history, both past and present should
• Chronic respiratory disease
be elicited to evaluate caloric and protein intake.
• Neoplasm
• Hyperthyroidism
Detailed Social and Family History
• Chronic or recurrent infection
A detailed social and family history provides useful clues
Altered growth potential/regulation for diagnosis of non-organic failure to thrive. Following
• Prenatal insult factors need special evaluation:
• Chromosomal abnormality 1. Lack of “support systems”: relatives and friends.
• Endocrinopathies 2. Financial constraints.
1Hank
3. Psychiatric problems/drug abuse in family.
DA, Jeisel SH. Failure to thrive. Pediatr Clin North Am
1998;35:1187-1205.
4. Marital problems, parental discord.
5. Serious illness or death in family.

Detailed Evaluation of Developmental Milestones
Physical examination Physical examination should be
thorough and complete. Detailed anthropometry should
include length/height, weight, head circumference,
upper/lower segment ratio, skinfold thickness and
midarm circumference.
• Routine and thorough general and systemic exami-
nation is a must, as it gives clues to do specific diag-
nosis and investigations.
• Detailed neurodevelopmental assessment should be
performed.
• Specific behavior patterns should be looked for. These
may give a positive clue for non-organic FTT. These
include unusual watchfulness, decreased vocaliza-
tion, lack of cuddliness, head banging, rocking
movements and rumination.
• Signs of abuse and neglect.
• Signs of vitamin and nutrient deficiencies should be
looked for.
Laboratory Investigations
In most instances, a detailed general and systemic exa-
mination will help in ruling out an organic cause for FTT.
Detailed laboratory investigations are indicated only
if the history and physical examination suggest that an
organic cause is responsible for FTT and to localize the
systems involved. A battery of routine investigations
should be avoided because they are unproductive in most
instances, expensive, may be misleading and diverting
attention. The following investigations are considered
adequate for initial evaluation:
• Complete blood count with ESR.
• Urine and stool examination.
• Urine culture and sensitivity.
• Tuberculin test.
• Blood urea and serum creatinine.
Radiological investigations are not routinely indi-
cated, unless the child needs evaluation for tuberculosis
or physical abuse. Determination of bone age may be
required in some cases. More invasive diagnostic proce-
dures are called for, when a specific diagnosis is sus-
pected.
MANAGEMENT
The major goals of management are nutritional rehabili-
tation, treating an organic cause if detected and addres-
Growth and Development 113
sing psychosocial and developmental issues involved.
Individual management of these have been discussed in
detail in subsequent chapters.
The first decision that one has to take is, whether the
child requires hospitalization or not. Indications for hos-
pitalization are as follows:
1. Weight for height less than 70 percent of the median
2. Detailed evaluation for a suspected organic disorder
3. Suspected abuse/neglect
4. Non-response to outpatient management.
Diet
• An experienced dietician should always be involved
in planning and supervising diet. Unless there is a
strong suspicion of an organic cause, one should
proceed directly for a two weeks trial feeding. Daily
monitoring during this period is extremely important.
Nutrition monitoring record includes daily weight
and total calories consumed during last 24 hours
against expected. Every effort should be made to feed
the child orally. If oral feeding is inadequate, tube
feeding may be tried for short periods.
• Help of a child psychologist may be sought, if indi-
cated. Organization of a program of intensive
environmental stimulation and affection is also
needed. Every attempt should be made to see that
parents are actively involved in the management.
At the end of two weeks of trial feeding, the child
is reassessed. A good intake during the feeding trial, and
a good response in terms of weight gain, suggest that
the primary problem was nutritional deprivation usually
associated with emotional deprivation. Further manage-
ment of the child who fails to respond to the feeding trial,
is shown in Figure 4.5.2. It is perfectly justified to
undertake detailed investigations in the child with FTT
who fails to respond to a two weeks trial of feeding.
However, by this time, the physician usually has an idea
of the diagnostic possibilities, and he/she can tailor the
investigations accordingly.
PROGNOSIS
It may be tentatively concluded, that for most children
with FTT in infancy and early childhood, the outlook for
linear, ponderal and brain growth recovery is good,
provided appropriately aggressive hyperalimentation is
provided. The outlook for complete intellectual, behavi-
oral and educational recovery is variable and less certain.
114 IAP Textbook of Pediatrics

Figure 4.5.2: Schematic diagram showing evaluation of FTT; (GI—gastrointestinal, GER—gastroesophageal reflux,
RTA—renal tubular acidosis, CRF—chronic renal failure, CNS—central nervous system)

BIBLIOGRAPHY 4. Suri M, Kabra M, Aggarwal A, Verma IC. Failure to thrive.

1. Maggioni A, Lifshitz F. Nutritional management of failure
to thrive. Pediatr Clin North Am 1995;42:791-810.
2. Marcovitch H. Failure to thrive. Br Med J 1994;108:35.
3. Overby KJ. Failure to thrive. In Rudolph AM (Ed),
Rudolph's Pediatrics 20th edn. Stamford, Connecticut;
Appleton and Lange, 1996;3-9.
Indian J Pediatr, CME programme 1994;8.
5. The American Board of Pediatrics-Programme for
Renewal of Certification in Pediatrics. Failure of Thrive.
Supplement to Pediatrics in Review 1993.
5.1 Infant and Young Child Feeding: RK Anand, SP Srivastava ........................................................................................................... 116
5.2 Breastfeeding and Weaning: RK Anand, SP Srivastava, Arun Gupta, JP Dadhich ........................................................................ 122
116 IAP Textbook of Pediatrics
5.1 Infant and Young Child Feeding
All children have three important needs to help achieve
their full potential—a feeling that they are loved, that
their stomachs are supplied with wholesome food, and
that they have freedom from infection. Enough evidence
is on record to show that a child who feels loved and is
well-nourished, has a rather low risk of getting serious
infections.
Nutrient Requirements
For children to be well-nourished, they need energy from
a wide variety of nutrients to lead a healthy and happy
life. Basic knowledge about the so called macronutrients
as well as micronutrients is essential to provide the right
type of food in sufficient quantities in health and disease.
While adequate food is important throughout childhood,
it is crucial during the first 5 years of a child's life,
particularly so, in the first 3 years when rapid growth
occurs, and the child is entirely dependent on her mother
and family for food.
Macronutrients and Micronutrients
The macronutrients like proteins, carbohydrates, fats,
fiber and water are required in large or gram quantities
to meet that daily optimum needs for energy and normal
functioning of the system. The micronutrients like
calcium, iron, zinc, iodine, sodium, potassium and
vitamins, though needed in small (milligram or micro-
gram) quantities, are equally important for fulfilling
several physiological needs of the body.
Energy
The child needs energy for: (i) growth, (ii) for daily
physical activities like crawling, walking and playing,
and (iii) catch-up growth following infections. Hence,
child needs to be offered an extra meal while recovering
from an infection. Even when a baby is at rest, energy is
required for basal metabolism to maintain essential
physiological functions like breathing, which go on round
the clock for as long as the individual remains alive.
Energy expenditure also takes place due to thermogenic
effect of food (TEF). This is due to increase in metabolism
RK Anand, SP Srivastava
over and above the basal rate of metabolism due to the
digestion and assimilation of food. A school-going child
spends about 12 percent of total energy for growth, 25
percent for physical activity, 50 percent for basal
metabolism, 5 percent for TEF and about 8 percent as
fecal loss due to unabsorbed fat.
Energy Requirements
In children, measurement of what healthy, well-growing
children actually eat, is mostly used for assessing the
energy requirements.
A comparison of energy requirement of infants as
elucidated in the FAO/WHO/UNU Expert Report of
1985 and the earlier FAO/WHO Report reveals that
infants need less energy than what was earlier thought
of (Table 5.1.1). The Indian Council for Medical Research
(ICMR) agrees with the revised estimates. It has also been
observed that the required energy intake of breastfed
children is lower then that of formula-fed babies. Based
on these reports as well as studies which show that
infants can grow normally on exclusive breastfeeding for
6 months of age, it is suggested that there need not be an
undue haste to add foods, other than breast milk until
that age.
The energy needs between 1 to 18 years are compu-
ted from energy needs per kg body weight of well-to-do
Indian children. As a rough estimate, a one-year-old
infant needs 1,000 calories daily. This is about half of
what most mothers eat. After the age of 1 year, an
approximation to the minimum energy needs can be
TABLE 5.1.1: Recommended energy
requirements for infants
Intake (cal/kg)
Age Estimates Estimates
(months) (1973) (1985)
0–3 120 116
3–6 115 99
6–9 110 95
9–12 112 101

TABLE 5.1.2: Recommended additional energy and protein
requirements during pregnancy and lactation
Group Daily additional Daily additional
requirement of requirement of
calories (cal) protein (g)
Pregnant 300 15
Lactating women
0–6 months 550 25
6–12 months 400 18
made by adding 100 calories for every year of the life, e.g.
a child of 5 years needs at least 1,400 calories each day. It
is advised that for malnourished children, the
recommended intakes for the actual age should be used,
and no adjustments for actual body weight should be
made.
The pregnant and lactating mother needs extra
energy, while she makes all efforts to adequately meet
the nutritional needs of her fetus and later her breast-
feeding baby. Therefore, it is important to provide extra
calories to such a mother (Table 5.1.2).
Recommended Dietary Allowances (RDA) and
Nutrient Requirements
Recommended dietary allowances are the amount of
nutrients present in habitual diets consumed by a given
population and also the level that would cover the
requirement of most of the individuals in that population.
This must not be blindly applied to the nutrient
requirements of an individual. The needs of an individual
vary widely. Nutrient requirement is the amount of
absorbed nutrient that is essential to fulfill the
physiological functions in a particular individual.
Recommended dietary allowances (RDA) does not refer
to this individual need. Hence, it should be used for
population-based studies. However, it may be used as a
reference while evaluating the adequacy of the diet of
an individual. In this connection, it may be noted that
we do come across children with normal growth who
appear healthy and happy even though they were not
consuming nutrients as per the recommended dietary
allowances.
Protein
Proteins are complex organic nitrogenous compounds
made available from food. Each gram of protein provides
4 kcal of energy. Proteins are made-up of amino acids.
Infant Feeding 117
Twenty-four amino acids have been identified so far, for
the synthesis of proteins within the body. Eight of these
cannot be synthesized and hence must be supplied in
adequate amounts from outside. These 8 (nine for infants)
are called essential amino acids. They are: leucine,
isoleucine, lysine, methionine, phenylalanine, threonine,
tryptophan and valine. Two amino acids are considered
semi-essential, because they are synthesized by the body
at rates inadequate to support the growth in children.
These are arginine and histidine. Histidine is the ninth
amino acid essential for infants, besides the eight
mentioned above. Low birth weight (LBW) babies need
to be supplied arginine, cystine and taurine as well. For
them, these three are also essential.
Proteins are needed by the body for growth, for repair
and maintenance of body tissue, maintenance of osmotic
pressure, catalytic functions through enzymes, protection
through immunoglobulins and interferon, hormonal role
as with insulin, transport through hemoglobin and
albumin, provision of energy when calorie intake is not
adequate, and during pregnancy and lactation for
synthesis of fetal tissue proteins and milk proteins (Table
5.1.2). Protein foods may also carry other important
nutrients such as vitamins and minerals.
Protein Quality
A protein is said to be biologically complete if it contains
all the essential amino acids in amounts needed by the
human body. Protein from egg and human milk satisfies
this criteria and serves as a reference for defining the
quality of other proteins. The proteins in animal foods
compare well with egg protein. Hence, such foods are
considered to be sources of good quality protein. For this
reason, vegetable proteins are said to be of poorer quality
than animal proteins because they lack one or more
essential amino acids in them. However, it is important
to note that when two or more vegetarian foods are mixed
together in such a way that the deficient amino acid in
one is supplemented by the other, it becomes a complete
food. Hence, it is possible to obtain a high-grade protein
at low cost, from a mixed vegetarian diet of cereals, pulses
and legumes.
Estimated Protein Requirement (Table 5.1.3)
The energy requirements of a child come from proteins,
carbohydrates and fats. All calculations of protein
requirement are done in a situation where energy
118 IAP Textbook of Pediatrics
TABLE 5.1.3: Estimated protein requirements
(g/kg) of infants
Age (months) Daily requirement (g/kg)
0–3 2.3
3–6 1.85
6–9 1.65
9–12 1.50
requirements of the child are met. If this condition is not
fulfilled, estimates of protein requirement will be wrong
since a part of proteins will be utilized to provide energy.
Fat
Fat in the diet is a source of essential fatty acids (EFA)
which are required for proper membrane function and
prostaglandin synthesis. The Indian diets which are
cereal based are bulky. The bulk presents a problem for
young children because of their small stomach. Fats help
in overcoming this problem. They improve the calorie
intake by enhancing the energy density of foods. Fats
also improve the palatability of diets. They are important
for the absorption of fat soluble vitamins like vitamin A.
Dietary fat may be derived from two sources namely,
visible fat and invisible fat. Visible fats are found in fatty
parts of animals, liver, egg yolk and the fat in milk.
Vegetable sources of visible fats are coconut, nuts and
various vegetable oils. Analysis of foods has revealed that
cereals and pulses in the Indian diet may contribute
significantly to dietary fat intake as invisible fat. It is
estimated that such a diet based only on cereals and
pulses without any fat can meet more than 50 percent of
the individual’s essential fatty acids requirement.
Fats are made-up of fatty acids which include
saturated fatty acids like palmitic and stearic, mono-
unsaturated fatty acids like oleic and polyunsaturated
fatty acids like linoleic and linolenic. The latter two
cannot be synthesized in the body and have to be
supplied through dietary fat. Dietary fats with an equal
proportion of saturated, monounsaturated and polyun-
saturated fatty acids components are considered
desirable. Adequately breastfed infants receive nearly
70 g fat per day of which about 10 percent is linoleic and
1 percent linolenic acid. Breast milk meets all the essentials
fatty acids needs of such infants. In this context, the
superiority of breast milk over cow and buffalo milk must
be emphasized since the former contains large chain
polyunsaturated fatty acids which are biologically more
potent. Infants who have been weaned completely or
partially should be given enough vegetable oil with high
linoleic acid content to meet their essentials fatty acids
requirements. Fats like ghee, hydrogenated fats and
coconut oil are comparatively saturated and are poor
source of essentials fatty acids. Other edible oils are better
sources of essentials fatty acids . Cotton seed, corn,
sunflower, soy-bean and safflower oils contain 50 to
70 percent essentials fatty acids, whereas groundnut has
25 percent essentials fatty acids.
Studies relating fat intake to cardiovascular disease
and obesity suggest that an intake of fat as an energy
source beyond one-third of total calories, is undesirable.
Since in India, almost 10 to 15 percent of this can be
derived from invisible fat, visible fat intake should be
restricted accordingly.
Carbohydrates
Carbohydrates are the third important source of energy.
In fact, they supply almost half of the body’s energy
requirement. They are classified as follows:
Monosaccharides
(e.g., glucose, fructose, galactose)
These cannot be hydrolyzed into any further simpler
form.
Disaccharides
(e.g., sucrose, lactose, maltose)
They yield 2 molecules of same or different mono-
saccharide on hydrolysis.
Sucrose = Glucose + Fructose
Lactose = Glucose + Galactose
Maltose = Glucose + Glucose
Oligosaccharides
Oligosaccharides (dextrins) yield 3 to 6 monosaccharide
units on hydrolysis.
Polysaccharides
(e.g., starch, dextrins, glycogen, cellulose)
These yield more than 6 monosaccharide units on hydro-
lysis.
The carbohydrates are ingested in above forms and
are oxidized as glucose (dextrose). It is advisable to have
more of complex carbohydrates i.e., polysaccharides or

starches in the diet rather than simple carbohydrates i.e.,
sugars including sucrose. Thus, the amount of sugar in
the diet should be restricted, right from an early age.
Cellulose is the indigestible component of carbohy-
drate in the diet with scarcely any nutritive value. It
mainly contributes to dietary fiber. Complex carbohy-
drates supply enough fiber. Intake of highly refined foods
containing little fiber, leads to constipation and other
intestinal disorders. Thus, wholewheat flour prepara-
tions are better than those made from refined flour.
Requirement for Minerals and Trace Elements
Macrominerals
Calcium and phosphorus are required for the formation
of bones and teeth, and calcium in ionic form is impor-
tant for transmission of nerve impulses. Phosphorus is
an important constituent of nucleic acid and phospho-
lipid compounds. The desirable ratio of Ca:P is 1:1 in
most cases except during infancy where the ratio should
be 1:1.5.
Infants require about 500 mg of calcium per day.
Children between 1 to 9, 10 to 15 and 16 to 18 years
require 400, 600 and 500 mg, of calcium, respectively.
The best sources of calcium are human and animal milk
and the bones of small fish. Millet and ragi are also good
sources, the latter being especially valued for its calcium
content which is about 344 mg per 100 g. Leafy vegetables
like amaranth, fenugreek (methi) and drumstick leaves
are also rich sources. The Indian diet is adequate in
phosphorus, and no dietary recommendations are
suggested. Magnesium is a component of cells and is
essential for various metabolic reactions. Its deficiency
leads to neuromuscular dysfunction. The Indian diet is
adequate in magnesium, and no specific recommenda-
tions are made.
Currently, there are no specific recommendations for
dietary intake of sodium and potassium. However, there
is need for fixing limits in view of evidence that high
sodium intake may be related to hypertension. In general,
children should be offered foods containing low sodium
from an early age. Later, fast foods containing high
amount of sodium should be avoided.
Trace Elements (Microminerals)
They are needed in very small amounts but are vital for
life. They include iron and copper, essential for blood
formation; iodine to prevent goiter and hypothyroidism,
Infant Feeding 119
zinc for quicker healing of wounds, and manganese, cobalt
and selenium for growth and general health.
Iron
An average adult male has about 4.0 g and an adult female
about 3.0 g of iron in the body. Seventy percent of iron in
the body is in the form of hemoglobin. Storage iron
constitutes about 26 percent of the body iron.
Iron is needed in the diet to replace the iron lost in
the stools and urine and through the skin. There is consi-
derable loss during menstruation and during delivery.
The requirement is higher during period of rapid growth
and during pregnancy. An intake of 20 to 30 mg a day is
adequate for older children and adults. During
pregnancy, although menstrual related iron losses are
nil, an additional 1000 mg iron is required for the fetus,
the placenta and the increased maternal blood volume,
especially during the second and last trimester.
Infants, children and adolescents require iron for their
expanding red cell mass and growing body tissue. In a
normal infant, two-thirds of body iron is present in red
blood cells. During the first 2 months of life, there is a
marked increase in iron stores due to a fall in hematocrit.
These stores are subsequently mobilized to supply iron
for growth needs and to replace losses. Hence during
this period, there is a minimal requirement for dietary
iron. By about 6 months, the iron stores decrease
significantly, and the infant needs a generous dietary
intake of iron. Breast milk contains a low amount of iron.
However, since the bioavailability of iron from breast
milk is very high, the iron requirements of breastfed
infants are fulfilled during the first 6 months of life. After
this, complementary foods must be added to meet the
increased demand for iron. By 1 to 2 years, children start
eating the family food, which in our country is predomi-
nantly cereal and pulse based. Iron absorption from this
diet is low.
There are several dietary factors influencing the
absorption of iron. The amount of iron that a person
absorbs depends on: (i) The total amount of iron in the
meal, (ii) The type of iron in the food, (iii) Other foods in
the meal, (iv) Amount of iron that the person needs.
There are two types of iron in food: (i) heme iron
found in meat, liver, chicken and fish. About 15 to 35
percent of this is absorbed, and (ii) nonheme iron. This
is found in plants, legumes, cereals, eggs and milk. Less
than 5 percent of this is absorbed.
120 IAP Textbook of Pediatrics
The other foods taken with a meal can increase or
decrease the amount of nonheme iron that is absorbed,
such as foods rich in vitamin C, e.g. guavas, oranges,
lemons, tomatoes and foods which contain heme iron
such as liver, meat, chicken or fish. Fermented and ger-
minated foods also increase absorption. Tea and coffee
and phytates in wheat and maize hinder absorption. Iron
absorption is very high in pregnant women especially
when they are anemic. Dried fish, meat, liver and egg
are good sources of iron. Green leafy vegetables and
cereals too are relatively good sources.
Low overall dietary intake is an important factor
responsible for low iron intake. Increasing the dietary
intake to meet the calorie needs increases the dietary
intake of iron by about one-third. Infections interfere with
food intake and the absorption of iron. Blood loss due to
gastrointestinal disorders and parasitic worms is an
important cause of iron deficiency anemia.
Iodine
Iodine is secreted by the thyroid gland. Vegetables grown
on iodine rich soil and sea foods are good sources of
iodine. Iodine is essential for normal growth and
development. The amount of iodine available in the body
is about 15 to 20 mg, of which 70 to 80 percent is trapped
in the thyroid. The normal daily requirements are about
100 to 150 mg. Iodine deficiency is a major public health
problem in India. An estimated 167 million people are
at risk for iodine deficiency disorders in India, out of
which 54 million have goiter and over 8 million have
neurologic handicaps. The government is encouraging
the common salt to be iodated to cut-down the high
incidence of iodine deficiency disorders in the country.
Zinc
Zinc is available from a wide variety of dietary sources.
Human breast milk contains a special zinc-binding ligand
which increases the bioavailability of zinc for the infant.
The body needs about 4 to 6 mg of zinc per day.
Important sources are meat, chicken, fish, cereals and
legumes. There is sufficient zinc in our food and so
supplements of zinc are not necessary. Severe zinc defi-
ciency can cause growth retardation, anorexia, hypo-
gonadism, persistent diarrhea and poor wound healing.
Fluoride
Fluoride is a mineral which is important for bones and
teeth. It makes bones harder and prevents tooth decay.
However, too much fluoride can cause discoloration of
teeth and make bones weaker, thereby resulting in
deformities. Fluorosis occurs in endemic form in parts
of Andhra Pradesh and Punjab because of high fluoride
content in water and soil.
Requirements for Vitamins
Vitamins are organic nutrients needed by the body in small
amounts. They are classified as:
i. Fat-soluble vitamins—A, D, E, K
ii. Water-soluble vitamins—like thiamine (B1), ribo-
flavin (B2), folic acid, vitamin B12, vitamin C
Water-soluble vitamins are not stored in the body
except for some storage of folic acid and vitamin B12 in
liver and the surplus is excreted in the urine. Extra doses
of such vitamins are therefore not required. Fat-soluble
vitamins are stored in the body and excess of these may
lead to toxicity.
Vitamins do not themselves yield energy, but they
enable the body to use other nutrients. Each vitamin has
a specific function to perform and deficiency of any parti-
cular vitamin may lead to specific deficiency disorder.
Vitamin A
Vitamin A is necessary for the normal functioning of the
eyes including the ability to see in the dark. Deficiency
of vitamin A is associated with increased infections and
protein energy malnutrition. Deficiency leads to loss of
vision and eventually to blindness. Colostrum i.e., the
first milk after childbirth is rich in vitamin A.
Breastfeeding prevents vitamin A deficiency up to 6
months of age.
There are two forms of vitamin A in foods. Retinol is
found only in animal foods. Carotene is found mainly in
yellow or green plant foods. The body changes much of
the carotene to retinol. Six molecules of carotene make
one molecule of retinol.
Vitamin A is present in the fatty parts of several
animal foods. The liver oil of certain fish like cod, halibut
and shark are very rich in vitamin A. Many vegetables
too are a good source of vitamin A, because they contain
β-carotene which is converted into vitamin A in the body.
β-carotene is important—1 mg of β-carotene yields 0.5
mg of retinol. Only 50 percent of the β-carotene in food
is absorbed, therefore 1 unit of β-carotene yields only
0.25 mg of retinol. About 50 g of common fresh leafy
vegetables a day, or 100 g of mango or 200 g of papaya
will provide an adequate quantity of this vitamin. Fresh

vegetables contain more carotene than stale ones. The
vitamin A lost while cooking is not so great, but frying
destroys 70 percent of it. On an average, there is a 50
percent loss in storage and cooking, as is practised in
Indian homes. Young children require about 300 mg
retinol per day. Vitamin A can be stored in the liver, and
the body can build-up a store which can be used in times
when vitamin A is lacking in the diet.
Important sources of vitamin A, i.e. (retinol) include
breast milk, animal milk, liver from animals, fish, eggs,
butter, ghee, and cottage cheese.
Important sources as carotene include red palm oil,
orange and yellow fruits such as mangoes, papayas and
oranges, vegetables such as carrot, pumpkin, dark green
leafy vegetables, tomato, yellow maize, and yellow banana.
Vitamin D
Vitamin D plays an important role in the absorption of
calcium and phosphorus from the intestine and in the
formation of bones and teeth. Vitamin D needs are greatest
at time of rapid growth, i.e., in infants and young children,
adolescents and pregnant women.
Sources: Fish liver oil is the richest natural source of
vitamin D. It is also found in liver, egg yolk and milk, to
a small extent. However, vitamin D is formed in the body
by the action of sunlight on certain chemicals in the skin.
This can be an adequate source, and it is important that
children are allowed to play in the sun. An infant and the
mother too, should be exposed to the sun and should not
be overclothed while doing so. Only five minutes exposure
to sunlight per day for persons with fair skin is sufficient
to meet the daily requirement of vitamin D. Adults, infants
and children, pregnant and lactating women and prema-
ture babies need 100 IU, 200 IU, 400 IU and 500 IU, per
day, respectively.
Thiamine (Vitamin B1)
Sources: Thiamine is found in meat, poultry, fish, liver,
whole grain cereals, legumes, oil-seeds, milk and egg.
Deficiency can lead to beri-beri. This deficiency disease
has become quite rare now.
Riboflavin (Vitamin B2)
The daily requirement of riboflavin is 0.6 mg per 1000
calories. The average loss during cooking is about
30 percent. Its deficiency leads to cracked lips and corners
of mouth and rough skin.
Infant Feeding 121
Sources: Milk and milk products, egg, liver, leafy vege-
tables, wheat, millet and pulses.
Folic Acid
Folic acid is important in the multiplication and matu-
ration of red blood cells, and its deficiency results in certain
types of anemia. It is credited with preventing neurological
defects in fetus. The intake of folic acid is low among rice-
eating population. The daily requirement is 25 to 100 mg,
but pregnant women require 150 to 300 mg.
Sources: Fresh green vegetables, liver, kidney, fish and
pulses. Cereals contain 5 to 12 mg per 100 g, and pulses
contain 23 to 70 mg per 100 g. Leafy vegetables contain 50
mg per 100 g.
Vitamin B12 (Cyanocobalamin)
Like folic acid, vitamin B12 is also involved in the matu-
ration of cells, and deficiency results in megaloblastic
anemia.
Sources: Animal foods like milk, meat and liver.
Vegetables do not contain B12, but the vitamin may be
provided by molds and yeasts, often in association with
plant foods.
Vitamin C (Ascorbic Acid)
Vitamin C helps body to use calcium and other nutrients
to build bones and blood vessels. It helps the body to absorb
nonheme iron. Vitamin C is very susceptible to destruction
by exposure to light, heat and drying. The daily
requirement is about 50 mg, allowing for a 50 percent loss
while cooking. Vitamin C helps in the absorption of iron.
Sources: Fresh fruits and vegetables are good sources.
Guava is particularly rich in vitamin C. Other rich sources
are citrus fruits. Amla is the richest source, but is rather
astringent and not easily acceptable to children. Other
sources are fresh potatoes with skin, plantains and cooking
bananas, fresh milk and breast milk. Dry pulses do not
contain vitamin C, but germinating pulses are rich sources.
About 80 percent of the vitamin is formed in the grain and
15 percent in the sprout. The best source of vitamin C for
the infant is breast milk.
Storage of leafy vegetables at room temperature
destroys 35 percent of the vitamin, and about 12 percent is
destroyed under refrigeration.
122 IAP Textbook of Pediatrics
General Guidelines about Infant and
Young Child Feeding
Ideal infant feeding comprises exclusive breastfeeding for
6 months, followed by sequential addition of semi-solid
and solid foods to complement (not replace) breast milk,
till the child is gradually able to eat normal family food
after one year. The latter period when other foods are added
is also referred to as weaning. The term weaning does not
denote termination of breastfeeding.
Appropriate feeding is crucial for the healthy growth
and development of the infant. However, lack of confidence
and widespread ignorance and misconceptions frequently
result in improper management of infant feeding. The
prominent areas of concern include discarding or minimal
feeding of colostrum to the newborn baby, exclusive
breastfeeding in only 46 percent babies in the first 6 months
of life, unnecessary utilization of commercial infant milk
foods and animal milks, early termination of breastfeeding
and premature or delayed introduction of semi-solids
which may be contaminated, low in caloric density and
fed less frequently. These inept feeding practices directly
or indirectly, contribute substantially to infections, illness,
malnutrition and mortality in infants.
Following are the salient practical guidelines for
optimal infant and young child feeding.
5.2 Breastfeeding and Weaning
RK Anand, SP Srivastava, Arun Gupta, JP Dadhich
BREASTFEEDING
It is now well-understood that breastmilk is the ideal milk
for both rich and poor babies, that colostrum is essential
for the newborn, that bottle-feeding is dangerous, that
complementary foods must be added after 6 months of
age while breastfeeding is continued for two years or
beyond, and that we must ensure that nutrition of the
lactating mother is well taken care of.
Anxiety associated with the unfounded fears of
lactation failure (the inability to produce milk) and of
milk insufficiency (the inadequacy of breastmilk for
meeting the nutritional needs of the normal infant) is the
most common reason for mothers failing to initiate
• Provide extra helping of family food and some green
vegetables to the pregnant and lactating mother.
• Discuss with the pregnant mother and her family,
about the importance of breastfeeding and dangers
of bottle-feeding.
• Prefer delivery in a “baby-friendly” hospital (see
page 137).
• Put the baby to the breast soon after delivery (see
page 130).
• Encourage intake of colostrum as first and subse-
quent feeds.
• Avoid prelacteal feeds like water, glucose water,
honey water, (janam ghutti) or artificial milk.
• Practise “exclusive breastfeeding” (give no other
food or fluids including water) for 6 months of life.
• Breastfeed as often as the baby wants.
• Ensure proper positioning while breastfeeding (with
enough breast in baby's mouth so that the infant is
beastfeeding and not nipple feeding).
• Allow the baby to empty one breast before offering
the other for suckling. Do not time the feed.
• Add mashed fruits and homemade cereals after 6
months, while breastfeeding is continued for 2 years
or more.
breastfeeding within one hour of birth, maintenance of
exclusive breastfeeding for the first six months,
interrupting breastfeeding prematurely, or beginning
complementary feeding, before it is nutritionally
required. The mother wrongly perceives that she is not
getting enough milk. In fact this perception is universal
and is the most common reason for non-exclusive
breastfeeding. All mothers need help from health
workers—especially with her first baby. The health
worker must be well-equipped to convince the mother
about the importance of breastfeeding and skilled enough
to counsel and support her when she has any difficulty in
breastfeeding.

Figure 5.2.1: Breastfeeding is central
(Courtesy: Baumslag)
Advantages of Breastfeeding to the Child
More and more people are now appreciating that
breastfeeding is central to growth monitoring, immuni-
zation programs, nutrition, diarrheal disease prevention
and family planning programs, all of which are related to
each other (Fig. 5.2.1).
Complete Nutrition
The human brain and the child has to grow very fast in
the first two years of life. Breast milk provides complete
nutrition for first 6 months and continues to be an
important source of nutrition in the second year of life.
It contains the most suitable protein and fat rich in essen-
tial fatty acids—linoleic acid and linolenic acid for the
baby in right quantities, has more lactose than other
milks, offers enough vitamins, iron and water, and has
the correct proportion of salt, calcium and phosphate.
The special enzyme ‘lipase’ in the breast milk helps in
proper digestion of fat.
Cover Against Infection
Human milk has following anti-infective factors which
protect the child from several serious bacterial and viral
infections
• Immunoglobulins especially secretory IgA
• Lactoferrin
• Lysozymes
• Complements
• Interferon
• Lactoperoxidase
• Cells (T and B lymphocytes and macrophages)
• Bifidus factor
Infant Feeding 123
• Antiviral factor
• Antistreptococcal factor
• Para-amino benzoic acid (PABA).
The presence of these factors help the breastfed child
to have less diarrhea than artificially fed babies, less
incidence of necrotizing enterocolitis (NEC), and fewer
respiratory and middle ear infections. The bifidus factor
helps a special bacteria called Lactobacillus bifidus to grow
in the baby's intestine which in turn prevents other
harmful bacteria from growing and causing diarrhea.
Lactoferrin in breast milk binds iron which prevents the
growth of some harmful iron feeding bacteria. High
concentration of PABA in breast milk may protect the child
from getting malaria. The bile salt stimulated lipase, kills
Giardia lamblia and Entamoeba histolytica. It is estimated
that exclusive breastfeeding for six months with
appropriate complementary feeding in addition to
breastfeeding could prevent the deaths of an additional
1.3 million infants each year.
The other advantages include:
• Counters risk of allergic disorders like asthma and
eczema.
• Cancer (lymphoma) risk is reduced.
• Configuration of jaw is better because of the mecha-
nism of suckling at the breast.
• Caries in teeth are less common.
• Coronary artery disease risk and incidence of obesity,
type-2 diabetes and hypertension in later life is
reduced.
• Clever children: Premature babies who were breastfed,
turned out to be more intelligent than the artificially
fed.
• Cot death or sudden infant death syndrome risk is
probably reduced in breastfed babies.
Advantages to the Mother
1. Convenient
2. Cheaper than artificial milk—all it costs the family is
the little extra food needed by the mother.
3. Cancer risk of breast and ovary and risk of osteoporosis
in later life is reduced.
4. Contraction of the uterus when the baby is put to breast
soon after delivery assists in expulsion of placenta
and minimizes risk of postpartum bleeding.
5. Contours of body come back to normal due to utili-
zation of fat reserves laid down during pregnancy and
124 IAP Textbook of Pediatrics

due to involution of uterus. Thus, a woman who
breastfeeds regains her figure faster, compared to a
woman who does not breastfed. Pregnancy alters the
shape of the breasts—whether a woman breastfeeds
or not. If she wears a well-fitting brassiere, her breasts
will have a good shape.
6. Calming effect: For many women, breastfeeding
provides a sense of calm and satisfaction, which is
probably related to the helpful hormonal changes
while breastfeeding.
Advantages to Both Mother and Child
1. Comforting body-contact between the mother and child
while breastfeeding facilitates a close loving bond
between the mother and her baby.
2. Child spacing: As long as a mother remains amenor-
rheic (bleeding before 56th postpartum day being
ignored) and breastfeeds exclusively, she gets 98
percent protection from pregnancy in the first six
months due to production of appropriate hormones.
However, it is advised to use other family planning
methods acceptable to the couple.
3. Considered beneficial for diabetic mother and for the
reduced risk of diabetes in children.
Cost Benefits
Breastfeeding provides economic as well as ecological
benefits to the family, the nation and the health sector.
Comparison of Human Milk and Cow’s Milk
This is summarized in Table 5.2.1.
Anatomy and Physiology of
Breastfeeding (Fig. 5.2.2)
The breast consists of gland tissue (alveoli), supporting
tissue and fat. The alveoli make the milk, which goes
along milk ducts towards the nipple. Under the areola,
these ducts widen to form the lactiferous sinuses where
milk collects. Therefore, enough of the areola should be
offered to the breastfeeding baby.
Every time the baby suckles at the breast, he or she
stimulates the nerve endings in the nipple. These nerves
carry messages to the anterior pituitary which synthe-
sizes prolactin. Prolactin stimulates gland cells in the
breast to secrete milk. As the baby continues to suckle,
sensory nerves help secrete oxytocin from the posterior
pituitary. Oxytocin contracts the muscle cells around the
alveoli, resulting in squeezing out or ejecting the milk
from the nipple. The oxytocin reflex is dependent on the
mother’s state of mind and it may be cut-off in a mother
who worries and doubts whether she could feed her baby.
Preparation for Successful Breastfeeding
Motivate the Mother before Birth
The expectant mother and her close relatives including
the husband, should be informed about the advantages of

Global Support for Breastfeeding

The global support for breastfeeding remains ongoing and
strong. According to the World Health Organization
(WHO), well over two-thirds of under-five child deaths,
which are often associatated with inappropriate feeding
practices occur during the first year of life. Under normal
circumstances, infants who are not breastfed are 5 times
more likely to die from pneumonia and 14 times more
likely to die from diarrhea, than infants who are
exclusively breastfed for the first 6 months. Protection that
breast milk confers is all the more important in environ-
ments without safe water supply and sanitation. The child
survival series published in july 2003 in the Lancet gives
additional evidence-based support for the importance of
breastfeeding. It reconfirms that breastfeeding is the single
most important preventive intervention, capable of saving
more than a million additional lives annually. Figure 5.2.2: Anatomy of the breast (Courtesy King)
 Infant Feeding 125

TABLE 5.2.1: Comparison of human milk and cow’s milk and the need for breastfeeding. The breasts should be
examined, and the mother reassured that the size of the
Parameter Human Cow’s
breasts and shape of nipples, flat or short whatsoever,
Bacterial have no relation to lactation performance. Ask the mother
contamination None Likely to rub the nipple and press the areola on either side of
Anti-infective the nipple. This makes most nipples stand out and appear
substances Antibodies Not active
longer. Let her then gently try and pull the areola and
Leukocytes
Lactoferrin the nipple to form a teat. If the nipple pulls out easily, it
Bifidus factor is protractile and normal. Many nipples which look flat
Others or short, pull out or protract well and do not cause any
Protein problem, while other nipples which do not protract well
Total 1% 4% (too much) develop during pregnancy and improve more after
Casein 0.5% 3% (too much) delivery when the baby suckles and stretches them.
Amino acids If a nipple does not pull out but goes deeper, it is
Cystine Enough for growing Not enough inverted. A simple technique has been described to help
brain
mothers with retracted nipples breastfeed by applying
Taurine Enough for brain, Virtually absent
retina and bile acid negative suction through a plastic syringe. The nozzle
conjugation end of the syringe is cut. The plunger is withdrawn from
Fat its usual position and inserted through the cut end.
Total 4% (average) 4% Negative suction is then applied via the new open end
Saturation of kept over the nipple and the adjacent areola. Once the
fatty acids Enough unsaturated Too much nipple protracts out, the syringe is removed and the baby
saturated
is put to breast with enough areola in the mouth. When
Linoleic acid
(essential) Enough for growing Not enough repeated before each breastfeed for a few days, the nipple
brain become protractile in most cases.
Cholesterol Enough Not enough
Lipase to digest fat Present None
Select the Right Place for Delivery
Lactose 7% (enough) 3-4% (not It is important to choose such a hospital for delivery where
enough) breastfeeding is supported. Such hospitals are now called
Salts (mEq/l) baby-friendly (see page 133).
Sodium 6.5 (correct amount) 25 (too much)
Chloride 12 (correct amount) 29 (too much) Avoid Unnecessary Use of Drugs Prior to Delivery
Potassium 14 (correct amount) 35 (too much)
Minerals (mg/l) While it is important to reduce a woman’s physical dis-
Calcium 350 (correct amount) 1,400 (too much) comfort, the indiscriminate or excessive use of sedatives,
Phosphate 150 (correct amount) 900 (too much) analgesics and anesthetics may prevent the mother
Iron Small amount, but Small amount, establishing a close contact with her infant immediately
well-absorbed poorly absorbed after delivery and diminish the newborn infant's suckling
(enough) (not enough) capabilities. Episiotomy, unless really indicated, must be
Vitamin Enough Extra needed avoided.
Note Infant milk powder or formula is similar to cow’s milk. The
expensive brands are modified so that they are more like human Initiate Breastfeeding Soon after Delivery
milk. However, the quality of protein and fat can never equal that
of breast milk, and no formula can contain all anti-infective After a normal delivery, most babies want to suckle
substances. Also, if the formula is mixed incorrectly, it can either during the first half or one hour after they are born. The
cause severe malnutrition or obesity and hypernatremia due to too baby should be given to the mother to be held as soon as
concentrated feeds. he/she is born. This also helps her to establish the bond
(Courtesy King) with her baby and to provide colostrum to the newborn.
126 IAP Textbook of Pediatrics
In cesarean delivery, the baby starts breastfeeding as soon
as the anesthetic effects are over. As the mother is on her
back, the baby is placed on pillow(s) raised to the level of
the mother’s breast for convenient positioning of the baby
on to the breast.
Give Colostrum and Avoid Prelacteal Feeds
Sit with the mother within 24 hours after delivery. Tell her
about colostrum which is produced in small amount but
is enough to meet all the needs of the baby in the first few
days. Colostrum is thicker and yellower than later milk.
Feeding this is important immunologically (since it is rich
in antibodies and protective substances), nutritionally (to
provide vitamins and minerals) and developmentally (to
ensure maturation of intestinal mucosa). Giving colostrum
has also been called the “first immunization” of the child.
Compared to that, the mature milk (which appears within
2 weeks of birth) is thin. In the beginning of a breastfeed,
foremilk is rich in proteins, lactose, vitamins, minerals
and water while towards the end of the feed (hindmilk) it
has more fat and is rich in energy.
A vast majority of newborns in our country are not
given colostrum but receive prelacteal feeds (feeds given
before the free flow of milk from the breasts) such as honey,
sugar, glucose, water and artificial milk. This should be
discouraged in a sympathetic manner by minimizing
conflict with traditional beliefs. Colostrum is all the food
needed at this time—no supplements are necessary. A
baby is born with enough water in the body to last several
days if necessary. Many babies lose a little weight in the
first week, but this is normal. If prelacteal feeds are given,
the baby does not suckle adequately from the breast as his
or her stomach gets full. Then he or she shall not get
colostrum. Such feeds may also be contaminated. Allergies
are more common in babies given artificial milk including
powder milk in the first months of life. If these feeds are
given with a feeding bottle, the baby may get used to the
nipple of the bottle and may not make the necessary effort
to suckle and empty the breast. This either results in
breastfeeding failure or may cause engorgement or even
infection of breast.
Help the Baby Suckle in a Good Position
The mother must offer enough of the areola into the baby’s
mouth so that the tongue can express the milk from the
lactiferous sinuses (Fig. 5.2.3). Mother can breastfeed while
lying down so long enough of the areola is in the babies
mouth.
Figure 5.2.3: Suckling in good position. Baby is unwrapped, is
close to the mother, chin touches the breast, mouth is wide
open, lower lip is everted, and much of the areola is in the
mouth. Baby takes slow deep sucks and causes no pain to
the mother (Courtesy King)
Recommend Demand Feeding
The baby must be breastfed as often as he/she wants.
Frequent suckling and emptying of breasts increase milk
production and help to prevent problems like engorgement.
In the initial days, babies have irregular feeding intervals.
They may feed 6 to 12, or as many as 18 times in 24-hour
period. This frequent feeding is likely to settle into more
predictable routine as lactation is established.
Continue Each Feed as Long as Baby Wants
For the baby to get hindmilk as well, allow the baby to
suckle from one breast until the baby releases the nipple
spontaneously. Then the other breast should be offered. If
the baby is not interested, start from the other breast the
next time to keep the milk flowing.
Do Not Wash the Nipple before and after Every Feed
Frequent washing especially with soap, removes the
natural oil from the breast making the skin dry and more
easily damaged. A daily bath is all that is needed to keep
the breasts clean.
Caution Mother in Advance about Breast Engorgement
After the first 3 to 4 days, some mothers may develop
painful engorged breasts. The best way to prevent the same
is to let the baby suckle as often and as soon after birth as
possible. If engorgement persists, relieve it by expressing
milk from the breasts. If health workers help to establish

exclusive breasfeeding, many problems like mastitis and
sore nipples can be prevented.
THE IMPORTANCE OF EXCLUSIVE BREASTFEEDING
Anything less than exclusive breastfeeding for 6 months
of an infant’s life greatly increases her chances of
infection and death, even among well-to-do families.
Unfortunately, only 46 percent women exclusively
breastfeed their babies during first 6 months and only
about 26% babies begin breastfeeding within one hour
after birth. Even at age 0 to 1 month, many mothers give
water or other supplements. Breast milk has enough water
in it to meet the hydration requirements, even under
extremely hot (up to 42°C) and dry (relative humidity 9–
13%) summer conditions of the country.
Exclusively breastfed babies grow rapidly in initial
stages and then may slow down normally at about 3 or 4
months. This so-called “faltering” is part of a normal
growth curve for such breastfed babies and has been
rightly labeled as “pseudofaltering”. Exclusive breast-
feeding should be continued in such babies for 6 months.
BREASTFEEDING BEYOND INFANCY FOR
TWO YEARS OR BEYOND
It is recommended that breastfeeding, in addition to the
complementary foods be continued for 2 years or more .
The observed malnutrition in some prolonged (beyond 12
to 18 months age) partially breastfed children is not due
to consumption of breast milk per se, but is primarily due
to inadequate quantity and quality of the complementary
foods.
Breast milk can act as a cheap and vital source of good
quality proteins, fat, calcium, vitamins and anti-infective
factors beyond the first year of age. It has the highest energy
density of all foods commonly consumed in this age group
in the developing countries and can still provide one-third
of all the energy and protein requirements that a child
needs during the second year of life. Further, the protective
effect of breastfeeding at this stage is likely to be critical for
the survival of malnourished children. Additionally,
breastfeeding, by extending the duration of amenorrhea
following childbirth reduces fertility. Longer intervals
between births can enable mother to provide better care
and attention to the child.
Diet of Lactating Mother
A lactating woman should be advised to eat an extra
helping of the family food and regular consumption of
Infant Feeding 127
green leafy vegetables. There is no need to avoid any
specific food. However, use of excessive caffeine, tobacco,
and alcohol is not desirable.
Important Practical Considerations
Related to the Infant
Adequacy of Breast Milk
A breastfed infant is consuming sufficient milk if he or
she is gaining weight checked at periodic intervals on the
same weighing scale, urinates six times or more a day
with colorless or light yellow urine and is feeding and
sleeping well. Some breastfed babies, however, demand
feeds frequently in the first weeks, at times even after 1/2
to 1 hour while sleeping for 3 to 5 hours at other times.
This is physiological and does not indicate milk
insufficiency.
Stool Frequency
Active, healthy, breastfed babies passing urine normally
may pass frequent watery or frothy motions. This is not
diarrhea and does not need any treatment. At times these
motions are green. Stool examination in some of them may
also show presence of reducing substance. This can also
be normal. No medicine needs to be given and
breastfeeding should be continued. In contrast, a few
breastfed babies evacuate the bowel only every alternate
or third day, but the stool is soft in consistency. This is
also normal and should not be treated as constipation.
Crying
Crying is one of the most common reasons of adding
artificial milk when it is not required. There are many
other reasons for crying in an infant which must be con-
sidered like passage of urine or stools, need for more body
contact, illness, infantile colic, etc.
Multiple Births
Breastfeeding of twins presents no problem. However, we
should ensure that a mother who is not well-nourished
gets adequate nutrition. The situation is obviously more
demanding for triplets.
Low-birth Weight (LBW) Infants
Mother’s milk is the best food for the LBW babies. The
borderline term and growth retarded LBW babies can
suckle fairly well at the breast and should be fed on
128 IAP Textbook of Pediatrics
demand. However, LBW and other high-risk infants who
cannot suckle should be given expressed breast milk in
preference to formula feeds with a small glass, cup and
spoon, tubes, paladai, etc. The child should be put directly
to the breast as soon as possible. Some of these babies may
also need artificial milk. Avoid giving it through a feeding
bottle.
Illnesses in the Infant
Breast milk is the most easily digestible food for an ill
baby. Feeding human milk is actually beneficial in common
infantile ailments including diarrhea and acute
respiratory infections. Breastfeeding, therefore, must be
ensured during such illnesses. The child may suckle less
vigorously or for a shorter time and should receive the
feeds at more frequent intervals. However, breastfeeding
and for that matter, any type of feeding may have to be
temporarily stopped in critically ill infants.
Cleft Lip or Palate
With a cleft of the lips or gums, there is usually no prob-
lem. If the cleft involves the palate, suckling becomes
difficult. Some babies need to be fed the expressed breast
milk through a tube or from a cup until they are able to
suckle well enough at the breast.
Suckling for Comfort
Babies suckle not only out of hunger but also for pleasure
and comfort. They suck on anything that goes into their
mouths—their fingers, a piece of cloth, their thumb, etc.
This does not necessarily mean that they are hungry.
Vitamin Supplementation
Full-term exclusively breastfed infants do not require any
supplementation. If a mother is malnourished with
multiple deficiencies, her diet should be improved and
multivitamin drops may be given to her baby.
Important Practical Considerations
Related to the Mother
Not Enough Milk
Some mothers wrongly perceive that they are not getting
enough breast milk. If the baby is passing a light colored
urine on exclusive breastfeeding, reassure such a mother
that her baby was getting enough milk from her. Doubting
about her ability to produce enough milk can interfere
with the “let-down” reflex. In such a situation, the mother
produces enough milk, but the milk does not flow down.
Also, inadequate suckling by the infant due to
inappropriate feeding technique, e.g. improper positioning
and other difficulties related to breastfeeding that go
unresolved for lack of proper guidance and support can
also lead to insufficient milk.
Frequent suckling in proper position is the secret of
successful breastfeeding. Often, the supplementary feeds
that were introduced because of unfounded fears about
the quality and quantity of breast milk contribute directly
to decreased milk secretion. To help such a mother to
increase her milk supply, it may be helpful to hospitalize
her for about a week, while she is helped to improve the
feeding technique and build up the milk supply. Metoclo-
pramide (10 to 15 mg three times a day) may be given for
10 days to two months to increase the milk supply. If the
mother uses a bottle for feeding the baby, that must be
stopped. The mechanisms of suckling from the breast and
sucking from the nipple of a bottle are different. A child, if
used to bottle, might not make any necessary effort required
to breastfeed. If essential, supplementary milk may be given
after breastfeeding (and not between two breastfeeds) in a
small glass or with a cup and spoon, until the mother’s
milk supply becomes sufficient again.
Engorgement of Breasts
When the milk first comes into the breasts, they feel hard
and painfully full. The best way to prevent this
engorgement is to let the baby suckle as often and as soon
after birth as possible.
To treat engorgement, act as soon as it develops. Use
warm compresses on the breast. Allow the baby to suckle
as far as possible. If the baby cannot get hold of an engorged
breast, help the mother to express milk. Hand expression
is preferable to a pump. After expressing some milk, help
the mother to put the baby to breast. Milk should be
expressed as often as necessary to make the breasts
comfortable.
Blocked Duct, Mastitis and Breast Abscess
If a milk duct becomes blocked, a painful lump forms.
Gently massage the lump towards the nipple to try and
unblock the duct. Continue feeding the baby from the
breast.

If a blocked duct is not cleared, the breast tissue may
become infected, and the breast itself becomes tender and
swollen. If untreated, an abscess develops. Encourage the
mother to continue breastfeeding the baby. If suckling is
painful, help her to express her milk every 3 hours. Warm
compresses help to relieve pain. If mother develops fever,
chills and bodyache, she may need a full course of
antibiotics or drainage of the abscess if required.
Sore Nipples
If the baby does not take enough breast into the mouth,
mother can get sore nipples. To prevent it, make sure that
the baby suckles in a good position. To treat sore nipples,
do not stop breastfeeding but correct the suckling position.
Do not put any cream on the nipples and do not wash
them with soap. If the baby has oral thrush, treat it and
apply the same medicine on the mother’s nipple. Exposure
of breast to air, or leaving a little creamy hindmilk on the
nipples helps healing. If suckling is impossible for a day
or two, express the milk and feed the baby from a cup.
Thin or Watery Milk
Breast milk is normally thinner and more watery than
cow's or buffalo's milk. The foremilk, which at the start of
a breastfeed is thin, is rich in protein, lactose, vitamins,
minerals and water. It contains less fat, while hindmilk,
near the end of a feed is thicker and rich in fat. Babies need
both foremilk and hindmilk and therefore must be allowed
to suckle from one side for as long as they want before
they are offered the other breast. Babies allowed such
freedom often get satisfied by suckling only from one side.
They must be offered the other breast for the next feed.
Maternal Malnutrition
Mothers with mild to moderate chronic malnutrition can
fully breastfeed their infants. If the mother's diet is poor in
vitamins and minerals, these must be supplied. Only with
severe malnutrition or under famine conditions, a woman
may produce a smaller amount of milk. In an under-
nourished mother, the milk is made at the expense of her
own body tissue. So, she must be provided with enough
food. The notion that mothers need to drink more milk or
eat more to produce enough breastmilk is not correct.
Menstruation and Pregnancy
Mother can feed during menstruation and half way
through pregnancy. If she is eating well, breastfeeding
can continue all through the pregnancy.
Infant Feeding 129
Maternal Illness
Most maternal illnesses do not require discontinuation of
breastfeeding. It is recommended even with mastitis, breast
abscess and other infectious illnesses including urinary
tract infection, tuberculosis, hepatitis, typhoid and
leprosy.
As far as the question of HIV and infant feeding is
concerned, the general principle is that in all populations,
irrespective of HIV infection rates, breastfeeding should
continue to be protected, promoted and supported. About
the risk of parent-to-child transmission of HIV, the risk is
reported to be less in exclusively breastfed or exclusively
artificially fed babies compared to those on mixed feeding.
Factors which affect the mother-to-child transmission are: recent
infection with HIV, severity of HIV infection, infection with
other sexually transmitted diseases, obstetric procedures,
duration of breastfeeding, type of feeding, i.e., exclusive
breastfeeding, exclusive artificial feeding or mixed feeding,
condition of the breasts and condition of the baby’s mouth.
Evidence is now available to suggest that breast problems
like sore nipples or mastitis can double the transmission
risks. To reduce this risk, mother may choose to breastfeed
exclusively and stop breastfeeding after six months, or to
avoid breastfeeding altogether. In India where majority of
babies are mixed fed, achieving either is a challenge.
Prevention of breast problems is critical, not only in HIV-
positive mothers but in general population as well to
enhance HIV free survival. This can only be achieved with
skilled assistance to mothers to ensure that the baby
suckles in a correct position to prevent such problems.
However, not breastfeeding has many disadvantages,
both for the mother and her baby. Infants who do not
receive breast milk at all may have 14 times risk of dying
from diarrhea compared to exclusively breastfed babies.
In India with IMR of about 57 per thousand, current
thinking is that “safe” (preventing breast problems and
additional antiretroviral drugs ) exclusive breastfeeding
for the first six months would be the best strategy. The UN
Guidelines for Health Care Managers and Policy Makers
2003 state that if formula feeding is not affordable, feasible,
acceptable, accessible or safe, exclusive breastfeeding is
recommended. National AIDS Control Organization
(NACO) offers antiretroviral drugs for the mother within
4 hours before the baby is delivered and the baby is also
given nivarapine.
Keeping yourself updated on this very complex issue
and a fast changing scenario would be very useful. Women
need access to infant feeding counseling and skilled
130 IAP Textbook of Pediatrics
assistance to help them to decide the best way to feed their
children in their situation and support them in their
choices.
In infections like typhoid, the mother makes specific
antibodies against the infective agent in her breast milk
to protect her baby.
Physically incapacitating systemic illnesses in the
mother may prevent or necessitate discontinuation of
breastfeeding. In the absence of an attendant, it may be
safe to keep the baby away from a psychotic mother. In
such situations, wherever feasible, the breasts should be
emptied frequently to maintain lactation.
Drug Therapy
Majority of the commonly used drugs are compatible with
safe breastfeeding. However, lactating women should
preferably take drugs during or immediately after
breastfeeding to avoid the period of maximum concen-
tration in the blood and milk. Only a few drugs neces-
sitate discontinuation of breastfeeding like anticancer and
antithyroid drugs, radioactive preparations, gold salts,
lithium, etc.
Mother Employed outside the Home
Mother employed outside the home should initiate
breastfeeding like all the mothers and she should take
care not to introduce a bottle feed, just to get the baby
“used” to it. If the child gets used to the bottle, it may
mean the end of a successful breastfeeding experience for
the mother. If a mother cannot take her baby with her to
breastfeed at work, she can express her milk by hand and
leave it for a helper to feed the baby in her absence. The
expressed breast milk (EBM) should be given to the baby
from a clean small glass or a cup. Feeding bottles should
not be used because they are hard to clean, and their use
makes the baby less eager to suckle at the breast. The EBM
can be stored at room temperature for up to 6 hours and
up to 24 hours if kept refrigerated. If the milk separates, it
can be shaken up. It remains good for use.
NONHUMAN MILK (BREAST MILK SUBSTITUTES)
Occasionally, artificial milk may have to be given to
adopted babies or those who have lost their mothers or
such infants who have been hooked to bottle-feeding and
have stopped breastfeeding completely since long. In such
cases, liquid milk consumed by the family should be
utilized and powder milk (commercial infant milk food)
should be discouraged. There is less risk of overdilution
and contamination with liquid boiled milk than with
powder milk. Child is given three parts of pure cow’s milk
and 1 part of water for the first 2 months. Then undiluted
milk is given. Part of excessive fat from pure buffalo’s milk
should be removed by separating the cream from milk
after boiling and cooling it. A teaspoon of sugar is added
to 4 ounces (120 ml) of the feed.
Aim at five, 4 hourly feeds. Starts with an ounce
(30 ml) per kg of weight per feed. For instance, if the
baby weighs 4 kg, give 4 ounces of milk 4 hourly—
omitting the midnight feed.
If powder milk is used, the proportion should be one
level measure of infant milk powder to 1 ounce (30 ml)
of water. Companies have also started marketing various
“follow-on milk” formulas to be given after the age of 6
months. There is no need to use these at all.
Infants who are solely on artificial milk need addi-
tional plain water supplementation.
Bottle-feeding should be avoided because it is diffi-
cult to keep the bottle clean. With a little patience, even a
LBW newborn baby can be taught to take the milk from
a small glass or a spoon, particularly the long spouted
spoons (paladai, jhinook, bondla, gokhari). These are
convenient to hold and easy to clean. If a bottle is used,
make sure that the baby gets a boiled bottle for each feed.
INFANTS MILK SUBSTITUTES ACT 1992
Realizing that aggressive marketing of infant foods and
feeding bottles leads to decline in breastfeeding, the
World Health Assembly in 1981 passed an International
Code of Marketing of Breast Milk Substitutes. In 1992,
the Government of India passed “The Infant Milk Substi-
tutes, Feeding Bottles and Infant Foods (Regulation of
Production, Supply and Distribution) Act, 1992”.
The Act does not allow advertisement of infant milk
substitutes powder or feeding bottle. No display of
placards or posters of baby foods or feeding bottles is
allowed in the hospitals. Incentives or inducement to
mothers or health workers for promoting the sale of
products under the Act is prohibited. The labeling on the
tin and educational material dealing with prenatal or
postnatal care or with infant feeding must include details
outlined in the Act. Those violating the Act can be fined or
imprisoned. The Act is now further strengthened by the
Infant Milk Substitute Feeding Bottles and Infant Feeds
(Regulation of Production, Supply and Distribution)
Amendent Act, 2003. This document has been reproduced

in the annexure. The Act does not allow advertisement of
infant milk substitutes powder or infant foods or feeding
bottles. In fact no baby food can be promoted for children
under the age two.
Those violating the Act can be fined or imprisoned.
Following are some example of the violations of the Act.
• Promotion of any baby food and feeding bottles by
what ever name for children up to two years
• Advertising of baby foods or feeding bottles by any
means of television, newspapers, magazines, journals,
through SMS, emails, radio, pamphlets etc.
• Distributing the product or samples of these to any
person.
• Contacting pregnant or lactating mothers by any
person in a hospital, residence, marketplace, or by
sending pamphlets, posters etc.
• Providing gifts and samples to the mother and
healthcare providers, use of tied sales by providing
free consumer products like soap/bowls with these
products.
• Distributing information and education material to
mothers, families etc.
(But educational material can be given to a health
professional like doctors, nurses provided it has
information prescribed in caluse 7 of the IMS Act, 2003.
The education material should have only factual
information and should not promote the products)
• Tins, cartons and accompanied leaflets of these
products having picture of mothers or babies, cartoons
or any other such images.
Figure 5.2.4: Optimal infant and young child feeding
Infant Feeding 131
• Display of placard, posters in a hospital, nursing
home, chemist shop, etc. for promoting these products
• Sponsoring hoardings of these products for hospitals
and chemist shops.
• Making payments to doctors, nurses for promoting
these products.
• Demonstrating mother or their family members how
to feed these products. However a doctor can
demonstrate this to the mother.
• Giving gifts to doctors, nurses or their associations.
• Giving funds to associations like IAP, IMA, NNF, etc.
for organising seminars, meetings, conferences,
contests, educational courses or sponsoring projects,
research, tours or article in medical journals.
• Fixing commission of employees on the basis of volume
of sales of these products.
ADDITION OF SEMISOLID AND SOLID FOODS
(COMPLEMENTARY FEEDING)
Getting the baby accustomed to other foods besides breast
milk (or other milk) is termed weaning. Some wrongly
interpret it as weaning the baby away from the breast.
Complementary feeding is a better term them weaning
(Fig. 5.2.4).
Importance of Appropriate Addition
After 6 months of age, while breastfeeding is being
continued, addition of other foods is essential to prevent
growth faltering. Delayed introduction of additional foods
132 IAP Textbook of Pediatrics
in an exclusively breastfed infant, results in malnutrition.
Improper introduction of these foods is fraught with
dangers of: (i) diarrhea due to infection from unhygienic
preparation, (ii) malnutrition related to inadequate calorie
intake due to low frequency of feeding and low calorie
density of additional foods.
Timing of Introduction of Semisolids
Semisolid foods to complement breast milk should be
introduced after 6 months of age. The individual decision
should be guided by the growth performance and
physiological maturation of the infant, but they should
never be started before completion of 4 months. To
minimize any interference with the normal course of
breastfeeding, semisolid foods should preferably be given
between breastfeeds.
Continuation of Breastfeeding
Initially, breast milk forms main food of the baby and the
weaning diet is extra. Later, even when more semi- solid
food is added, breast milk still continues to remain an
important component of the infant's diet. Breastfeeding
should be continued for 2 years or more.
Feeding Guidelines
Formulate additional foods from the usual family diet.
The weaning foods in a thickened but mashed, i.e. softened
form, and variety should be attempted. Use of commercial
weaning foods should be avoided as far as possible.
Family pot feeding—giving the family food in a mashed
form, and providing something extra like oil/fat and green
vegetables is best, since it is economical, saves time and
the infant grows up accustomed to the traditional foods.
Enhancing Nutritive Value
The nutritive value of these foods should be enhanced by
enrichment of the staple cereals with pulses (for proteins)
oil/fat and sugar for increasing calorie density and green
vegetables for vitamins, especially, A, B and C, and iron.
Advantage should be derived from the usual diet pattern
of a mixture of cereals and pulses (idli, dosa, pongal, khichri,
missi roti, etc.) by addition of some oil/fat/sugar and green
vegetables. Dilution of weaning diet and use of watery
gruel and lentil or rice water should be strongly discou-
raged. Use of animal milk, milk products, fruits, eggs, fish
or meat, if culturally acceptable and affordable, should be
encouraged. The bulk of the weaning food can be reduced
by malting of grains/cereals.
Frequency, Amount and Consistency of Feeding—Broad
Age-related Guidelines
Infants vary grossly in the amount that they require and
eat. Therefore, in general, mother should be advised to
prepare and offer a mixed nourishing diet based on the
usual family foods and leave it to the baby to take as much
as is desired. The child's general activity and growth, as
judged by the family and the health worker and confirmed
by weighing as often as possible—depending on the
facilities, is good evidence of adequate food intake.
However, the following broad feeding guidelines can be
offered:
Six to Nine Months
After 6 months, one can start with cereal based porridge
(suji, wheat flour, ground rice, ragi, millet, etc.) enriched with
oil/fat and/or animal milk if possible, or mashed fruits
like banana or other seasonal fruits like papaya, mango,
etc. One or two teaspoonfuls are enough to start with, and
the quantity and frequency should be increased gradually.
The baby at the end of this phase should be consuming
half a cup of food.
Gradually the baby should be used to feeding from the
family pot (mashed rice with dal; khichri; egg, meat and fish
if culturally acceptable; a little chappati softened in dal or
milk; dahi; mashed vegetables; fruits, etc. enriched with
some oil/fat and green vegetables). They need four to five
weaning meals a day, in addition to regular breastfeeding.
Nine to Twelve Months
At about 9 months, babies can start chewing on soft food.
The food at this time does not need to be mashed but, can
be chopped or pounded. A variety of household foods
should be given four to five times a day and the quantity
gradually increased. By about one year, young children
should be eating foods cooked for the family but at least
four to five times a day. A child of one to two years needs
about half the food that the mother eats.
Preparation and Storage of Weaning Foods
Careful hygienic preparation and storage of weaning
foods is crucial to prevent contamination. The hands
should be thoroughly washed with soap and water before

preparation and feeding, and the cooking place and
utensils must be clean. The foods should be preferably
fresh, cooked or boiled well and if feasible, prepared
immediately before they are to be eaten. If food has been
kept for over two hours, it is desirable to reheat it thoroughly
until it boils, before consumption.
Feeding during and after Common Illnesses
Feeding should continue during ailments like diarrhea,
respiratory infections, etc. unless the medical condition of
the child contradicts it. Restriction or dilution of food
should be discouraged. Despite anorexia, the infant can
be coaxed to eat small quantities but more frequently, i.e.
after every 2 to 3 hours. After illness, the child should be
provided more than the usual diet to regain the weight
lost.
BABY-FRIENDLY HOSPITAL INITIATIVE (BFHI)
It is now being increasingly recognized that while mothers
want to breastfeed, certain hospitals and health workers
lag behind in their support to the mother. This support is
being provided through the concept of BFHI.
Baby-friendly hospital initiative is a global effort with
hospitals to provide support to the mother before, during
and after delivery so that she has a joyful breastfeeding
experience. These hospitals must fully practise all ten of
the “ten steps to successful breastfeeding” given in a joint
WHO/UNICEF document.
Ten Steps to Successful Breastfeeding
Every facility providing maternity services and care for
newborn infants should:
• Have a written breastfeeding policy that is routinely
communicated to all health care staff.
• Train all health care staff in skills necessary to imple-
ment this policy.
• Inform all pregnant women about the benefits and
management of breastfeeding.
• Help mothers initiate breastfeeding within half-hour
of birth.
• Show mothers how to breastfeed, and how to main-
tain lactation, even if they should be separated from
their infants.
• Give newborn infants no food or drink other than
breast milk, unless medically indicated.
• Practice rooming-in—allow mothers and infants to
remain together 24 hours a day.
Infant Feeding 133
• Encourage breastfeeding on demand.
• Give no artificial teats or pacifier like dummies or
soothers to breastfeeding infants.
• Foster the establishment of breastfeeding support
groups and refer mother to them on discharge from the
hospital or clinic.
Hospitals which practice the “ten steps to successful
breastfeeding” are given public recognition and are given
a plaque that they can put by their front entrance
designating them as “baby-friendly”. Country level
guidelines for achieving “baby-friendly” hospital status
have been developed. Assisted by the Government,
UNICEF and WHO, a National Task Force has been formed
with representatives from Indian Medical Association,
Association of Obstetricians, Pediatricians, Nurses and
Hospital Administrators, Breastfeeding Promotion
Network of India (BPNI) and Association for Consumers
Action on Safety and Health (ACASH). More and more
hospitals are now being given this status.
The concept of supporting mothers to breastfeed is
important. However, promotion of breastfeeding alone is
not enough to make a hospital baby-friendly. This should
also include practices which will make hospitals safe and
friendly for newborns and their mothers such as:
i. Safer and “mother-friendly” delivery practices,
ii. Proper care of the umbilical cord,
iii. Warming and temperature regulation of newborn
after birth,
iv. Early diagnosis and management of conditions
such as absence of spontaneous breathing, aspira-
tion, sepsis, hypoglycemia, etc.
National Guidelines on Infant and
Young Child Feeding
The Government of India has issued a set of guidelines for
the promotion of optimal feeding practices of infants and
young children. These are available from the website of
the Ministry of Women and Child Development. The
contents of this chapter are in line with the spirit of the
national guidelines.
BIBLIOGRAPHY
1. Anand RK, Kumta NB, Kushwaha KP, Gupta A (Eds).
The Science of infant feeding. Jaypee Brothers: New Delhi,
2002.
2. Baumslag N, Putney PG. Breastfeeding: The Passport to
life. NGO Committee on UNICEF, New York, 1989.
134 IAP Textbook of Pediatrics
3. Breastfeeding promotion network of india (2006). Joint
statement on infant and young child feeding.
www.bpni.org Accessed on June 17,2008.
4. Ghosh S. Nutrition and Child Care. Jaypee Brothers:
New Delhi, 1997.
5. Gupta A, Rohde Jon E. Infant and young child under-
nutrition:Where lies the solution ? Economic and political
weekly. December 4, 2004.
6. Kesaree N, Banapurmath CR, Banapurmath S, Shamanur
K. Treatment of inverted nipples using a disposable
syringe. J Hum Lact 1993;9:27–29.
7. King FS, Anand RK. Helping Mothers to Breastfeed.
Association for consumers action on safety and health:
Mumbai, 1994.
8. National family health survey. http://www.nfhsindia.
org/nfhsz.html.Accessed on June 17,2008.
9. Sachdev HPS. Infant feeding—major practical considera-
tions. In Sachdev HPS, Choudhary P (Eds): Nutrition in
Pediatrics. Department of Pediatrics, Maulana Azad
Medical College: New Delhi, 1994;79–128.
6.1 Protein Energy Malnutrition Meenakshi N Mehta .................................................................................................................................... 136
6.2 Water Soluble Vitamins: B Complex Vitamins Shashi N Vani .............................................................................................................. 163
6.3 Fat Soluble Vitamins Panna Choudhury .................................................................................................................................................. 166
6.4 Trace Elements B Bhandari ...................................................................................................................................................................... 171
6.5 Child and Adolescent School Health Education Sushil Madan ............................................................................................................ 176
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6.1 Protein Energy Malnutrition
“Underlying every other condition is malnutrition, due to both
calorie and protein deficiency. Though poverty is the main
contributing cause, it is greatly aggravated by lack of proper
dietary knowledge.”
INTRODUCTION
Protein energy malnutrition (PEM) and growth
retardation are probably the most widespread health and
nutritional problems of the developing countries,
including India. UNICEF’s report “The Progress for
Children” identifies that in the developing world 146
million children under five years are under weight,
predisposing them to serious complications from
common childhood illnesses. Consequently protein
energy malnutrition is the most deadly form of
malnutrition. It is estimated that it is the primary or
associated cause of around half of the nearly 11 million,
i.e. 5.6 million annual deaths each year or 30,000 each
day in children under five years. Maternal and child
undernutrition is the underlying cause of 3.5 million
deaths, 35 percent of the disease burden in children
younger than 5 years and 11 percent of total global
DALYs (disability adjusted life year). As per the estimates
stunting, severe wasting and intrauterine growth
restriction together were responsible for 2.2 million
deaths and 21 percent of DALYs, for children younger
than 5 years. Not only these deaths are preventable, but
these needless deaths on regular basis is a “humanitarian
disaster that cannot be allowed to continue” UNICEF
says A recent update using data from 2001 and DALY
approach confirmed that undernurition/protein energy
malnutrition remains the single leading cause of health
loss in the world today Child underweight for age
accounts for 8.7 percent of the total disease burden in
people living in low and middle income countries,
mainly those of South Asia and sub-Saharan Africa.
Eighty percent of the world’s undernourished children
live in just 20 countries. Of an estimated 178 million
children aged younger than 5 years who are stunted (i.e.
have height for age Z score of less than—2), most live in
sub-Saharan Africa and South Central Asia. 160 million
(90%) stunted children live in just 36 countries and make
up 46 percent of the 348 million children in those
Meenakshi N Mehta
countries About 55 million children are wasted (i.e. have
a weight for height Z score of less than–2) of whom 19
million have severe wasting (weight for height Z score
of less than—3) or severe acute malnutrition (weight for
height Z score of – 3 or associated edema) Although
nutritional deficiencies are epidemic throughout
developing world South Asia (Bhutan, Maldives,
Afghanistan, Sri Lanka, Bangladesh, Pakistan, India and
Nepal) is home to more than half the total number of
underweight children, most of who live in India. With a
rate of 46 percent, the levels of children underweight in
South Asia are staggering. Three countries, India,
Bangladesh and Pakistan account for half the world’s
UW children, despite having just 29 percent of the
developing world’s under five population. In South Asia
other forms of undernutrition have persisted 44 percent
of U5 are stunted and 15 percent wasted. In many
countries a chronically poor diet and lack of access to
safe sanitation is compounded by gender discrimination.
South Asia is the only region in which girls are more
likely to be underweight than boys. In India, one out of
every three adult women is underweight and therefore
at risk of delivering low birth babies. After the
World Summit for Children in 1990 announced key
requirements for improving child health with a crucial
focus on nutrition, the UN incorporated these nutritional
aims into its first Millennium Development Goal (MDG
1: to eradicate extreme poverty). A target for MDG 1 is
to reduce by half, between 1990 and 2015, the proportion
of people who suffer from hunger which is to be
measured by assessing the percentage of children under
five years who are underweight.
DEFINITION
WHO defined PEM as range of pathological conditions
arising from coincidental lack in varying proportions of
proteins and calories , occurring most frequently in
infants and young children and commonly associated
with infection. The extent of weight loss and growth rate
varies with severity of PEM, i.e. in the early stages, there
is failure to maintain weight or growth rate, but as it
becomes progressive, there is loss of weight associated
with loss of subcutaneous fat and muscle mass with
 Nutrition 137

dysfunction of many vital organs which lead to a variety

of clinical features. With increasing severity, there is
increasing failure in the homeostatic mechanisms of the
body and damage to the immune defences which may
result in infections, shock and death. In Nelson’s
Textbook of Pediatrics XVI ed., Heird William has used
the word undernutrition for malnutrition interchange-
ably; however he has coined a new name “Severe
Childhood Under nutrition“ for Protein Energy
Malnutrition. His argument is that under/malnutrition
is a result of inadequate dietary intake of single nutrient,
energy and/or protein, whereas PEM is usually
accompanied by deficiencies of other nutrients and the
term “severe childhood undernutrition” more accurately
describes the condition. But in the next paragraph it is
mentioned that this is a spectrum ranging from mild
undernutrition resulting in some decrease in length for
age and/or weight for age through severe forms of
undernutrition resulting in more marked deficits in
weight for age and length for age as well as wasting. Use
of term “Severe Childhood Undernutrition” for milder
variety of PEM is misleading and unjustifiable, since mild
is opposite to severe. Hence the conventional term PEM
seems to be more appropriate. If at all, we may call it
Energy Protein Malnutrition (EPM) to denote PEM, as
energy deficiency is much common than protein
deficiency and the incidence of energy deficiency is 10 Figure 6.1.1: Morbidity and mortality
to 15 times higher compared to protein deficiency in the
children suffering from PEM.
trated in a relatively small number of states, districts and
villages. A recent World Bank report noted that five states
MAGNITUDE OF THE PROBLEM
account for about 80 percent of malnourished children.
Despite all time high India’s economic growth, A follow-on mapping study has identified the districts
improving literacy and even declining infant mortality, where problem is most severe. The incidence of PEM is
India continues to have the dubious distinction of being higher in nutritionally vulnerable groups: young children
among the worst off in the world: a high percentage of and women during pregnancy and lactation, as the
malnourished children (Fig. 6.1.1). The last National calorie and protein requirements are larger, relative to
Family Health (NFHS) survey data released in 2007 their size than in older children and adults. Evidence
showed that 45 percent of Indian children are under shows that most of the damage caused by malnutrition
weight and 70 percent are anemic. Of the underweight happens either when child is in the womb or in the first
children (0-59 months) 19.8 percent were wasted and 48 two years of life. Most of the impairment to brain
percent stunted, 43 percent are from rural area and 33.7 development and future productivity in these early
percent from urban area. Indian children are twice as months of life is irreversible. As per the last NFH survey,
likely to be malnourished as even those in sub–Saharan the most common age of PEM is between 6 months and
Africa and five times more likely to be than children in 2 years and around 50 to 60 percent children are mal-
China. Even with its remarkable economic programs, nourished by 2 years; stunting is a major problem and
India’s malnutrition levels in the last 7 years since the was observed in almost half of children. About 6,600
last NFH survey have not been getting any better. As under five children die everyday of malnutrition in India.
per geographic focus, malnutrition in India is concen- PEM accounts for death in about 7 percent of cases and
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is underlying cause of death in 46 percent cases below 5
years of age. Majority of PEM (60-70%) is of mild to
moderate degrees and is severe in only 2 to 5 percent of
cases.
Apart from weight for age, other indicators like height
for age, and weight for height are also used to assess the
nutritional status of the children. In Z score classification,
children below 2 standard deviation (SD) are classified
as malnourished.

ECOLOGY/ETIOLOGY OF MALNUTRITION
Protein energy malnutrition (PEM) is the result of a
complex interplay of interacting and related factors in
the individual, family and community. Inadequate
dietary intake and disease are immediate determinants
of PEM. Disease may affect PEM by various mechanisms. Figure 6.1.3: Socioeconomical and biological
Conversely, PEM may increase susceptibility to and determinants of PEM
severity of infections. The causes in individual are
anorexia, increased losses from intestine, malabsorption
and micronutrient deficiency disease, infectious diseases,
inadequate intakes of breast milk, early weaning from
breast, late weaning and inadequate access to food. The
familial causes are maternal illiteracy, poor knowledge
and practices of child rearing, maternal malnutrition,
large number of under 5 children, abrupt or early
weaning from breast, poverty, overcrowding, poor living
and sanitary conditions, unemployment, alcoholism or
debt. The community causes include national poverty,
poor educational status, inadequate medical facilities,
cultural practices and beliefs, marginalizing of girls and
women, natural and man-made disasters, poor rainfall

Figure 6.1.4: Socioeconomical milieu of PEM

or excess rain, or poor facilities for storage and transport,

Figure 6.1.2: Ecology of PEM
and hoarding and black marketing. The community and
national causes have direct impact on the family and
individual child. Thus, PEM is an end result of many
ecological problems (Figs 6.1.2 to 6.1.6). Occasionally, the
terms primary malnutrition and secondary malnutrition
are used to denote the etiology. These terms refer
respectively, to malnutrition resulting from inadequate
food intake and malnutrition resulting from increased
nutrient needs, decreased nutrient absorption, and/or
increased nutrient losses. Both primary and secondary

Figure 6.1.5: Mortality related to bottle feeding
Figure 6.1.6: Relation of morbidity due to milk tin foods
resulting into severe PEM
malnutrition occur in developing as well as developed
countries; malnourished children often present with
gastroenteritis, pneumonia.
In dealing with the problem of PEM, certain common
myths need to be dispelled, for it is not poverty and lack
of food alone that cause malnutrition. In fact, in the
richest 20 percent of India’s population, more than 1 in 4
children are underweight and nearly 2 out of 3 anemic.
In the developed nations like USA, PEM has been
reported in families who use unusual and inadequate
Nutrition 139
foods to feed infants, whom the parents believe to be at
risk for milk allergies and also in families who believe in
fad diets. Many cases are associated with rice milk diet,
a product that is very low in protein content.
In addition, PEM has been noted in chronically ill
patients in neonatal or pediatric intensive care unit as
well as among patients with burns, HIV, cystic fibrosis,
failure to thrive, chronic diarrhea syndromes, malig-
nancies, bone marrow transplantation and inborn errors
of metabolism.14
Malnutrition does not only affect children in
developing countries. In more developed areas of the
world the prevalence of obesity in childhood is increasing
rapidly and in Europe in 2004, there were an estimated
14 million overweight children, 3 million of who were
obese .This trend has also been seen in India as well in
economically well to do families the school going
children have been found to be overweight due to faulty
food habits—consumption of junk foods of high
carbohydrate and fat content—burgers, pizzas, chips,
popcorn, “batatawadas, samosas”, sweets, chocolates,
etc. aerated beverages like Coke, Thumbs up and
sweetened synthetic fruit juices. Fruity, etc. compounded
by TV culture, video games, computer with decreased
physical activity and thus increase of anabolism.
PATHOPHYSIOLOGY OF PEM
Many of the manifestations of PEM represent adaptive
responses to inadequate energy and/or protein intakes.
In the face of inadequate intakes, activity and energy
expenditure decrease. However, despite these adaptive
responses fat stores are mobilized to meet the ongoing,
albeit lower, energy requirement. Once these stores are
depleted, protein catabolism must provide the ongoing
substrates for maintaining basal metabolism. In the etio-
pathogenesis of PEM, there has always been a vigorous
debate. Why is it that among children destined to become
malnourished some develop kwashiorkor while others
develop marasmus? What are the determinants? Several
insults have been proposed as principal causes of
kwashiorkor including dietary protein deficiency,
aflatoxin in food as well as diarrhea, impaired renal
function, decreased Na + , K + ATPase activity, and
depressed cellular protein synthesis reinforced by
infection. The latest theory proposes that kwashiorkor
arises from excessive noxious insults, resulting in the
generation of sufficient reactive oxidative free radicals
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to exceed the host’s antioxidant capacity. Children with
kwashiorkor, when compared with marasmic or normal
controls have greater concentrations of biomarkers of
oxidative stress and damage as well as lower blood
concentrations of antioxidants. Furthermore, clinical
resolution of kwashiorkor coincides with the return to
normal of these markers. This proposal is supported by
low plasma concentrations of methionine, a dietary
precursor of cysteine, which is needed for synthesis of
the major antioxidant factor glutathione. This possibility
also is supported by lower rates of glutathione synthesis
in children with edematous compared to non edematous
PEM.
CLINICAL MANIFESTATIONS
The clinical manifestations of malnutrition depend on
the severity and duration of nutritional deprivation, the
age of the undernourished subject, relative lack of
different proximate principals of food and micronutrients
and the presence or absence of associated infections.
Nutritional marasmus and kwashiorkor are two different
extreme forms of a continuous process of malnutrition.
Nutritional marasmus results from predominant energy
deficiency whereas kwashiorkor is due to predominant
protein deficiency though some energy deficiency may
co-exist. As per Gopalan a well known nutritionist, the
dietary background of children suffering from
kwashiorkor and marasmus may well be the same; the
difference is of adaptation to deficiency. As per this
adaptation theory marasmus is an extreme degree of
adaptation to prolonged inadequacy of energy in the diet,
whereas kwashiorkor is due to adaptation failure or
dysadaptation to two situations; first, continued prolon-
gation of the stress of malnutrition and second, sudden
precipitation or aggravation by a fulminant infection such
as measles, diarrhoeal episode, pneumonia or pertussis.
Further he explains that relatively mild effect of
adaptation may lead to nutritional dwarfism.
Occasionally, patients who are initially marasmic may
develop edema due to protein loss when the individual
is known as marasmic kwashiorkor. In clinical practice,
such extremes account only for a small proportion of
cases of malnutrition. Malnutrition can be compared to
an iceberg; while only tip of the iceberg, i.e. the severe
forms are seen above the surface of the water, those
hidden under the surface constitute a vast majority of
children suffering from mild and moderate forms of PEM
which remain hidden in the community. Since they are
Figure 6.1.7: The “Iceberg” of malnutrition
not brought for any medical attention they are at a high-
risk of deterioration and progress to severe forms if
uncared for prolonged period (Fig. 6.1.7) A majority have
mild to moderate deficiency with varied clinical
manifestations, and this range is known as protein energy
malnutrition (PEM). Besides these specific syndromes,
protein energy deficiency impairs resistance to infection
and is consequently associated with high morbidity and
mortality rates, especially among toddlers in poorly
nourished communities. Mild degrees of protein energy
deficiency, leads to growth retardation rather than frank
malnutrition: this may be associated with some degree
of retardation in mental development.
CLINICAL FEATURES
Protein energy malnutrition (PEM) is most common in
under 5 children, with peak incidence between 6 months
to 3 years. Artificially fed babies usually from lower
socioeconomic status develop PEM below 6 months of
age. They are usually associated with infection also. Initial
response to nutritional deprivation is of two types:
1. Dynamic children: The infants remain active but fail
to gain weight and later length, and
2. Sedentary children: The children who maintain their
growth initially by limiting their activities. But
ultimately they also fail to grow. About two-thirds of
children with PEM do not present with clinical signs
and are diagnosed by anthropometry. However,
children with long standing nutritional deprivation
fail to develop any of the following manifestations:
depigmented lusterless hair—easily pluckable. Skull
circumference gets arrested. Other features of chronic
PEM may be glossitis, stomatitis, gingivitis, pallor,
thin lusterless skin, wasting, edema, vitamin A
deficiency, rickets, parotid enlargement, etc.
These children may manifest as prekwashiorkor,
kwashiorkor, marasmus, marasmic kwashiorkor, and
nutritional dwarfism.
 Nutrition 141

Marasmus
Marasmus can develop in the first months of life, and
will result, if mother’s milk supply is insufficient, as a
result of which the mother feeds the baby with diluted
buffalo’s , cow’s, goat’s or even tin milk, and very little
or no other food is offered. Hence common age of
occurrence is 0 to 2 years, but it can occur at a later age
also. Marasmus is characterized by failure to gain weight
and irritability, followed by weight loss and listlessness
until emaciation results. Marasmus is diagnosed by gross
loss of subcutaneous fat and the infant seems to have
only skin and bones. There is conspicuous absence of Figure 6.1.8: Marasmus
edema. Growth retardation is severe and obvious. The
head appears disproportionately large with very little
of stamina, loss of muscle tissue, increased susceptibility
hair and if cut does not grow back easily. Weight is less
to infections, vomiting, diarrhea, anorexia, flabby
than 60 percent of expected weight.
subcutaneous tissues and edema. The edema usually
The ribs are visible and the costchondral junctions
develops early and may mask the failure to gain weight.
look prominent because of loss of subcutaneous tissue.
It is often present in internal organs before it is recognized
The child is conscious, alert but apathetic. In extreme
in the face and limbs.
cases, the child is disinterested in surroundings and sits
Edema is characteristically pitting. It usually occurs
listless for long hours. The facial pads of the fat are last
first above the ankles and is detected by pressing firmly
to go, and when that happens, the child looks like a
over the lower third of the medial surface of the tibia,
wisened old man. Usually, there is moderate anemia, but
rarely fullness of dorsum of the feet or puffiness round
may be associated with vitamin deficiencies, infections
the eyes, occurs even earlier. In later stages, the whole
and infestations and electrolyte balance with diarrheal
face, hands and body may be edematous, but ascites is
instances. In the early stages, the child’s appetite is good
rarely due to kwashiorkor alone. Edema is mainly due
and readily accepts what is offered. However, in
to tissue wasting, together with low plasma osmotic
advanced stages, there is loss of appetite and it requires
pressure caused by low serum albumin level. The child
a lot of tact and patience to coax the child to eat. Infants
is listless, lethargic, apathetic and miserable, his moaning
are often constipated but may have starvation diarrhea
cry is characteristic. The hair changes are variable. Hair
with frequent, small stools containing mucus. The
may be thin, dry, brittle and lusterless. These become
abdomen may be distended or flat, with the intestinal
straight and hypo pigmented—become grayish-white or
pattern readily visible. There is muscle atrophy and
reddish-brown. During recovery, the growing part of the
resultant hypotonia. As the condition progresses, the
hair gets approximately pigmented, and gives
temperature usually becomes sub normal and pulse
appearance of “Flag”. The skin changes are not constant
slows (Fig. 6.1.8).
and manifestations are known as dermatosis. Skin
becomes darkened in irritated areas but in contrast to
Kwashiorkor
pellagra, it does not occur in areas exposed to sunlight.
The word “kwashiorkor” was suggested by Dr Cicely Depigmentation may occur after desquamation in these
Williams in early 1930s. It is an African word which areas, or it may be generalized. The skin lesions appear
means “the disease that occurs when the child is as large areas of erythema, followed by hyperpigmen-
displaced from the breast by another child”. The age tation. The skin becomes dry and hyperkeratotic. The
incidence is later than that of marasmus and this epidermis peels off in large scales, exposing a raw area
condition is uncommon under the age of 1 year underneath which is prone to infection. It resembles old
Kwashiorkor may initially present with vague paint flaking off the surface of the wood. The lesions are
manifestations that include lethargy, apathy and/or moist, common on areas exposed to continuous pressure
irritability. When advanced there is lack of growth, lack and irritation. In severe cases petchiae or ecchymoses
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CLASSIFICATION OF PROTEIN ENERGY
MALNUTRITION (PEM)
Protein energy malnutrition (PEM) is a generalized
syndrome complex, and it is very difficult to classify it
using a single parameter. A large number of
classifications using anthropometric, clinical, and
biochemical parameters have been proposed.

Gomez’s Classification
This is the first proposed classification based on weight
for age.
Figure 6.1.9: Kwashiorkor—extensive dermatosis
Standard weight for age measurement used was
may appear. Alternate areas of hypo and hyperpigmenta- Harvard growth standard, 50th centile being 100 percent.
tion give a resemblance to pavement and is known as Weight of the child Grade
‘pavement dermatosis’. Similarly, the various skin
changes are sometimes seen in a particular mosaic form, 90-110% of standard Normal
giving the name of mosaic dermatosis. Liver may be 75-90% of standard 1st degree malnutrition (mild)
enlarged and fatty, there may be associated infections in 60-74% of standard IInd degree malnutrition
the form of diarrhea, respiratory infections or urinary (moderate)
tract infections and vitamin deficiencies—vitamin A Less than 60% of IIIrd degree malnutrition
standard (severe)
thiamine, riboflavin and niacin. Eventually, there is
stupor, coma and death (Fig 6.1.9).
Jellife’s Classification
Marasmic Kwashiorkor
Nutritional grade Percentage of standard weight for
Children with severe muscle and fat wasting, but with age (50th centile of Harvard standard)
presence of edema are called ‘marasmic kwashiorkor’.
This syndrome is seen in children with those who have Normal More than 90 percent
marasmus, but suddenly develop edema due to increased Grade I 80–90 percent
deficiency of protein than before. Thus the clinical
Grade II 70–79 percent
features are those of both marasmus and kwashiorkor.
Anemia may be moderate, and one or more vitamin Grade III 60–69 percent
deficiencies may be evident (Fig. 6.1.10). The usual Grade IV Less than 60 percent
differentiating features of marasmus and kwashiorkor
are summarized in Table 6.1.1.
Classification Based on National Centre for Health
Statistics (NCHS) (USA) Standards

Indices Nomenclature Cut-off points for defining

for deficit of malnutrition
index % of refe- Z or SD score
rence from reference
median median
Weight for Wasting < 80 <–2
height
Height for age Stunting < 90 <–2
Weight for age Underweight < 80 <–2
Figure 6.1.10: Marasmic Kwashiorkor
 Nutrition 143

TABLE 6.1.1: The principal differentiating features of protein energy malnutrition (PEM)

Marasmus Kwashiorkor
A. Usual age 0–3 years 1–3 years

B. Essential features
1. Edema None * Lower legs, sometimes face or generalized.

2. Wasting *Gross loss of subcutaneous fat Sometimes hidden, sometimes fat blubbery.
“All skin and bone”
3. Muscle wasting Obvious Sometimes hidden

4. Growth retardation Obvious Sometimes hidden

5. Mental changes Usually apathetic quiet Usually irritable moaning, also apathetic.

C. Variable features

1. Appetite Usually good Usually poor

2. Diarrhea Often (past or present) Often (past or present)

3. Skin changes Seldom Often—diffuse depigmentation occasional

flaky paint or enamel dermatosis
4. Hair changes Seldom Often sparse, straight silky, dyspigmentation,
gray or reddish
D. Biochemistry/pathology

1. Serum albumin Usually normal (or low) * Low

2. Urinary urea per g creatinine Usually normal (or low) * Low

3. Urinary hydroxyproline * Low * Low

per g creatinine
4. Serum essential * Low * Low
amino acid index

5. Anemia Uncommon * Common

6. Liver biopsy * Normal or atrophic * Fatty changes

*These are the most characteristic or useful distinguishing features.

Classification Suggested by FAO/WHO IAP Classification

Expert Committee Nutrition Subcommittee of the Indian Academy of
Pediatrics 1972, using the standard value (100%) as 50th
Nutritional Body Weight Edema Deficit in percentile of Harvard growth standard.
status as % Standard Weight for
for age Height Nutritional grade Percentage of standard weight for age
Under weight 80–60 0 Minimal Normal More than 80 percent
Nutritional dwarfism <60 0 Minimal Grade I 71–80%
Grade II 61–70%
Marasmus <60 0 ++ Grade III 51–60%
Kwashiorkor 80–60 +/++ +/++ Grade IV < 50% or less
Marasmic kwashiorkor <60 + ++ Add (K) for presence of edema
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Waterlow Classification Acute vs chronic deficiency: These parameters no doubt
are the most useful and easily used procedures currently
Normal Wasted Stunted available for field surveillance. Weight and arm
Weight/Age (%) 100 70 70 circumference are affected within a short duration of
inadequate nutrient intake and ill-health, while height
Weight/Height (%) 100 70 100
and head circumference do not change so rapidly. A
Height/Age (%) 100 100 84 slowing in the rate of growth indicated by poor gain in
height would take 6 months to manifest itself while a
slowing of weight gain or loss can be demonstrated
Interpretation of Indicators within a month. A child can loose weight but not height.
Weight/Height = Weight of the child/Weight of a Anthropometric parameters can be classified into 2
normal child of same height × 100 main groups, the age dependent and age independent
(used when child’s age is not known) criteria.
Height/Age = Length or Height of the child/
Length or Height of a normal child Age Dependent Criteria
at same age × 100 Weight for age: Serial weighing and recording of weight
Nutritional status Stunting % Wasting % for age charts is the most useful and commonly used
of Height/Age of Weight/Height method for monitoring and supervising growth as it is
the most sensitive method for identifying those with
Normal > 95 > 90
nutrition and health problems. Weighing is a quick and
Mildy impaired 87.5–95 80–90 easy task both for the medical as well as the paramedical
Moderately impaired 80–87.5 70–80 health workers the only necessary tools being weighing
Severely impaired < 80 < 70 scales and charts. The weight can be expressed as:
(i) percentage of the median value as suggested by
Gomez et al. Normal more than 90 percent, Grade III
Arnold’s Classification
below 60 percent of the expected weight for age. In India,
(Based on Midarm Circumference-MAC) or
Indian Academy of Pediatrics has suggested that the limit
(Mid-upper Arm Circumference-MUAC)
of normal be lowered to 80 percent and that various
Nutritional Status MAC (cm) grades be defined accordingly: Normal > 80 percent,
Grade I: 80 to 70 percent, Grade II: 70 to 60 percent, Grade
a. Normal 13.5 and above
III: 60 to 50 percent, and Grade IV: < 50 percent.
b. Mild to moderate PEM 12.5–13.4
c. Severe PEM 12.4 or less.
It can be expressed by use of median and standard
deviation values or as the percentage so the reference
data where the median value is 50th percentile. This
Wellcome Trust Classification method is employed to chart the upper and lower lines
Weight for age Edema Clinical type of PEM of the ‘Road to Health’ on the growth chart. In these
(% of expected) charts the upper line is equal to the 50th percentile of the
weight for boys, the lower line being the 3rd centile for
< 80 Absent Under weight
girls.
60–80 Present Kwashiorkor
Height for age: Compares a child’s height with the
< 60 Absent Marasmus expected height/length for a healthy reference child of
< 60 Present Marasmic kwashiorkor the same age. It is not useful for early diagnosis of
malnutrition as changes in height occur relatively slowly
NUTRITIONAL ANTHROPOMETRY compared to changes in weight.
It is a valuable index of assessment of nutritional status
Age Independent Criteria
of children and mothers. Among the most studied are
weight, length/height arm circumference, skinfold Mid-upper arm circumference (MUAC) or midarm
thickness, chest circumference and head circumference. Circumference (MAC): Between 1 to 5 years, the MUAC is

relatively constant between 16.5 to 17.5 cm. Any child in
this group whose MUAC is less than 12.5 cm is classified
as undernourished. MUAC is a useful method of
screening large number of children during nutritional
emergencies but is less useful in long-term growth
monitoring programs.
Weight for height: The degree of wasting can be assessed
by comparing the child’s weight with the expected
weight of a healthy child of same height. Combinations
of these measurements have been suggested sometimes
to distinguish ‘types’ of malnutrition. For example,
Waterlow proposed that weight/height allows one to
distinguish between children who have suffered
malnutrition in the past from those who are currently
experiencing malnutrition. In chronic malnutrition, the
child is ‘stunted’, i.e. his weight for age and height for
age are low. In acute malnutrition, however, his height
for age is appropriate, but he is ‘wasted’ (low weight for
height and age) Thus, weight and height measurements
together are useful to understand the dynamics of
malnutrition, distinguishing between current malnutri-
tion and long-term or chronic malnutrition.
Quackstick: Quacker’s Midarm circumference measuring
stick is a height measuring rod calibrated in MUAC
rather than height, values of 80 percent of expected
MUAC for height are marked on the stick at corres-
ponding heights levels and the child is made to stand in
front of this stick. His nutritional status is easily read as
50, 60, 70, or 80 percent of the standard. If a child is taller
than his circumference level on the stick, he is considered
malnourished. The ‘quackstick’ originally designed in
Mexico, has been adapted in Africa and India after local
modifications (Fig. 6.1.11).
Mid arm circumference to head circumference ratio: A ratio
of 0.280-0.314 indicates mild malnutrition, 0.250 to 0.279
moderate PEM, and less than 0.249 severe PEM.
Midarm/height ratio: Less than 0.29 indicates gross
malnutrition (normal—0.32 to 0.33).
Chest/head circumference ratio: Chest circumference
becomes equal to head circumference at 1 year, and after
2 years, it becomes more than head circumference. In
PEM, it is still smaller than head circumference beyond
2 years of age.
Skin fold thickness: It is an indicator of availability of caloric
stores in the form of subcutaneous fat. Sites for
measurements are usually the triceps and subscapular
Nutrition 145
region. Type of instrument used is skin caliper of
Harpenden and Best type. Its normal value is present in
Tanner’s chart and measurements below 90 percent of
the standard are considered subnormal (80-90% mild,
60-80% moderate and less than 60% severe malnutrition).
Mid-thigh and calf circumference: Standards for mid thigh
and calf circumference have been developed. The values
are typically low in weaning retardation of weight gain.
THE GROWTH CHART
While the reliability of a single anthropometric
measurement may be a suspect and difficult to interpret
because of existing wide variations in any population
and may also lack adequate predictive value, measure-
ments at regular intervals permit systematic assessment
of a child’s growth. The idea of monitoring the growth
of the individual child on a long-term basis which would
be useful in the provision of child health care, gave rise
to the concept of “growth chart”, pioneered by Morely
in 1959 as result of long -term study of child growth in
Imesi-West Nigeria. The growth chart has been prepared
on the principle of regular monthly weighing of the child
under 5 to 6 years. The child’s weight is plotted every
month against his or her age, giving a “weight for age
“graph—a growth curve. Since Morley’s original
suggestion and design over last 40 years, various
modifications have been made and these growth cards
are printed in various languages and are used in about
80 countries all over the world (Figs 6.1.12 and 6.1.13).
MULTIPLE NUTRITIONAL DEFICIENCIES
As the nutritional deficiencies are generally multiple,
anemia due to deficiencies of iron, vitamin B12 or folate
or protein may be associated. Thus the anemia may be
hypochromic microcytic, macrocytic, rarely megaloblas-
tic or normocytic normochromic. Deficiencies of vitamin
B-complex factors, especially ariboflavinosis, are not
unusual. Vitamin A deficiency manifesting as
keratomalacia, reported in 10 to 20 percent of cases of
kwashiorkor can result in xerophthalmia, leading to
blindness. Vitamin C deficiency may become severe to
develop frank scurvy, which manifests in as painful
joints–with restricted movements, subperiosteal
hemorrhages, ecchymoses at pressure points and rarely
even bleeding gums. Since growth gets arrested in severe
PEM, rickets may become manifest when the child starts
growing with nutritional rehabilitation.
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Figure 6.1.11: Quacstick—modified for Indian children

Mineral Content Serum magnesium levels are significantly low in children

Potassium: The total body potassium may be markedly
decreased in PEM. The loss is due partly to the cellular
breakdown but more so by the loss in diarrheal stools.
Potassium being mainly an intracellular ion, its deficits
has an impact on the cellular metabolism particularly in
the organs like muscles, kidneys and pancreas.
Other electrolytes: There is also deficit of total body
sodium, calcium, phosphorus, magnesium and chloride.
The body sodium is 93 percent of the expected values
There is significant loss of magnesium from the cells as
confirmed by muscle biopsy and histochemical studies.
with moderate and severe malnutrition and in children
with marked linear growth retardation.
Protein Energy Malnutrition (PEM) and
Endocrine Glands
Growth hormone secretion may be raised, so also the
plasma cortisol levels. Insulin levels are reduced both in
marasmus as well as kwashiorkor. Thyroid stimulating
hormone (TSH) of pituitary is elevated, T3 levels are
decreased and T4 levels are increased in PEM but
markedly decreased in marasmus and kwashiorkor.
 Nutrition 147

Figure 6.1.12: Prototype of growth chart (Full open)

Infection and Immunity in Protein Energy
Malnutrition (PEM)
Infectious disease nearly worsens when malnutrition is
present and conversely malnutrition usually weakens
resistance to various infections which are more serious
in a malnourished host than in a well nourished child.
These effects are synergistic and result in strikingly high
mortality rate among toddlers and under five children
in developing countries. The vast majority of children
with PEM have recurrent infections and present with
episodes of acute infections or a chronic insidious
infection which may go undetected unless carefully
looked for. Thus, recurrent infection of gastrointestinal
tract particularly diarrheal diseases, lower respiratory
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Figure 6.1.13: Prototype of growth chart (front and reverse sides)

tract like pneumonia are very common and have high
morbidity. Measles is usually a preceding illness.
Tuberculosis must be always ruled out and intestinal
parasitosis like ascariasis, hookworm, and giardiasis are
commonly present. In endemic regions malaria must also
be considered. All these infections impair nutritional
status and contribute to high mortality or in less serious
states to growth retardation and frank malnutrition.
Urinary tract infection often goes undetected and hence
must be ruled out. Occasionally septicemia especially in

infants and toddlers may be the cause of high morbidity
and mortality in developing countries.
Regarding humoral immunity IgG, IgM, and
secretory IgA blood concentrations are not significantly
affected in mild and moderate form of PEM and show a
good response when challenged with bacterial and viral
vaccines, but is depressed in severe forms of PEM with
infections. The cell mediated immunity (CMI) is
definitely impaired in all grades of malnutritions except
in Grade I. It is severely impaired in Grades III and IV
PEM and kwashiorkor. This explains a high incidence of
gram-negative bacterial infections and serious morbidity
and high mortality to viral infection like herpes simplex
and measles. It is because of the depressed CMI that the
tuberculin skin test is often negative in marasmus and
kwashiorkor in spite of active tuberculosis. Following
dietary treatment of four to six weeks, the CMI might
improve and the skin test may become positive. Serum
C reactive protein and C3 complement are depressed in
severe malnutrition but rise in presence of infections and
thus behave as acute phase reactants.
COMPLICATIONS
The complications of PEM are usually seen with severe
malnutrition. They are dehydration, hypothermia,
hypoglycemia, infections, anemia, xerophthalmia,
congestive heart failure, hypomagnesemia, hypocal-
cemia, zinc, copper, chromium and manganese
deficiency and deficiencies of other vitamins.
CONSEQUENCES OF PEM
Why should we be concerned about PEM? Malnourished
children are more susceptible to disease, have a reduced
capacity to learn and are much more likely to drop out
of school. Once in the job market their productivity is
low. For the economy as a whole, this translates into
losses of nearly 3 percent of GDP. All this places India’s
large young population—the basis of its much awaited
demographic dividend at a growing disadvantage in
today’s globalizing world.
The evidence suggests that Undernutrition has
pervasive effects on immediate health and survival as
well as on subsequent performance. These include not
only acute effects on morbidity and mortality but also
long term effects on cognitive and social development,
physical work capacity, productivity, and economic
growth.31 The magnitude of both the acute and the longer
term effects is considerable. Prospective studies suggests
Nutrition 149
severely underweight children (< 60% of reference
weight for age) have more than an 8 fold greater risk of
mortality than normally nourished children, that
moderately underweight children (60-69% of reference
weight for age) 4 to 5 fold greater risk, and that even
mildly underweight children (70-79% of reference weight
for age have 2 to 3 fold greater risk. The high prevalence
of mortality, even in children with mild and moderate
undernutrition, suggests that more than fifty percent of
child deaths may be caused directly or indirectly by
undernurition. Survivors of undernurition have deficits
in height and weight that persist beyond adolescence into
adulthood. These may be accompanied by deficit in
frame size as well as muscle circumference and strength.
The implications of these deficits with respect to the work
capacity of both men and women and to women’s
reproductive performance are obvious. Survivors of PEM
also have deficits in cognitive function and school
performance than normally nourished children from the
same background. These deficits are related to the
severity of PEM and can be decreased probably by a
combination of dietary and behavioral interventions,
coupled with improvements to the overall quality of the
home and/or school environment. Such interventions
appear to be much more effective if instituted in early
life.
MANAGEMENT
The management of PEM depends on nutritional status,
degree of hypermetabolism, expected duration of illness
and associated complications. The goals are to minimize
weight loss, to maintain body mass and to encourage
body mass repletion or growth.
The principles of management are as follows:
1. The patient is evaluated with regard to the severity
of protein–energy malnutrition, presence or absence
of associated systemic infections, other associated
nutritional deficits such as vitamin deficiencies or
anemia and associated fluid and electrolyte
disturbances.
2. The intake of food is promoted by all available means.
Locally available and culturally acceptable foods,
which the family can afford, are advised.
3. Complications of malnutrition and sequelae are
prevented by careful surveillance and prompt
remedial action.
4. Possible epidemiological factors for malnutrition are
considered and attempt is made to eliminate these as
far as possible.
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Mild to moderate PEM is best managed at home.
Majority of cases of severe PEM are associated with some
of the complications listed above and hence are best
managed in hospital. The indications for hospitalization
are hypothermia, infection, fluid and electrolyte
imbalance, convulsions, unconsciousness, xerophthal-
mia, severe dermatosis, extreme weight deficit, bleeding,
marked hepatomegaly, jaundice, purpura, raised liver
enzymes, severe anemia and cardiac failure, persistent
vomiting, severe anorexia, distended tender abdomen
and age less than one year.
Domiciliary Management
It is for mild to moderate PEM and those uncomplicated
severe PEM who have fairly good appetite, normal body
temperature, who are conscious and active and without
evidence of serious infection. These children are managed
at home by parents under observation and supervision.
They are monitored through weekly visits by
paramedicals or visits to the hospital or at a nutritional
rehabilitation center every week. The main goal of
treatment is to provide adequate calories for dual
purpose, to replace losses and to build-up nutrition and
to promote growth. Caution must be taken to gradually
build-up the calories and proteins. The energy
recommended is 120 to 150 kcl/day and protein 2 to
3 g/kg/day of high biological value. Both of these should
be based on locally available and affordable food sources,
commonly consumed by the family. The common foods
advocated are double or triple mixes of cereals and pulses
like dal, rice, khichadi, seasonal green leafy and yellow
orange vegetables, root vegetables, sugar, jaggery, milk
and milk products, if family could afford nuts like
groundnuts. Empasis must be laid on adding enough oil/
vanaspati ghee/butter to the diet, to increase calories and
palatability. Parents are educated to prepare suitable
diets from these food sources, liquid, semisolid or solid
depending on the acceptability and appetite of the child.
Frequent small feeds with calories and proteins
distributed proportionately are encouraged rather than
1 or 2 major bulky meals. Non-vegetarian articles like
egg, fish, chicken, meat, etc. are allowed for those whose
cultural and religious practices permit them. Parents are
educated about hygienic way of preparation and
handling of food, use of safe and clean drinking water
and importance of personal hygiene. Some basic advice
is also given, for management of diarrhea by oral
rehydration solution (ORS), immediate attention for
treatment of common infestations and infections and
appropriate management of anemia by oral iron and folic
acid supplements and associated vitamin deficiencies.13
To promote growth, zinc supplements are given when
positive nutrition balance starts occurring and child
manifests with increase in weight gain. Due attention
should be given to check and advise proper
immunization.
Severe Malnutrition
The best approach to the management of severe
malnutrition has been a controversial topic for many
years especially in circumstances where resources are
limited in terms of shortage of staff, medical supplies
and the budget. The encouraging reports of the
management of uncomplicated severe malnutrition using
simple, ready to use therapeutic foods with community
based care is worthwhile. This has immediate advantage
of easier access for rural populations, promoting earlier
intervention in the course of disease, improving coverage
rates and preventing nosocomial infections. The limited
hospital staff can focus on complicated cases that require
inpatient care. The risk of death rises progressively with
worsening nutritional status. More than 80 percent of
malnutrition associated deaths occur in children with
mild to moderate malnutrition as these greatly
outnumber children with malnutrition. This indicates
that, in addition to dealing with severe malnutrition, it
is vital to intervene in children with mild and moderate
malnutrition to have a greater effect on child survival.
Case fatality rates in children with severe mal-
nutrition have remained unchanged at 20 to 30 percent
over the past five decades. Even in the 1990s, death as
high as 60 percent has been reported for children with
edematous malnutrition. Infection, including diarrhea
with accompanying water and electrolyte disturbances
is common in severely malnourished children and
been found to be the worst prognostic factor.
According to the World Health Organization a death
rate of >20 percent is considered unacceptable in the
management of severely malnourished children, 11 to
20 percent is poor, 5 to 10 percent is moderate, 1 to
4 percent is good, and < 1 percent is excellent.
Appropriate feeding micronutrients supplementation,
broad spectrum antibiotic therapy, less use of intra-
venous fluids for rehydration and careful management
of complications are factors that can reduce death,
morbidity and cost of treating these children.1 Based

upon these factors, WHO has prepared guidelines for
the inpatient case management of severe malnutrition.
Severe malnutrition is defined in these guidelines as
the presence of severe wasting (< 70 % weight for
height or – 3 SD and/or edema). Not all severely
malnourished children need hospitalization. However,
since majority of the severely malnourished children,
have some complications, they need hospitalization
for critical care and intense monitoring.
The hospital management consists of 3 phases:
1. Resuscitation: lasts for 6 to 24 hours.
2. Acute phase: 1 day to 1 week+
3. Rehabilitation: Through second and third week to
6 weeks. The period of phases especially the first two
phases may vary depending on the condition of the
child when brought for medical attention.
WHO has suggested guidelines for the inpatient
treatment of severely malnourished children, the general
principles are as follows:
Phase of Resuscitation/Stabilization and
Treatment of Complications
Dehydration
Assessment of dehydration is difficult due to wasting
and edema. However, dry oral mucosa, acidotic
breathing, oliguria, absence of tears and peripheral
circulatory failure are most reliable signs. The amount
of fluid and sodium should not exceed 75 percent of the
allowances calculated on the basis of weight and age
(because of reduced capacity to excrete water and
inability to excrete sodium). Additional fluid can be given
if needed. Fluid deficit and maintenance fluids are
calculated. Deficit fluid volume is replaced by 5 percent
dextrose in N/2 saline in 6 to 8 hours, and maintenance
fluid volume is given as Isolyte P over 16 hours. If child
has shock, Ringer’s lactate 30 ml/kg or 20 ml/kg of 0.45
percent saline (1/2) in dextrose is given in 1 hour, then
70 ml/kg of Ringer’s lactate or 10 ml/kg in 1 hour of
glucose saline for two hours. If shock does not improve
then 10 ml/kg of plasma is infused. Potassium is added
in infusion in dosage of 2 to 3 mEq/kg (maximum dose
40 mEq/L) when a flow of urine is observed. In mild
dehydration, ORS (oral rehydration salt-WHO-sodium
chloride 3.5 g, potassium chloride 1.5 g, sodium citrate
2.9 g, glucose 20 g) should be given. Severely malnouri-
shed children with dehydration may not tolerate this
high sodium low potassium ORS. For them special
Nutrition 151
rehydration solution for malnutrition ResoMal 5 ml/kg
every 30 minutes may be given. Assume all children with
watery diarrhea, may have dehydration; give (i) ResoMal
5 ml/kg every 30 minutes for 2 hours orally or by
nasogastric tube (ii) 5 to 10 ml /kg/h for next 4 to 10
hours, exact amount determined by ongoing losses; (iii)
initiate re-feeding with low calorie formula. Some of the
children may require ORS by intragastric tube. Ongoing
loss of water in stool is provided at 10 ml/kg/stool. Once
child is stable and he is able to accept oral feeds, milk
based therapeutic nutrition is started.
Correct Electrolyte Imbalance
All severely malnourished children usually have
potassium and magnesium deficiencies which may take
at least 2 weeks to correct. Give:
A. Extra potassium 2 to 4 mmol/kg/day
B. Extra magnesium 0.3 to 0.6 mmol/kg/day
C. Restrict salt, do not use diuretics
D. When rehydrating give low sodium rehydration fluid
(e.g. ResoMol—contains 45 mmol Na, 40 mmol K and
3 mmol/Mg/l). The extra potassium and magnesium
can be prepared in a liquid form and added directly
to feeds during preparation. Make a 10 percent stock
solution of potassium chloride (100 g KCl in 1 liter of
water) and 1.5 percent solution of zinc acetate (15 ml
zinc acetate in one liter of water). For milk feeds add
22.5 ml of the stock KCl solution instead of 20 ml of
electrolyte/mineral solution to 1000 ml of feed. Give
50 percent magnesium sulfate intramuscularly once
0.3 ml/kg to a maximum of 2 ml.
Hypothermia: It is common in marasmus and is usually a
manifestation of infection, hypoglycemia or severe
energy deficit. Child is kept in warm room well covered
close to mother and is given frequent feeds and antibiotics
for infection. If the axillary temperature is <35oC take
rectal temperature using a low reading thermometer, if
below 35.5°C (95 oF) feed straight away (or start
rehydration if needed).
Hypoglycemia: (Blood sugar less than 50 mg/dl)/ It is
again more common in marasmus with hypothermia,
septicemia and coma. It requires 10 percent glucose 1 to
2 ml/kg in bolus followed by 10 percent dextrose in
N/5 saline in maintenance dose for 24 hours. Use of 50
percent dextrose is not recommended. Alternatively, if
10 percent intravenous glucose is not available give
10 percent sucrose solution (1 rounded teaspoon of sugar
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GENERAL PRINCIPLES FOR ROUTINE CARE

Stabilization Phase
Rehabilitation
Steps Day 1–2 Day 2–7+ Week 2–6

1. Hypoglycemia ...........................

2. Hypothermia ...........................

3. Dehydration ...........................

4. Electrolytes .......................................................................................................................

5. Infection .....................................................................................

6. Micronutrients ........................... No iron ............................................. With iron .................

7. Cautious feeding .....................................................................................

8. Rebuild tissues ................................

9. Sensory stimulation .......................................................................................................................

10. Prepare follow-up .......................................................................................................................

in 3.5 tablespoonfuls water) orally or by nasogastric tube.
Then feed every 30 minutes for 2 hours, giving one
quarter of the 2-hour feed each time. Give antibiotics and
continue 2 hourly feeds, day and night. As hypoglycemia
and hypothermia usually occur together and are signs
of infection, check for hypoglycemia whenever
hypothermia is found. Frequent feeding is important in
both condition.
Infection: Diagnosis of fulminant infection is made by high
index of suspicion or in the presence of hypothermia,
apathy, convulsion or come. Antimicrobials (broad
spectrum) are started immediately while awaiting culture
reports. Gastric aspirate examination and culture, X-ray
chest and Mantoux test are done to diagnose pulmonary
tuberculosis. Blood film for malaria may be required. If
child has no complications, cotrimoxazole 5 ml orally
twice daily for 5 days (2.5 ml if weight <4 kg) (5 ml is
equivalent to 40 mg TMF + 200 mg SMX) or if the child
is severely ill, has complications give intravenous
ampicillin (50 mg/kg/6 hourly for two days) then oral
amoxicillin for 5 days or continue ampicillin for 5 days.
Add gentamicin 7.5 mg/kg IM/IV for once. If no
improvement within 48 hours add chlorophenicol 25
mg/kg/IM/IV for 5 days or appropriate antibiotic, if
specific infections are identified. If anorexia persists after
5 days course, antibiotics are continued for full 10 days.
If no/poor response, reassess the child fully. Some
experts routinely give metronidazole 7.5 mg 8 hourly for
7 days to hasten intestinal repair of mucosa and reduce
the risk of potential anaerobic infection.
HIV/AIDS: In children with HIV/AIDS, good recovery
from malnutrition is possible though it may take longer
and treatment failures may be common. Lactose
intolerance occurs in severe HIV related chronic diarrhea.
Treatment should be same as for HIV negative children.
Anemia: If hemoglobin is less than 5 g/dl, small packed
cells transfusion (5-10 ml/kg) is given. In children with
impending cardiac failure, partial exchange transfusion
(10-20 ml/kg) may be quite beneficial. Whole blood
transfusion (10 ml/kg) has been recommended for
severely ill-malnourished children Iron supplementation
for anemia is withheld for first 1 to 2 weeks to allow
transferrin regeneration and to permit resolution of
infection. Iron may interfere with the protein’s host
defense mechanisms. There is also concern that free iron
during the early phase of treatment, may exacerbate
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oxidant damage, precipitating infections (malaria, clinical of vomiting, hypoglycemia and hypothermia. The intake
kwashiorkor, or marasmic kwashiorkor in a child with can be gradually stepped up so that by the end of first
clinical marasmus. week the child is able to take approximately 100 cal/
Xerophthalmia: Vitamin A, 2 lac units aqueous preparation kg/day and 1 g protein/kg/day. Some authorities,
should be given to all severely malnourished children suggest 100 kcal/kg/day and 1 to 1.5 g of proteins/kg/
on days 1, 2 and 28th in children above 1 year of age or if day. If the child is breastfed, continue to breastfeed but
infant below 1 year or weight less than 10 kg, half of give starter formula (milk based formulas containing
above dose is given. If the infant is between 0 to 6 months 75 kcal/100 ml (0.9 g protein/100 ml) which will be
50,000 units are given. satisfactory for most children. Very weak children may
be fed by spoon, dropper or syringe. A recommended
Congestive heart failure is most common after 3 days of
schedule in which volume is gradually increased and
acute phase usually in kwashiorkor. Oxygen inhalation
feeding frequency gradually decreased is:
and diuretics are helpful.
Hypocalcaemia: Requires correction by calcium gluconate
Days Frequency Vol/kg/feed Vol/kg/day
IV 1 to 2 ml/kg or calcium lactate powder 3 g/day orally.
Zinc deficiency: Dose of zinc is 2 mg/kg/day. In presence 1–2 2 hourly 11 ml 130 ml
of diarrhea 10 mg/day in infants < 6 months is recom- 3–5 3 hourly 16 ml 130 ml
mended 20 mg/day in older children for 10 to 14 days. 6–7 + 4 hourly 22 ml 130 ml

Other vitamins: Appropriate vitamins should be supplied

with 10 ml, MVI—1-2 ml daily in drip and later orally
plus vitamin K 1-5 mg weekly.
Copper, chromium and manganese deficiency: Dose of copper
is 20 ug/kg/day, that of chromium is 0.20 ug/kg/day
and manganese is 10 ug/kg/day.
Although the phases of resuscitation and acute phases
are divided separately, quite often the medical treatment
started during the phase of resuscitation continues into
acute phase. The acute phase also may be prolonged to 2
to 3 weeks instead of 1 week as suggested.
Dietary Management of Severe PEM
Initial Phase
At no other place the golden rule of “go slow- rather than
hurry” is appropriate than in the dietary intervention of
severely malnourished children. In the initial
stabilization phase a cautious approach is required
because of the child’s fragile physiological state and
reduced homeostatic capacity. Feeding should be
designed to provide just sufficient energy protein to
maintain basic physiological processes. The regime
recommended is one that provides near maintenance
requirement, i.e. approximately 80 cal/kg/day and
0.7 g protein/kg/day with the calculation being based
on actual rather than expected weights. The second rule
is to offer small amount of feeds of low osmolarity and
low lactose at frequent intervals to avoid the incidence
For children with a good appetite and no edema this
schedule can be completed in 2 to 3 days (e.g. 24 hours
at each level). Severely malnourished children often have
refusal to feed and hence “forced feeding” by intragastric
tube has to be resorted to. Rarely, children with
intractable diarrhea may have to be given total parental
nutrition. Milk is the most common nutritional liquid
food and is also well tolerated, except by children with
secondary disaccharide (lactose) intolerance. Fluid
volume is usually calculated at approximately 130 ml/
kg/day. This may be divided into 2 hourly feeds in the
first week and 3 hourly thereafter, the calorie content of
milk can be increased by adding oil as follows:
Composition of Enriched Milk
Component Energy (Cal) Protein (gm)
1. Cow’s milk (300 ml) 198 9.6
2. Sugar (85 g) 340 —
3. Vegetable oil (30 g) 270 —
Total 808 9.6
The amount of water added to this formulation would
depend on the desired concentration of calories and
proteins required and state of hydration of the individual
patient since milk is the only fluid offered to the child. If
the volume is made up to 1000 ml then 120 ml/kg/day
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of diluted formula (milk) should provide 96 calories/ Alternately, fresh curds also have been very well
kg/day and 1.1 g protein/kg/day. Coconut oil is the tolerated by lactose intolerant children. Curd plain or
recommended oil as it is supposed to provide medium curd-rice is traditionally eaten by most communities, and
chain triglycerides (MCT); other oils are equally effective is easy to prepare and feed. It can be given even to an
besides coconut oil is not culturally used by all young infant in homogeneously mashed and mixed form.
communities for feeding. Dietary LC-PUFA (long chain WHO has recommended milk-based formulas
polyunsaturated fatty acids) have been known to namely, starter F-75 containing 75 cal/100 ml and 0.9 g
improve intestinal repair in severe protein energy protein/100 ml in the initial feeding schedule and then
malnutrition, therefore its quantitative and qualitative gradually increasing to F-100 and F-135 supplying 100
supply should be considered. and 135 calories/100 ml of feed respectively for catchup
In children with lactose (disaccharide intolerance, any growth. These formulas are mainly based on the use of
of the following preparations can be tried. In mild lactose dried skimmed milk or dried whole milk and the use of
intolerance, milk need not be omitted completely but the these formulas is limited because of the economic
lactose content can be decreased by fortifying with other constraints of the less advantaged communities of India
articles of diet like rice. For severe grade, lactose may where the problem of PEM is most common. Refer
have to be completely eliminated and replaced by other Appendices for details.
articles as shown below:
Phase of High Energy Feeding
Diet for Lactose Intolerance (of Varying Severity)
After the child passes through the initial phase and shows
Name (g) Constituents Calories Proteins signs of improvement, tolerates the prescribed diet, one
Low lactose diet
can then gradually increase the calorie intake to
1. Dried skimmed Skimmed milk 60 g 400 20
approximately 150 to 180 cal/kg/day. The amount of
Milk Sucrose 12 g
milk could be gradually decreased and the intake of
Vegetable oil 15 g
semisolid/solids increased. The protein intake
recommended during phase is in the range of 1.5 to 2 g/
2. Milk + rice Milk 75 ml 79 3
kg/day. High energy foods that can be offered are:
Rice 5 g
Sugar 25 g
Energy Rich Foods
Water 100 ml
Lactose free diet
Name Ingredients Calories/ Proteins/
1. Rice-egg Rice 50 g 710 10
100 gm 100 gm
Glucose 45 g
egg-1 1. Besan mix/ Bengal gram flour 500 9
ladoo/Panjiri wheat flour
Oil 30 g
Jaggery, ghee
2. Cereal pulse Rice 50 g 715 9.2 (1 part of each)
Green gram pulse 25 g 2. Sooji (Rawa) Toned milk 750 ml 1432 28.4
Jaggery 50 g Kheer Sugar 100 g
Oil 25 g Sooji 25 g
Oil 5 g
3. Soya rice gruel Rice 25 g 715 12.5
Soybean 25 g 3. Hyderabad Whole wheat 40 g 330/86 11.3/86
mix Bengal gram 16 g
Glucose 50 g
Groundnuts 10 g
Oil 35 g
Jaggery 20 g
Chicken gruel Chicken 100 g 720 26
4. Shakti Ahar Roasted wheat 40 g 390 11.4
Glucose 40 g
Roasted gram 20 g
Oil 50 g Roasted peanut 10 g
Water 1000 ml Jaggery 30 g

Transfer of Family Type Diet or
Phase of Rehabilitation 19
Once the child is able to tolerate a high dose of therapeutic
nutrition and has started gaining weight, he or she may
be offered solid/semisolid family foods containing
cereals, pulses, vegetables rich in calories and
quantitatively appropriate Bengal gram, groundnuts,
and dark green leafy vegetables should be added to
regular family foods. Oils, sugar and fruits should also
be given and minerals and vitamins could be continued
for 5 to 6 weeks. Parents could be given nutrition
education with emphasis that nutritionally adequate diet
need not be expensive and special foods need not be
purchased or cooked. The diet prescribed for the child
should be such that the family can provide within their
limited income, can be easily cooked at home, does not
perish easily, is culturally acceptable, as well as locally
available.
Discharge from hospital: No definite guidelines can be
provided as criteria vary from hospital to hospital.
Prolonged hospitalization is associated with the risks of
acquiring a nosocomial infection while premature
discharge may result in incomplete recovery. Discharge
can be contemplated once the acute problems are over,
appetite has returned and oral intake is adequate.
Discharge criteria based on attainment of certain
anthropometric indices, e.g. 80 percent of weight or 75
percent of weight for age, though described in literature
are difficult to attain as it means prolonged hospital stay
which in itself may be associated with considerable
morbidity and mortality risk in developing countries.
Provide Sensory Stimulation and
Emotional Support
In severe malnutrition there is delayed mental and
behavioral development provide:
A. Tender loving care during recovery and follow-up.
B. A cheerful stimulating environment
C. Structured play therapy 15 to 30 minutes/day
D. Physical activity as soon as well enough
E. Maternal involvement when possible (e.g.
comforting, feeding, bathing, play).
Assessment of Recovery and Follow-up
Recovery can be assessed by: Improvement of general
condition, alertness, smile.
Nutrition 155
1. Return of appetite
2. Gain in weight 50 to 70 g/day.
3. Disappearance of edema (7-10 days) and
hepatomegaly.
4. Rise in serum albumin over the first 2 weeks of
therapy.
Recovery is complete when the child reaches his or
her standard weight which usually takes 6 to 8 weeks.
Follow-up of such children is essential because, mortality
rates of 10 to 30 percent have been reported after
discharge from hospital. Continued supervision is
necessary, till the expected weight for height has been
achieved.
PROGNOSIS
Mortality rates in severe PEM vary between 10 and 30
percent. The causes of deaths are same which determine
hospitalization. Long-term sequelae of PEM are
irreversible stunting and mental impairment.
PREVENTION OF PEM
PEM is a socioeconomic disease of multifactorial origin.
As seen here; its prevention requires a coordinated
approach of many disciplines such as nutrition,
agriculture, food technology, health administration,
health education and strong political commitment.
The Indian Academy of Pediatrics has come with
recommendation on infant feeding which is crucial for
optimum growth and health of our children.
Following actions are qualitative, and may be taken
as guidelines at family and community level to prevent
PEM (Fig. 6.1.14).
1. Protection, promotion and support for exclusive
breastfeeding, right from birth to 6 months of life
2. Correct infant and child rearing practices.
3. To impose no restriction on feeding during illness.
4. Supplementary feeding with energy dense semisolid
foods from 6 months, along with extended breast-
feeding up to 2 years of age. Gradually, increasing
the number, frequency and the amount of family
foods so that baby is able to take all by 1 year of age.
Appetite is a central component in the decision—
making process and skills used by care givers to
determine when and how much to feed their infants.
Chronic anorexia and illness are among problems
among infants and children in developing countries.
Chronic anorexia is associated with parent—child
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Figure 6.1.14: Prevention of PEM
interaction, characterized by unclear messages,
premature termination of feeding, inconsistent meal
times and limited food availability. This leads to poor
and appetite behavior development in children.
Similarly, a diet which is monotonous, and non-
nutritious or filling up by liquids, e.g. fruit juice leads
to growth failure and poor appetite should be
discouraged. An active parent-child interaction,
motivation and response to queries of child, tasteful
and diversified diet of good quality and quantity,
good food hygiene, health care including
breastfeeding and care during illness and adequate
feeding time are some of the measures to enhance
the acceptance of the food by a child.
5. Integrated health care package of appropriate
feeding, immunization, ORS (Oral rehydration salt)
for ADD (Acute diarrheal disorders), periodic
deworming and early diagnosis and treatment of
illnesses.
6. Special nutritional and health care to women before
pregnancy, while pregnant and lactating mothers.
Following actions are required at community level:
i. Supplementary feeding program
ii. Agricultural development.
iii. Education and environmental sanitation
iv. Population control
v. Nutritional intervention programs
vi. Universal immunization program (UIP)
vii. National control programs, e.g. control of
diarrheal diseases (CDD),
Acute respiratory infections (ARI), malaria, anemia,
etc.
National Nutrition Programs
Following programs already exist at national level to
prevent PEM:
1. Applied nutrition program
2. School lunch program
3. National goiter control program
4. Cash program in nutrition (special feeding programs
for 0 to 3 years, school feeding programs for 3 to 5
years, prophylaxis against blindness.
5. Integrated child development services (ICDS)
These programs need special attention to make
appropriate feeding of the young child a national
movement.
Intensified nutrition action in 20 countries where 80
percent of undernourished children live, can lead to
achievement of the 1st MDG and greatly increase the
chances of achieving goals for child and maternal
mortality. (MDGs 4 and 5). Nutrition should be a priority
at national and sub national levels because it is central
for human, social and economic development. In
addition to health and nutrition interventions, economic
and social policy addressing poverty, trade and
agriculture that have been associated with rapid
improvement in nutritional status should be
implemented. Nutrition resources should not be used to
support actions unlikely to be effective in the context of
country or local realities. Interventions with proven
effectiveness that are selected by countries should be
rapidly implemented at scale There is reservoir of
important experience and expertise in individual
countries about how to build commitment, develop and
monitor nutrition programs, move towards acting at
scale, reform or phase out ineffective programs and other
challenges. This resource needs to be formalized, shared
and used as the basis for setting priorities in problem
serving research for nutrition.
Recent evidence, indicates that if high impact
interventions such as breastfeeding, complementary
feeding and vitamin A and zinc supplementation are
scaled up, they will have a synergistic impact on growth
and development, as well as survival. Even countries

Figure 6.1.15: The time to act is now
with low per capita incomes can make significant
progress if appropriate policies are matched by political
will. The priority of nutrition interventions must be
children under 2 years old, when they are most
vulnerable to disease and mortality. Early childhood
offers a window of opportunity; nutrition related
interventions during this period have the greatest impact.
In addition, interventions need to focus on women—
before they become pregnant, while pregnant, when
lactating —through antenatal care and other
opportunities, because mothers deprived of good
nutrition are likely to give birth to underweight babies.
The health and nutrition needs of children in complex
emergencies must remain a priority But there is, further,
an urgent need to focus on the major causes of death
and undernurition in “silent” emergencies—outside
camps, in stable environment and in communities
Nutrition 157
affected by HIV/AIDS, particularly in Southern Africa.
As the World Bank advocates, nutrition needs to be
repositioned in national development if the MDGs are
to be achieved. Achieving the MDG target—halving the
proportion of underweight children between 1990 and
2015 will involve effort at micro, meso, macro, and global
levels (Fig. 6.1.15) as well as parternerships among all
sectors of society.
To begin with the MDGs have been adopted by
United Nations Member States—already a big step
forward for children and humankind. And in the push
towards the MDGs the battle against poverty has moved
to center stage. The world is certainly capable of getting
on track to meet the MDGs on child nutrition and
health. There can be no excuses if another generation
of children is allowed to fall by the way side. The time to
act is now.
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APPENDIX 1:RECIPE FOR RESOMAL ORAL REHYDRATION SOLUTION

Ingredient Amount
Water 2 liters
WHO-ORS one 1 liter-packet*
Sucrose 50 g
Electrolyte/mineral solution 40 ml
• 3.5 g sodium chloride, 2.9 g trisodium citrate dihydrate, 1.5 g potassium chloride, 20 g glucose. ReSoMal contains approximately
45 mmol Na, mmol K and 3 mmol Mg/liter.

RECIPE FOR ELECTROLYTE/MINERAL SOLUTION*

USED IN THE PREPARATION OF ReSoMal AND MILK FEEDS
Weight the following ingredients and make up to 2500 ml. Add 20 ml of electrolyte/mineral solution to 1000 ml of milk feed.

Quantity g Molar content of 20 ml

Potassium chloride: KCl 224 24 mmol

Tripotassium citrate: C6H5K3O7H2O 81 2 mmol

Magnesium chloride: MgCl26H2O 76 3 mmol

Zinc acetate: Zn (CH3COO)22H2O 8.2 300 μmol

Copper sulphate: CuSO45H2O 1.4 45 μmol

Water: make up to 2500 ml

If available, also add selenium (sodium selenate 0.028 g NaSeO410 H2O) and iodine (potassium iodine 0.012 g KI per 2500 ml).
Note: Dissolve the ingredients in cooled boiled water. Store the solution in sterilised bottles in the fridge to retard deterioration.
Discard if turns cloudy. Make fresh each month.
*If the preparation of this electrolyte/mineral solution is not possible and if pre-mixed sachets are not available, give K, Mg and Zn
separately:
Make a 10% stock solution of potassium chloride (100 g KCl in 1 liter of water) and a 1.5% solution of zinc acetate (15 g zinc acetate
in 1 litre of water).
For the oral rehydration solution, use 45 ml of the stock KCl solution instead of 40 ml electrolyte/mineral solution.
For milk feeds, add 22.5 ml of the stock KCl solution instead of 20 ml of the electrolyte/mineral solution of 1000 ml of feed.
Give the 1.5% zinc acetate solution by month 1 ml/kg/day.
Give 50% magnesium sulphate intramusculary once (0.3 ml/kg to a maximium of 2 ml).
 Nutrition 159

APPENDIX 2: RECIPE FOR F-75, F-100 AND F-135

Recipes for F-75a,b,c F-100d F-135e

(Starter) (Catch-up) (Catch-up)
Dried skimmed milk (g) 25 80 90
Sugar (g) 100 50 65
Vegetable oil (g) 30 60 85
Electrolyte/mineral solution (ml) 20 20 27
Water: make up to 1000 ml 1000 ml 1000ml
Energy kcal 75 100 135
Protein (g) 0.9 2.9 3.3
Lactose (g) 1.3 4.2 4.8
Postassium (mmol) 4.0 6.3 7.7
Sodium (mmol) 0.6 1.9 2.2
Magnesium (mmol) 0.43 0.73 0.8
Zinc (mg) 2.0 2.3 3.0
Copper (mg) 0.25 0.25 0.34
% energy from protein 5 12 10
% energy from fat 36 53 5.7
Osmolarity (mOsmol/L) 413 419 508

To make up:
• Using an electric blender mix the dried skimmed milk, sugar and oil with warm boiled water, add electrolyte/mineral
solution-make up to 1000 ml and blend at high speed.
• If no mixer is available, mix the milk, sugar, oil and electrolyte/mineral solution to a paste, and then slowly add the warm
boiled water-make up to 1000 ml.
aComparable starter formulas can be made from 35 g whole dried milk, 100 g sugar, 20 g oil, 20 ml electrolyte/mineral and

water to 1000 ml, or with 300 ml fresh cow’s milk, 100g sugar, 20 ml oil, 20 ml electrolyte/mineral solution and water to
1000 ml.
bIsotonic versions of F-75 (280 mOsmol/L) are available commercially from Nutriset in which maltodextrins replace some
of the sugar, and in which all the extra nutrients (K, Mg and micronutrients) are incorporated.
cA low osmolar cereal based F-75 (334 mOsmol/L) can be made by replacing 30 g sugar by 35 g cereal flour. Cook for 4

minutes. This may be helpful for children with osmotic diarrhea.

dComparable catch-up formulas can be made from 110 g whole dried milk, 50 g sugar, 30 g oil, 20 ml electrolyte/mineral

solution and water to 1000 ml or 880 ml fresh cow’s milk, 75 g sugar, 20 ml oil, 20 ml electrolyte/mineral solution and water
to 1000 ml.
eFor use in special circumstances (see section C2 inadequate feeding)
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APPENDIX 3: F-75 FEED VOLUMES BY FEEDING FREQUENCY AND BODY WEIGHT (Columns 2, 3 and 4
are approximately 11 ml/kg/feed, 16 ml/kg/feed and 22 ml/kg/feed respectively)

Child’s 2-hrly 3-hrly 4- hrly Child’s 2-hrly 3-hrly 4-hrly

weight (kg) (ml/feed) (ml/feed) (ml/feed) weight (kg) (ml/feed) (ml/feed) (ml/feed)

2.0 20 30 45 6.0 65 100 130

2.2 25 35 50 6.2 70 100 135

2.4 25 40 55 6.4 70 105 140

2.6 30 45 55 6.8 75 110 150

2.8 30 45 60 7.0 75 115 155

3.0 35 50 65 7.2 80 120 160

3.2 35 55 70 7.4 80 120 160

3.4 35 55 75 7.6 85 125 165

3.6 40 60 80 7.8 85 130 170

3.8 40 60 85 8.0 90 130 175

4.0 45 65 90 8.2 90 135 180

4.2 45 70 90 8.4 90 140 185

4.4 50 70 95 8.6 95 140 190

4.6 50 75 100 8.8 95 145 200

4.8 55 80 105 9.0 100 145 200

5.0 55 80 105 9.2 100 150 200

5.2 55 85 115 9.4 105 155 205

5.4 60 90 120 9.6 105 155 210

5.6 60 90 125 9.8 110 160 215

5.8 65 95 130 10.0 110 160 220

 Nutrition 161

APPENDIX 4: STRUCTURED PLAY ACTIVITIES

Play therapy is intended to develop language skills and motor activities aided by the use of simple toys. It should take place in
a loving, relaxed and stimulating environment.
Language skills: At each play session:
• Teach local songs and finger and toe games.
• Get child to laugh and vocalise, repeate what (s) he says.
• Describe all activities.
• Teach action words with activities, e.g. ‘bang bang’ as (s) he beats a drum, ‘bye bye’ as (s) he waves, etc.
• Teach concepts at every opportunity, examples are in italics in the text below.
Motor activities:
Every day encourage the child to perform the next motor milestone, e.g.:
• Bounce the child up and down and hold under the arms so that the feet support child’s weight.
• Prop child up, roll toys out of reach, encourage child to crawl after them.
• Hold hand and help child to walk.
• When starting to walk alone, give a ‘push-along’ and later a ‘pull-along’ toy.
Activities with toys:
Simple toys can easily be made from readily available materials.
These toys can be used for a variety of different motor activities.
‘Ring on a String’
• Swing ring within reach and tempt child to grab it.
• Suspend ring over crib and encourage child to knock it and make it swing.
• Let child explore the ring, then place it a little distance from child with string stretched towards him/her and within
reach. Teach the child to retrieve the ring by pulling on the string horizontally.
• Sit child on lap, then holding the string, lower the ring towards the ground. Teach child to get the ring by pulling up on
the string vertically. Also teach child to dangle the ring.
‘Rattle and Drum’
• Let the child explore rattle. Show child how to shake it saying ‘shake shake’.
• Encourage child to shake the rattle by saying ‘shake’ but without demonstrating.
• Teach child to beat drum with shaker saying ‘bang bang’.
• Roll drum out of reach and let child crawl after it, saying ‘fetch it’.
• Get child to say ‘bang bang’ as (s) he beats drum.
‘In and Out’ Toy with Blocks
• Let child explore blocks and container. Put blocks into container and shake it, then teach child to take them out, one at a
time, saying ‘out’ and ‘give me’.
• Teach child to take out blocks by turning container upside down.
• Teach child to hold a block in each hand and bang them together.
• Let child put blocks in and out of container saying ‘in’.
• Cover blocks with container saying ‘where are they, they are under the cover’. Let the child find them. Then hide them
under two and then three covers (e.g. pieces of cloth).
• Turn the container upside down and teach the child to put blocks on top of the container.
• Teach child to stack blocks, first stack two then gradually increase the number. Knock them down saying, ‘up up’ then
‘down’. Make a game of it.
• Line up blocks horizontally, first two then more, teach child to push them along making train or car noises. In older
children teach stop and go, fast and slow and next to. After this teach to sort by colors, first two then more, and teach high
and low building. Make up games.
Posting Bottle
• Put an object in the bottle, shake it and teach the child to turn bottle upside down and to take object out saying ‘can you
get it’? Then teach child to put the object in and out. Later try with several objects.
Stacking Bottle Tops
• Let child play with 2 bottle tops then teach to stack them saying ‘I’m going to put one on top of the other. Later increase
the number of tops. Older children can sort tops by color and learn high and low.
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BIBLIOGRAPHY 19. Mehta Meenakshi N. Nutritional management of
diarrhoeal diseases. Indian Pediatrics; 1996;32:149-57.
1. Ahmed T, Bilqis B, Badiuzzaman, Ali M, Fuchs G.
20. Mehta Meenakshi N, Rangnekar J. Assessment of growth
Management of severe malnutrition and diarrhoea.
and growth charts. In Agarwal KN (Ed): Update Growth:
Indian J Pediatr 2001;68:45-51.
Varanasi 1988;101-07.
2. Allen S, Lagunju I. The Management of Severe
21. Proceedings of the Workshop on Protein Calorie Malnut-
malnutrition: taking a broader view. Perspectives. Arch
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Dis Child 2007;92:191-92.
22. Reddy V, Pralhad Rao, Gowrinath Sastry J, Kashinath
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Whitehead RG. In Protein Energy Malnutrition, The
Nutrition, Hyderabad, 1992;31-32.
ELBS and Edward Arnold Ltd, London 1981;1-3.
23. Schofield C, Ashworth A. Why have mortality rates for
4. Anon. Global childhood malnutrition (editorial) Lancet
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2006; 367:1459.
1996;74:223-29.
5. Baqui AH, Ahmed T. Diarrhoea and malnutrition in
24. Shekar Meera.Can an Undernourished India compete ?
children Editorial. BMJ 2006 332, 18th Feb;:378.
Don’t lose your appetite, but — Budget 2008-09, Home
6. Beaton GH, Bengoa JM. Nutrition in Preventive Medicine.
and the World, World Bank, Washington,oped special
Geneva: World Health Organization 1976;2-3.
to Hindustan Times, India, February 22, 2008.
7. Bhutta ZA, Ahmed T, Black RE, Cousens S, et al. What
25. Singla PN, Chand Prakash, Kumar A, Kachhawaha JS.
works? Interventions for Maternal and child under-
Serum magnesium levels in Protein Malnutrition. J Trop
nutrition and survival. Maternal and child undernutri-
Pediatr 1998;44:117-18.
tion. Series 3. The Lancet 2008, Feb 2-8,371,(9610):417-40.
26. The health aspects of food and nutrition. A manual for
8. Black RE, Allen LH, Bhutta ZA, et al. Maternal and child
developing countries in The Western Pacific Region of
undernutrition Global and Regional exposures and
World Health Organization. Western Pacific Regional
health consequences.Maternaland child undernutrition
Office, Manila 1969; 41-89.
series .The Lancet 2008;19-25, 371(9608)243-59.
27. The Lancet Series on Child Survival (2003) and Neonatal
9. Bryce J, Coitinho D, Dampton-Hill I, et al. Maternal and
Survival (2005); The World Bank , World Development
child undernutrition: Effective action at national level .
Report 2004: Making services work for Poor people, The
Maternal and child undernutrition series 4. The Lancet
World Bank, Washington, DC, 2003; World Health
2008;Feb 9-15,371 (9611):510-26.
Organization, The World Health Report: Make every
10. Fuchs GJ. Antioxidants for children with kwashiorkor.
mother and child count, WHO, Geneva, 2005; Copen-
BMJ 2005;14 th May 1095.
hagen Consensus 2004 reports accessed at < http:/ www.
11. Ghosh S. The Feeding and Care of Infants and Young
copenhagen Consensus .com>; UN Millennium Project,
Children, New Delhi, Voluntary Health Association of
Investing in Development: A practical Plan to achieve
India, 6th revised edition 1992;109-18.
the Millennium Development Goals, UNDP, New York,
12. Gopalan C. Kwashiorkor and marasmus. Evaluation and
2005, and other Millennium Project reports accessed at
distinguishing features. In McLarne RA, Windowson
< http://www. Unmillinniumproject.org/report
EM (Eds) Calorie Deficiencies. London; Churchill
Index.htm >
Livingstone 1968;49-58.
28. The World Bank; Repositioning Nutrition as Central to
13. Gupte S. Nutritional deficiency states. In The Short
Development: A strategy for Large-scale action,
Textbook of Pediatrics (7th edn). Jaypee Brothers Medical
Directions in Development, The International Bank for
Publishers (P) Ltd.: New Delhi, 1995,13.
Reconstruction and Development/ The World Bank,
14. Heird WC. Food insecurity, Hunger and under nutrition
Washington, DC, 2006.
in Nelson’s Textbook of Pediatrics (18th edn). Kliegman
29. Udani PM. Protein Energy Malnutrition (PEM). In Udani
RM, Behrman RE, Jenson HD, Stanton BF (Eds):
PM (Ed): Textbook of Pediatrics. Jaypee Brothers Medical
Saunders–2007, Published by Elsevier, A Division of
Publishers (P) Ltd. New Delhi, 1991;476-556.
Reed Elsevier India Pvt. Ltd, New Delhi; 225-32.
30. UNICEF-Progress for Children–South Asia. A report card
15 Jellife DB. The assessment of the nutritional status of the
on Nutrition: No 4, May 2006.
community. Geneva: WHO Monograph Series No 53
31. Victoria CG, Adair L, Fall C, et al. Maternal and child
1966;64-69.
undernutrition. Consequence for adult health and human
16 Lopez AD, Mathers CD, Ezzati M, et al. Global and
capital. Maternal and undernutrition series 2, The Lancet
regional burden of disease and risk factors. 2001,
2008, Jan 26–Feb 1, 371 (9609):340 -57.
Systematic analysis of population health data. Lancet 2006;
32. WHO Guidelines for the Inpatient Treatment of Severely
367;1747-67.
Malnourished Children. Nutrisearch 1999;6:3-9 and
17. Mathur GP, Kushawaha KP, Mathur S. Protein energy
2000;1:3-8.
malnutrition (PEM) updated. In: Gupte S (Ed) Recent
33. World Health Organization. Management of Severe
Advances in Pediatrics. Special Volume, Nutrition,
Malnutrition . A Manual for Physicians and other Senior
Growth and Development. Jaypee Brothers Medical
Health Workers, Geneva, 1999.
Publishers (P) Ltd: New Delhi, 1997;94-122.
34. World Health Organization . Nutrition for health and
18. McLaren DS, Burmaqn D. Nutritional Assessment. In The
development: a global agenda for combating malnutri-
Textbook of Pediatric Nutrition. New York, Churchill
tion, Geneva. WHO 2000.
Livingstone 1982;88-89.

6.2 Water Soluble Vitamins:
B Complex Vitamins
Thiamine (Vitamin B1): Anti-Beriberi
Vitamin or Aneurin
Thiamine is water and alcohol soluble, fat insoluble,
stable in slightly acidic solution and labile to heat, alkali
and sulfites.
Physiology
Active coenzyme form of thiamine is thiamine pyrophos-
phate (TPP) also called “cocarboxylase”, which acts in
various oxidative decarboxylations: (i) conversion of
pyruvic acid with eventual entry into Krebs cycle via
acetyl coenzyme A and that of alpha-ketoglutaric acid
with entry into Krebs cycle via succinyl coenzyme A, and
(ii) transketolase reaction in hexose monophosphate
(HMP) shunt. In thiamine deficiency, utilization of
pyruvic acid is decreased and therefore pyruvic acid and
lactic acid accumulate in the tissues.
Clinical Features of Deficiency
The classical deficiency syndrome of thiamine—beriberi
has been eradicated from the country in older children.
It is of two types.
1. Dry beriberi affects the nervous system. Its symptoms
include irritability, fatigue, emotional disturbances,
headache, polyneuritis, calf muscle tenderness, diffi-
culty in standing from sitting position, sluggish
tendon reflexes, reduced appetite, indigestion,
constipation, slow growth and gradual emaciation.
2. Wet beriberi is characterized by palpitation, tachy-
cardia, dyspnea and edema.
Infantile beriberi may be of three types.
1. Cardiovascular type is characterized by tachycardia,
dyspnea, shrill cry, cyanosis and vomiting (onset—
very acute).
2. Aphonic type—It has a subacute onset, hoarse cry,
which is followed soon by aphonia. Terminal mani-
festations include dyspnea, puffiness and pitting
edema.
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Shashi N Vani
3. Neurologic type—Features include vomiting’ tremors
and convulsions. Ptosis, nystagmus and extraocular
muscular paralysis also occur due to thiamine
deficiency. It starts in infants of 6 to 12 months age
and runs a chronic course.
Sources
Good sources of thiamine include yeast, unmilled cereals,
pulses, oil seeds, groundnuts.
As soon as the diagnosis of thiamine deficiency is
made, the child should receive 10 mg thiamine intra-
venously. In the next 5 days, he or she should be given
10 mg of vitamin twice daily followed by 10 mg daily
orally for next 6 weeks. A breastfeeding mother should
also receive thiamine therapy.
Riboflavin (B2)
Riboflavin is sparingly soluble in water, sensitive to light
and alkali and stable to heat, oxidation and acid.
Physiology
It is a constituent of flavoprotein enzymes important in
hydrogen transfer reactions, amino acid, fatty acid and
carbohydrate metabolism and cellular respiration. It is
also a constituent of retinal pigment for light adaptation.
Clinical Features of Deficiency
Symptoms confined to skin and mucosa include glossitis,
cheilosis, nasolabial dysbecia, circumcorneal vasculari-
zation and keratitis, watering of eyes, photophobia and
blurring of vision. If the pregnant mother is riboflavin
deficient, the growth and development of the fetus may
be retarded.
Sources
Good sources include milk, cheese, meat, eggs, fish, green
leafy vegetables, and whole grains.
Therapy is by administering riboflavin 3 to 10 mg
orally or 2 mg IM daily for a few days. This should be
followed by 10 mg orally daily, for about 3 weeks.
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Niacin (Nicotinamide, Nicotinic Acid,
Antipellagra Vitamin)
Niacin is water and alcohol soluble and stable to acid,
alkali, light, heat and oxidation.
Physiology
It is constituent of coenzymes I and II. Nicotinamide
adenine dinucleotide (NAD) and nicotinamide adenine
dinucleotide phosphate (NADP) are cofactors in a
number of dehydrogenase systems. L-tryptophan—an
essential amino acid can be converted to niacin. This
meets parts of the requirement of this vitamin. Therefore,
deficiency is more prevalent in maize eating population.
Clinical Features of Deficiency
This is characterized by 3 Ds, i.e. diarrhea, dermatitis
and dementia. Other gastrointestinal symptoms include
loss of appetite, nausea, vomiting and achlorhydria.
Other neurological manifestations are muscle weakness
and loss of memory. Dermatitis consists of pigmented,
scaly, cracked skin on those parts of the body which are
exposed to sunlight such as neck and back of hands.
Hartnup’s disease is a genetic transport defect of amino
acids, leading to niacin dependency.
Sources
Good sources include groundnuts, whole cereals, pulses,
meat and fish. Therapy comprises nicotinamide, 50 to
300 mg, daily in divided doses orally, given for 2 weeks,
followed by adequate supply of B-complex vitamins in
diet to bring about complete recovery.
Pyridoxine
Physiology
Pyridoxine includes a number of derivatives of pyridine
such as pyridoxine, pyridoxal and pyridoxamine.
Through its active coenzyme form (pyridoxal phosphate),
pyridoxine plays a central role in amino acid metabolism,
e.g. in transamination, decarboxylation and desulfuration.
In pyridoxine deficiency, urinary excretion of xan-
thurenic acid increases after tryptophan loading. Dietary
deficiency is rare. Deficiency of the vitamin results from
an inborn error of metabolism or is secondary to some
other disease. Prolonged use of isoniazid is one of the
causes of pyridoxine deficiency.
Clinical Features of Deficiency
It includes hyperacusis, hyperirritability, hypochromic
anemia, nausea, vomiting and failure to thrive.
The manifestations include convulsions, normocytic
and hypochromic anemia refractory to iron therapy.
Growth retardation and gastrointestinal tract (GIT)
symptoms like diarrhea, and vomiting may occur.
Sensory neuropathy, cheilosis and glossitis are infrequent
in children.
When metabolic causes like hypoglycemia, hypocal-
cemia have been ruled out, we should think of vitamin
B6 deficiency, if an infant has persistent convulsions. Such
infants should receive 50 to 100 mg of pyridoxine
intravenously.
Sources
Good sources are liver, meat, fish, cereals and legumes.
Administration of 5 mg of pyridoxine IM followed
by 0.5 mg daily orally for 2 weeks causes complete
recovery.
Folate (Folic Acid, Ketoglutamic Acid, Folacin)
These are a group of related compounds containing
pteridine ring, para-aminobenzoic acid and glutamic
acid. Pteroylglutamic acid (PGA) is slightly soluble in
water and labile to heat, light and acid.
Physiology
Folates are concerned with formation and metabolism of
one carbon units: (i) participates in synthesis of purines
and pyrimidines for nucleic acid synthesis, (ii) intercon-
version of amino acids—glycine and serine, and
(iii) breakdown of histidine. The active form of folate is
tetrahydrofolate produced by the enzyme folate reductase
in 2 steps: Folate → dihydrofolate → tetrahydrofolate.
Clinical Features of Deficiency
Impaired DNA synthesis in cells results in abnormali-
ties of cell division so that the tissues affected are those
with rapid cell turnover, i.e. the intestinal mucosa and
bone marrow. Therefore, the predominant symptoms are
megaloblastic anemia and diarrhea.
Sources
Good sources are leafy vegetables, liver and eggs.
Overcooking and boiling destroys folate in food.

Recommended dietary allowance (RDA) is
100 microgram. Requirements increase during pregnancy
and lactation.
Vitamin B12 (Cyanocobalamin)
Vitamin B12 is slightly soluble in water, stable to heat in
neutral solution, labile in acid or alkaline ones, and
destroyed by light. Castle intrinsic factor of the stomach
is required for absorption of vitamin B12. Vitamin B12 is a
cyclical compound containing cobalt atoms. It is
converted to coenzymes such as methyl cobalamin and
5 deoxyadenosyl cobalamin in the body. These coenzy-
mes play essential roles in the following metabolic
reactions:
1. Conversion of methyl malonyl coenzyme A to
succinyl coenzyme A. In deficiency of vitamin B12,
methyl malonyl coenzyme A accumulates in the body
and is excreted in the urine as methyl malonic acid.
2. Conversion of homocysteine to methionine in pre-
sence of tetrahydrofolate is catalyzed by an enzyme
containing methyl cobalamin as a coenzyme.
Vitamin B12 also plays important roles in nucleic acid
metabolism and protein synthesis.
Absorption, Transport and Storage
Vitamin B12 is absorbed in the lower part of the ileum by
highly specific intestinal cells. Intrinsic factor, present in
gastric juice, combines with vitamin B12 forming vitamin
B12 intrinsic factor complex that binds to specific receptor,
sites on the intestinal brush border. From here the vitamin
B12 is internalized and intrinsic factor is left behind.
Transport of vitamin B 12 in the body is by trans-
cobalamine II and storage bound to transcobalamine I.
Clinical Features of Deficiency
Deficiency of vitamin B12 leads to impaired deoxyribo-
nucleic acid (DNA) synthesis, which further leads to
maturation arrest of cells in the bone marrow and
defective myelination of large nerve fibers in the spinal
cord and especially the long tracts of lateral and posterior
columns.
So, the hematologic manifestations involve entry into
the circulation of immature cells that are larger in size
and in the absence of concomitant iron deficiency are
adequately hemoglobinized leading to macrocytic
normochromic anemia. The neurological manifestations
due to long tract demyelination in lateral and posterior
columns is known as subacute combined degeneration.
Nutrition 165
Sources
Good sources include foods of animal origin such as milk,
eggs, meat and liver,
Recommended dietary allowance (RDA):
Children—0.2 to 1 microgram/day.
Adults—1 microgram/day.
Vitamin C
It is also known as ascorbic acid and antiscorbutic
vitamin.
Important Actions
These include oxidation of tyrosine and phenyl-alanine,
conversion of proline to hydroxyproline which is neces-
sary for collagen formation, integrity and maintenance
of ground substances, conversion of folic acid to folinic
acid, and absorption of iron.
Clinical Features of Deficiency
Scurvy is usually seen between 6 months and 7 years of
age. Initial symptoms are vague and include irritability,
tachypnea, digestive disturbances and loss of appetite.
Other features of severe deficiency include:
i. Generalized tenderness, especially along the shafts
of lower limbs leading to pseudoparalysis and
characteristic frog position of limbs (semiflexed hips
and knees and outwardly turned feet).
ii. Palpable swelling along the shaft of legs due to
subperiosteal hemorrhages.
iii. Hemorrhages in gums, especially around erupted
teeth leading to spongy, swollen, bluish purple
gums.
iv. Petechiae or purpura due to bleeding in skin.
v. Hematuria, melena, subdural bleeding.
vi. Follicular hyperkeratosis and hemorrhages at root
of hair follicles.
vii. Rosary at costochondral junction and depressed
sternum.
Diagnosis
Diagnosis is made on the basis of:
i. Clinical picture
ii. Characteristic roentgenographic appearance of long
bones, ground glass appearance due to osteoporosis
and loss of trabeculae, dense “white line of Frenkel”
at epiphyseal ends of long bones with adjacent area
of rarefaction (fracture zone), thin cortex, signet ring
appearance of epiphyses.
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iii. laboratory tests are less satisfactory
a. Plasma vitamin C level below 0.6 mg/dl
b. Vitamin C concentration in buffy layer of
centrifuged blood
c. Vitamin C excretion in urine, after a test dose of
vitamin C given intravenously.
Differential Diagnoses
1. Poliomyelitis: Due to pain, in scurvy the patient
assumes limited movements and frog-like posture.
So, poliomyelitis may be mimicked. Differentiation
may be done by acute pain on movements, muscle
charting and true flaccid paralysis in polio.
2. Leukemia: Due to bone tenderness, and bleeding
tendency, this may mimick scurvy. Differentiation
can be done by associated hepatosplenomegaly and
raised blood counts and presence of premature cells
in circulation.
3. Nephritis: Presence of hematuria may mimick scurvy.
Associated hypertension and urine abnormality helps
to differentiate.
4. Meningitis: Neck rigidity, fever and irritability may
confuse with meningitis. Meningeal signs help to
differentiate.
6.3 Fat Soluble Vitamins
VITAMIN A DEFICIENCY
Vitamin A is a generic descriptor of retinoids that exhibit
qualitatively the activity of all-trans-retinol compounds.
Retinol signifies vitamin A alcohol and is found in foods
of animal origin only. Some carotenoids which are found
in plants, bacteria, algae and fungi can be converted into
retinol and are called provitamin A. The carotenoid with
the highest vitamin A activity is beta carotene. Beta
carotene yields two molecules of retinol. Retinol is
esterified in the mucosal cell with palmitic acid. Retinyl
palmitate is stored in the liver. Being fat soluble, retinol
mobilized from the liver must be bound in serum to
retinol binding protein (RBP) which is synthesized in the
liver. RBP also protects retinol from oxidation and
releases it to specific receptor sites on the surface of the
Sources
Good sources include fruits and juices especially citrus
fruits. Indian gooseberry is one of the richest source.
Drumstick leaves are also very good source of vitamin
C.
Requirement
Adult 75 mg/dl, Infant 30 mg/dl, Adolescence—
80 mg/dl, Pregnant women—100 mg/dl, Lactating
women—150 mg/dl.
Treatment
Recommended therapy is loading dose of vitamin C—
500 mg orally or parenterally followed by a daily dose of
100 to 300 mg for several weeks. Clinical response occurs
rapidly, and prognosis is good, though radiological
improvement and subperiosteal swellings take time to
improve.
Prevention
Breastfeeding of infants should be encouraged. Lacta-
ting mothers should receive vitamin C supplements.
Panna Choudhury
target cell. Recently, it has been suggested that RBP
synthesis may be affected in zinc deficiency.
Physiology
Vitamin A is an essential nutrient required for normal
reproduction, vision, growth, hematopoiesis and
immune competence. The key to most of these functions
is the role of vitamin A in regulating the gene expression
and cell differentiation practically for every cell in the
body. The importance of vitamin A in maintaining
integrity of epithelial tissues and functioning of the retina
for vision has been well established. Visual pigment in
rods is called rhodopsin, which is composed of a protein
called opsin and a pigment, 11-cis retinine (vitamin A).
Rhodopsin is light sensitive and when light falls on eyes,

rhodopsin splits and 11-cis retinine, is converted to
11-trans retinine. This initiates an electrochemical signal
to be carried to the brain, where visual images are
constructed. In vitamin A deficiency, the threshold for
stimulating rods is raised, thus, affecting the vision under
dim light.
Quantification of vitamin A is expressed in various
ways. One International unit (IU) equals 0.3 μg retinol.
Rich sources of vitamin A include fish liver oils, butter,
egg, carrot, green leafy vegetables, tomato, and ripe
mangoes. Breastfeeding protects children through the
first 3 to 4 years of life in rural areas of Asia and Africa.
In India, daily intake of vitamin A as retinol equivalent
has been recommended as 350 μg for infants, 400 μg for
preschool children, and 600 μg for school children and
adolescents.
Deficiency of vitamin A can occur from deficient diet,
decreased absorption due to chronic intestinal disorders
or reduced storage in liver diseases. There could be an
increased requirement of vitamin A in presence of
infections. Supplementation of vitamin A has been
shown to have an impact on childhood mortality. In
India, Bitot spots are seen in 0.7 percent of preschool
children with overall prevalence as 0.21 percent in all
age groups. Vitamin A deficiency is responsible for 0.04
percent of all blind cases.
Clinical Features
Ocular lesions affect the posterior segment of eye initially
with impairment of dark adaptation and night blindness.
Often the mother of the infant notices that he or she takes
considerable time to adjust to dim light or darkness
(twilight blindness). Xerosis of conjunctiva is usually the
first sign that can be seen on examination. The
conjunctiva becomes dry, lusterless, wrinkled and dirty
brown in color. These changes are most obvious in the
interpalpebral bulbar conjunctiva. Conjunctival xerosis
may lead to formation of the so called “Bitot's spot” which
consists of almost a triangular area, usually about the
temporal aspect of the limbus covered by a fine white
foamy or greasy substance. It is composed of heaped up
sloughed-off keratinized cells and saprophytic bacilli,
which collect on conjunctival surface. Nasal involvement
reflects more advanced deficiency. Keratomalacia is seen
in the late stage and consists of softening, necrosis and
ulceration of the cornea. Once cornea gets involved,
photophobia accompanies the clinical profile. WHO has
proposed a classification for xerophthalmia (Table 6.3.1).
Nutrition 167
Extraocular lesions include dry, scaly skin, especially
over the outer aspect of the limbs, called follicular
hyperkeratosis, toad skin or phrynoderma. Increased
susceptibility to infections due to squamous metaplasia
of respiratory, urinary and vaginal tract epithelium; renal
and vesical calculus may occur more often in such
subjects.
TABLE 6.3.1: WHO classification for xerophthalmia
Classification Primary signs
X1A Conjunctival xerosis
X1B Bitot's spots
X2 Corneal xerosis
X3A Corneal ulceration
X3B Keratomalacia
Secondary signs
XN Night blindness
XF Fundal changes
XS Corneal scarring
Diagnosis
In the presence of clinical manifestations, diagnosis is
not difficult. In vitamin A deficiency state serum retinol
level is usually below 20 mg/dl. Conjunctival impression
cytology is a noninvasive technique that assesses vitamin
A status by detecting early losses of vitamin A-
dependent, mucus secreting goblet cells and early
metaplasia of the epithelium.
Treatment
Prevention of vitamin A deficiency can be achieved by
making available, 1 only the recommended daily
allowances of vitamin A to all children. According to the
National Program for Prevention of Blindness, children
in the age group 6 to 11 months should receive 100,000
IU of vitamin A orally (preferably during measles
immunization) and other children between 1 and 5 years,
should receive 200,000 IU vitamin A every six months in
the target areas. Use of vitamin A and beta carotene rich
food should be encouraged. Fortification of commonly
eaten foods with vitamin A can be an effective
prophylactic measure.
For treatment of xerophthalmia, according to WHO
guidelines, 200,000 IU vitamin should be given orally on
presentation, the following day and, whenever possible,
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1 to 4 weeks later. Infants' 6 to 12 months receive a half
dose, and infants less than 6 months one-quarter the dose,
following the same schedule. Children with wasting
malnutrition, recurrent diarrhea, pneumonia and severe
infections should also receive full treatment course of
vitamin A.
HYPERVITAMINOSIS A
Signs of toxicity may appear with massive doses or with
large doses over a large time period. Child may have
nausea, vomiting, drowsiness, papilledema and symp-
toms suggestive of raised intracranial tension (pseudo-
tumor cerebri). In chronic cases, marked anorexia, failure
to thrive, alopecia, seborrheic dermatitis, hepatomegaly,
and tender bone swelling may develop. Radiographic
examination may show hyperosteosis of the shafts of long
bones. However, beta carotene ingestion is seemingly
without toxicity. With chronic high consumption, the
skin, but not the sclerae are stained yellow-orange, which
is benign and reversible.
VITAMIN D DEFICIENCY
Antirachitic properties of vitamin D are the result of small
structural changes, under the influence of ultraviolet
irradiation in a number of steroids related to cholesterol.
However, only ergosterol and 7-dehydrocholesterol have
practical importance. Ergosterol is of plant origin and on
irradiation, it transforms to Vitamin D2 (calciferol). 7-
dehydrocholesterol is normally present under the skin,
and on exposure to ultraviolet rays of the sunlight, it
converts to vitamin D3 or cholecalciferol. The latter is
converted to 25-hydroxycalciferol in the liver and is
further converted to 1, 25-dihydroxycholecalciferol,
which is specifically helpful in promoting synthesis
of “calcium transport protein” in the intestinal
wall. Parathormone controls the production of
1, 25-dihydroxycholecalciferol, the metabolically active
form of vitamin D.
Vitamin D, unlike other vitamins is not abundantly
available in foodstuffs. Rich source of vitamin D is fish
liver oil and to some extent it is available in butter and
egg. Thus, infants are more prone to vitamin D deficiency
as, natural diet of infants like milk, cereals, vegetables,
fruits are deficient in vitamin D. This gets aggravated if
there is also lack of access to sunlight. Vitamin D
deficiency also occurs in presence of malabsorption, liver
and kidney diseases. Rickets, a metabolic disorder of
growing bone leading to bony deformities, when results
from vitamin D deficiency is known as nutritional rickets.
The normal daily requirement of vitamin D for infants
and children is 200 IU. It has been estimated that only
five minutes of exposure to sunlight is sufficient to meet
the daily requirement of vitamin D. However, it should
be remembered that the effective ultraviolet rays in
sunlight are cut-off by haze, windowpane, etc.
Biochemical Changes
Vitamin D deficiency causes decreased absorption of
calcium from gut. The resulting hypocalcemia leads to
increase in parathormone secretion. This helps in release
of calcium from bone. Parathormone also reduces the
excretion of calcium by kidneys and renal tubular
reabsorption of phosphate. As a result, the serum calcium
level tends to become normal, while the serum phosphate
level falls. After sometime, this compensatory
mechanism fails and both calcium and phosphorus levels
fall. Since calcium phosphate is necessary for deposition
of calcium in growing bones, decrease in blood levels of
calcium, phosphorus or both interfere with the
calcification of the osteoid tissue. Serum alkaline
phosphatase level also gets increased due to increase in
osteoblastic activity.
Pathology of Rickets
The epiphyseal plate is a narrow well-defined strip from
where cartilage cells grow in parallel column towards
the metaphysis. After initial proliferation, the old
cartilage cells degenerate and disappear, leaving spaces
into which the blood vessels and osteoblasts of the shaft
can penetrate. Calcium is deposited in the zone of
degenerating cartilage, which is then called “Zone of
preparatory calcification”. In rickets, the cartilage cells
go on multiplying giving rise to a broad irregular
cartilaginous zone. The process of degeneration and
calcification becomes incomplete, leading to softness of
the bone. Rapidly growing cartilage cells particularly
affect the costochondral junctions and end of long bones.
There is also defective mineralization in the subperiosteal
bone. In long-standing cases, the bones under stress may
become deformed or even have pathological fractures.
Supplementation of vitamin D restores the normal
development of the bone with calcification starting at
the zone of preparatory calcification, which in a
radiography would be seen as a thin dense line near the
epiphysis.

Figure 6.3.1: Case of rickets showing widening of
wrists and beading of ribs on chest
Clinical Features
Rickets is a disease of growing bones and its incidence is
particularly high between 4 and 18 months. Skeletal
deformities are the most striking feature of rickets.
One of the early signs of rickets is craniotabes. In this
condition, on pressing occipital or posterior part of
parietal bone, a sensation like pressing a ping-pong ball
can be felt. It results from the thinning out of the inner
table of the skull due to absorption of noncalcified osteoid
tissue. Fontanel may remain wider than normal and close
late. Other early evidences of osseous changes are,
palpable enlargement of costochondral junctions, i.e.
rachitic rosary and widening of the wrists (Fig. 6.3.1) and
ankles.
Signs of advanced rickets can be easily recognized.
Bossing of skull generally starts after the age of six months.
It occurs due to heaping up of osteoid tissue in the frontal
and parietal regions so that the skull appears squarish
or box-like shape. In thorax, the sternum is pushed
forward, producing a “pigeon chest”. A horizontal
depression known as Harrison's groove, corresponding
to costal insertion of the diaphragm, develops. The chest
deformities decrease the lung resilience and predispose
the child to intercurrent infections. Bending of the spine
backwards (kyphosis) and laterally (scoliosis) may occur.
Pelvis may become softened and, the promontory of the
sacrum is pushed anteriorly and the acetabulae inwards,
resulting in a narrowed pelvic inlet. This is helped by
Nutrition 169
lax ligaments. Deformity of the pelvis in a female, results
in difficulty during labor at a later stage. Long bones of
the legs get deformed when the child starts bearing
weight and is thus, usually seen after the age of one year.
Bending of the femur, tibia and fibula, result in “bow-
legs” or “knock-knees”. Coxa vara and green stick
fractures may also occur. All deformities of bones result
in rachitic dwarfism. Dentition may be delayed and
disordered eruption of temporary teeth occurs. In
children between 8 and 18 months, permanent teeth,
which are undergoing calcification, may be affected.
Besides skeletal deformities, there is a generalized
hypotonia with delay in motor development. The
abdomen is protuberant, and generalized flabbiness of
muscles may result into visceroptosis with downward
displacement of spleen and liver.
Diagnosis
The diagnosis of rickets is based on the clinical features,
biochemical findings and characteristic radiological
picture. The serum calcium level may be normal or low,
the serum phosphorus level is below 4 mg/dl, and the
serum alkaline phosphatase is usually elevated.
Radiological changes are best seen in the lower end of
radius and ulna. Skiagram of the wrist shows widening,
cupping and fraying of the epiphyses, in contrast to the
normally sharply demarcated and slightly convex
epiphyseal line (Figs 6.3.2A and B). The density of shafts
decreases with prominent trabeculae. There is an increase
in distance between concave epiphyseal line and the ends
of metacarpals. Green stick fractures, expansion of bone
ends and bending of bones may be evident on
radiographs. Some raising of the periosteum is due to
excess of osteoid lying under the periosteum.
Differential Diagnosis
Nutritional rickets should be differentiated from other
types of rickets and chondrodystrophy. Other conditions
producing bony deformities may, sometimes, need
consideration. Craniotabes and a large head apart from
rickets, occurs in hydrocephalus, congenital syphilis and
osteogenesis imperfecta. Enlargement of costochondral
junctions may also be seen in scurvy and chondrodys-
trophy.
Management
Vitamin D is given in a dose of 15000 μg (or 600,000 IU)
orally or intramuscularly. If there is no sign of healing
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Figure 6.3.2A: Florid rickets showing cupping, fraying and
widening of metaphysis of distal end of radius and ulna
Figure 6.3.2B: Healing rickets showing zone of calcification at
the distal end of radius and ulna; also seen the periosteal
calcification of metaphysis
line in skiagram taken 3 to 4 weeks after therapy, the
same dose can be repeated. If there is no response within
3 to 4 weeks of the second dose, investigations for
refractory rickets should be initiated. Rickets can also be
treated with a dose of 50 to 125 μg (2000 to 5000 IU) daily
for four weeks. After the healing of rickets, normal daily
requirement of vitamin D should be continued.
Deformities of bones are corrected by orthopedic
measures.
HYPERVITAMINOSIS D
High-dose of vitamin D given over a long period may
cause anorexia, vomiting, hypotonia, irritabiliy,
polydipsia and polyuria. There is hypercalcemia and
hypercalciuria. Radiological examination reveals evi-
dence of metastatic calcification and osteoporosis of long
bones.
VITAMIN E DEFICIENCY
Vitamin E is a group of closely related naturally occur-
ring fat-soluble compound of which tocopherol is
functionally the most potent. It is active as an antioxidant
and, probaby involved in the metabolism of nucleic acids.
It is widely present in most foods. One mg of alpha-
tocopherol provides 1.5 IU activity of vitamin E. The
deficiency of vitamin E is rare. The most common causes
are diarrhea and poor intake of food. Deficiency may
result in arcflexia, ataxia, muscle weakness and
dysarthria. In premature infant, low levels of vitamin E
are associated with hemolytic anemia, hyperbilirubi-
nemia and intraventricular hemorrhage. This responds
quickly to 5 to 25 mg of vitamin E therapy. Generally,
infants should receive 3 mg of alpha-tocopherol daily.
VITAMIN K DEFICIENCY
Vitamin K is a naphthoquinone derivate. Absence or
failure of its absorption from the intestine leads to
hypoprothrombinemia and decreased synthesis of some
coagulation factors (VII, IX and X). The normal require-
ment of vitamin K is met by bacterial synthesis in the
intestine. In addition, it is also found in high
concentration in a wide variety of foods and vegetables
like spinach, cabbage, peas, tomatoes, soybean and liver.
The deficiency of vitamin K can occur in mal-
absorption states, biliary obstruction, after oral antibiotic
therapy or in newborn before colonization of the guts.
In general, vitamin K deficiency or hypoprothrom-
binemia should be considered in all patients with
hemorrhagic disturbances. Hemorrhagic disease of the
newborn is one of the most common manifestations. The
bleeding is variable and can occur anywhere, though,
most common is gastrointestinal bleeding. A daily dose
of 1 to 2 mg of vitamin K orally is sufficient for treatment.

In severe deficiency state, 5 mg of aqueous vitamin K
can be given parenterally.
BIBLIOGRAPHY
1. Dietary Guidelines for Indians. Indian Council of Medical
Research, New Delhi, 1998.
2. Report. Micronutrient Deficiency Disorders in 16 Districts
6.4 Trace Elements
Minerals occur in all living tissues, some of them in such
small amounts that routine analytical methods available
in the past were unable to measure them. Minerals found
in < 0.01% of body weight are termed trace elements.
Out of 81 elements found in the human body, following
are essential (E) for humans, e.g. arsenic, bromine, carbon,
chlorine, cobalt, copper, flourine, iodine, iron,
molybdenum, nickel, manganese, nitrogen, selenium,
silicon, sodium, sulfur, phosphorus, potassium, tin,
vanadium and zinc. These are essential for growth and
maintenance of life or health. Other trace elements
constantly occur in living tissues but are non-essential
(NE), e.g. aluminium, antimony, cadmium, mercury,
germanium, rubidium, silver, lead, gold, bismuth,
titanium, zirconium, etc.
Trace elements catalyze and control biochemical
reactions. More than half of the enzymes in human bodies
have one or more of these at active sites. Some trace
elements like magnesium and calcium form complexes
with enzymes and nucleic acid and act as biological
triggers. Others are essential for enzyme activity (zinc,
copper), hormone synthesis (iodine), and vitamin
functions. Safe and adequate concentration for each
element is required in the body for optimal function.
Every trace element is potentially toxic when this range
exceeds, and deficiency occurs when it falls short of
requirement.
Trace Element Deficiency and Toxicity
Etiological factors for trace element deficiencies have
been summarized in Table 6.4.1. Excess trace ele-
ments inhibit enzyme activities, alter nucleic acid
structure and function, impair synthesis of protein, effect
Nutrition 171
of India, Indian Council of Medical Research, New Delhi,
2001.
3. Sommer A. Vitamin A Deficiency and its Consequences:
Field Guide to Their Detection and Control (3rd edn).
World Health Organization: Geneva, Switzerland, 1995.
4. West KP Jr: Vitamin A deficiency—a pediatric priority
in tropics. In David TJ (Ed): Recent Advances in
Pediatrics. BI Churchill Livingstone: New Delhi,
1997;14:159–75.
B Bhandari
TABLE 6.4.1: Etiological factors implicated in
trace elements deficiency
Primary Deficiency
• Inadequate intake—zinc, copper, iron, iodine
Secondary Deficiency
• Genetic or inborn errors of element metabolism—zinc,
copper
• Total parenteral nutrition—copper, zinc, selenium, iron,
manganese
• Drugs and iatrogenic—copper, zinc, iron
• Environmental—iodine, selenium
• Malabsorption and chronic diarrhea—iron, zinc, copper
• Protein energy malnutrition—zinc, copper
• Prematurity and LBW (poor stores)—iron, copper, zinc
• High requirements (pregnancy, lactation, rapid growth,
viz prematurity)—zinc, iron
• Element interactions with other nutrients and elements—
copper/zinc, iron/zinc, iron/copper, iron/manganese
• Increased excretion: nephrosis, liver, cirrhosis, chelating
agents, trauma, burns, pica, hemolytic anemia—zinc.
Adapted from References 3,5,7,8
cell wall permeability and lead to toxicity Table 6.4.2
summarizes functions, essentiality, effects of deficiency,
excess and sources including recommended daily
allowances (RDA) for some of the trace elements.
Diagnosis
As the signs and symptoms of deficiency except for
severe zinc deficiency, and excess of trace elements in
early period are often nonspecific, a high degree of
clinician's suspicion, knowledge and advanced labo-
ratory facilities are required to confirm the diagnosis.
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TABLE 6.4.2: Disorders of trace elements

Trace Function Deficiency Excess Sources RDA

element (mg or mg/day)

Aluminium Binds mainly to Not described Encephalopathy, Cooking utensils, spinach,

(NE) albumin and trans- anemia, cardiac food additives, tea leaves,
ferrin and bone toxicity infant milk formula,
dialysis and intravenous
fluids, antacids
Arsenic Unknown Not described Diarrhea
(E) May be taurine and Anemia
sulfate production Cancer
from methionine Hyperkeratosis
Chromium Regulation of blood Impaired glucose Renal failure Widely distributed 0.005–0.2 mg
(E) sugar, potentiates tolerance in PEM? Lung cancer
insulin metabolism Peripheral Dermatitis
neuropathy
Cobalt Part of erythropoitin Hypothyroidism? Cardiomyopathy Milk, meat and sea foods 0.0001 mg
(E) and cyanocobalamine Goiterogenic
Synthesis of thyroid
hormone
Copper Transferrin Refractory anemia Indian childhood Liver, oysters, fish 0.05–0.1 mg/kg
(E) Hemoglobin Osteoporosis cirrhosis whole grains, nuts,
Absorption of iron Neutropenia Wilson’s disease legumes, contaminated
Oxidative enzyme Delayed bone age Hemolytic anemia water-milk stored in brass
activation—tyrosinase, Ataxia Renal dysfunction copper utensils
catalase, uricase, Pseudoparalysis (Fancon-like anemia)
cytochrome oxidase, Hypercholesterolemia Acute copper poisoning—
lysyl oxidase, etc. Menkes disease vomiting, hemolytic anemia
Defective hair and gastric hemorrage
pigmentation
Hypothermia
Degenerative changes
in elastin of aorta
Mental deterioration
Retarded growth
Fluoride Constituent of bone Dental caries Fluorosis Drinking water, 1 ppm in water
(E) and tooth Osteoporosis Vomiting, diarrhea, sea foods (100 µg/dl)
Abdominal pain Toothpaste
Tetany
Iodide Part of T3 and T4 Endemic cretinism Cardiovascular collapse, Iodized salt, sea < 6 mo 40 µg
(E) Simple goiter Goiter food, food grown in 6–12 mo 50 µg
Hypothyroidism Maternal excess may known goiterous areas 1–3 yr 70 µg
cause congenital hypo- 4–6 yr 90 µg
thyroidism and goiter 7–10 yr 120 µg
> 11 yr 150 µg
Iron Transport of oxygen Anemia Hemosiderosis, Liver, meat, egg yolk, < 6 mo 6 mg
(E) and carbondioxide growth failure iron poisioning green vegetables, 6 mo 10 yr–10 mg
(hemoglobin and Impaired learning whole grains, legumes > 11 yr (male) 12 mg
myoglobin), part of and alertness nuts > 11 yr (female)
oxidative enzyme 15 mg
–cytochrome-C
and catalase

contd...
 Nutrition 173

Table 6.4.2: contd...

Trace Function Deficiency Excess Sources RDA
element (mg or mg/day)
Lead Anemia, abdominal Leaden petrol lead
(NE) colic, muscular based paints, canned
weakness low IQ low fruits, lead toys
attention encephalo- cosmetics
pathy
Magnesium Constituent of bone Tetany Unknown Cereals, legumes, nuts 40–340 mg
(E) Enzyme activator Milk, meat
Muscle and nerve
irritability
Cation
Manganese Constituent of Increased Encephalopathy, Cereals, legumes, nuts 0–1 yr 0.8–1.0 µmol
(E) mitochondrial super- prothrombin pneumoconiosis, Manganese containing 1–12 yr 0.7–0.9 µmol
oxide dismutase and bleeding time syndrome like dust absorbed via >12 yr 0.6–0.8 µmol
Structure of bone Hypercholesterolemia Parkinson's disease alveolus
Antioxidant Cholestatic jaundice
Molybde- Constituent of Cancer of esophagus Hyperuricemia Cereals, grains, lagumes, 0.15–0.5 mg
num (E) xanthine oxidases, green leafy vegetables
Sulfate oxidase
Mercury Toxic for many Minimatta disease
(NE) enzymes and RNA Acrodynia
Nickel Stabilization of DNA Not known Dermatitis,
(E)-? and RNA nasal and pulmonary
Urease-matalloprotein carcinoma,
contains nickel as liver necrosis
essential constituent
Selenium Cofactor of Keshan Alopecia, Vegetables, meat, water <6 months 10 µg
(SE) glutathione cardiomyopathy nail deformity 6–12 months 15 µg
peroxidase Kashin-Beck disease lassitude, 1–6 yr 20 µg
Decreased fertility garlic odor to 7–10 yr 30 µg
breath > 11 yr 50–75 µg
Silicon Structure of Impaired early bone Pulmonary inflammation,
(E) collagen and elastin development granuloma and fibrosis
Vanadium Not known Not known Not known
Zinc Part of several Failure to thrive Food cooked in Grains, nuts, cheese 0–12 months 5 mg
(E) enzymes Anemia galvanized utensils Meat, oysters 1–10 yr 10 mg
Stabilization of Hypogonadism may lead to nausea, > 11 yr 15 mg
membranes Acrodermatitis vomiting and diarrhea,
Development enteropathica decrease in high
of taste buds Reduced immuno- density lipoproteins,
and brain incompetence. gastric ulcer, pancreatitis,
Poor wound healing pulmonary fibrosis,
Alopecia copper deficiency
Congenital
malformation
Decreased acuity
of taste

Essential—(E), Nonessential—(NE), Adapted from references 3–5

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Further presence of trace elements in laboratory atmo-
sphere, glassware, water, reagents, etc. contaminate
samples unless meticulous care is taken. Currently
techniques used for trace element analysis are atomic
absorption spectrometry (AAS) and neutron activation
analysis (NAA). Sometimes estimation of enzymes depen-
dent on these elements and outcome of therapeutic
supplementation may help in establishing diagnosis.
Zinc
Deficiency
Zinc deficiency syndrome was first discovered in the
Middle East. Cereal diets decrease its absorption due to
high phytates, fibers and phosphates as also chronic
diarrhea. Nephrosis, liver cirrhosis, hypoalbumenic
states, chelating agents, total parenteral nutrition (TPN),
trauma, burns and hemolytic anemia cause increased
excretion of zinc in urine causing deficiency. Deficiency
is also seen when body requirements are increased as in
developing fetus, pregnant women, and adolescents. Pica
in children is associated with hypozincemia. Acroder-
matitis enteropathica is autosomal recessive disorder due
to failure of zinc absorption. It is characterized by growth
retardation, hypogonadism, poor appetite, eczematoid
skin lesions, alopecia and diarrhea which usually
manifest on weaning. If left untreated it progresses to
severe malnutrition, superinfection and death within 3
years. Mild subclinical zinc deficiency is frequent in
infants and children. Early clinical features of zinc
deficiency include anorexia, impaired taste and delayed
wound healing. Moderate deficiency features as seen in
West Asian dwarfs include hypogonadism, impotency,
anemia, hepatomegaly, night blindness, hyperkeratosis,
acrodermatitis, alopecia and superinfections with
bacteria or monilia due to defective T-cell function. Zinc
deficiency can lead to intrauterine growth retardation
(IUGR) and small-for-date (SFD) babies as it inhibits
growth and DNA synthesis. A strong relationship exists
between low plasma-zinc values and stunting, skin
ulceration, wasting and PEM with nutritional edema.
Diagnosis
Diagnosis can be confirmed by low zinc levels in plasma,
granulocytes, urine and sweat, latter being less reliable.
Clinical response to zinc supplementation can be
assessed in mild zinc deficiency by monitoring growth
velocity. Normal serum zinc levels in children are 66 to
194 μg/10 ml. The serum levels are particularly low in
children with kwashiorkor.
Toxicity
Acute zinc toxicity leads to nausea, vomiting, abdominal
pain, diarrhea, convulsions and collapse. Chronic toxicity
which causes lethargy, anemia, neutropenia and CNS
disturbances is principally due to its competition with
copper for absorption. Inhalation of fumes leads to
respiratory distress, fever and chills (metal fume fever).
Therapy
Diet should include rich sources of zinc viz, meat, eggs,
nuts, cheese, oysters and grains. Zinc as acetate, sulfate,
gluconate, amino acid-zinc chelates and oxide have been
put to many therapeutic uses. Established uses are in
treatment of acrodermatitis enteropathica (50-150 mg/
day). Local application as cream is used in ulcer, wounds,
burns and acne. It could possibly be of use in hypo-
gonadism, growth retardation, “anemia, tremor
pigmentation syndrome” pica, schizophrenia. Zinc is
widely used to reduce incidence and severity of diarrhea,
pneumonia and possibly malaria. Zinc (20 mg/day)
orally for 14 days improves morbidity and mortality in
children with diarrhea.
Copper
Normal serum levels in children are 77 to 185 mg/100
ml. Copper is a component of several enzymes which
are associated with electron transfer. Its essentiality for
proper utilization of iron has only been established
recently. Its role as an antioxidant is widely recognized.
Copper is present in whole grains, nuts, legumes, liver,
meats, etc. Copper concentrations in mothers' milk show
steady decline with lactation. It is essential for production
of red blood cells, transferrin, hemoglobin formation,
absorption of iron, and activities of tyrosinase, etc. It is
transported bound to alpha-2-globulin as ceruloplasmin.
Metallothionine, a zinc and copper binding protein
present in most human tissues is potential indicator of
copper nutritional status, while ceruloplasmin measuring
serum or plasma copper is subject to considerable
variation as an acute phase reactant protein.
Deficiency
Copper deficiency is extremely rare in well-nourished
full-term infants unless associated with gastrointestinal

abnormalities. It has been reported in formula-fed prema-
ture infants where copper deficiency may be presumably
due to inadequate intake for the rapidly growing infant,
or copper absorption was diminished by amount of iron
present in formula milk. Deficiency is characterized by
anemia, neutropenia, recurrent diarrhea and scurvy-like
bone changes. Deficiency is also seen in infants fed on
unfortified formula, with PEM, during prolonged
parenteral feeding and when zinc is given for several
weeks.
Toxicity
Menkes disease a X-linked recessive disorder is associated
with impaired absorption of copper. In neonate non-
specific features like hypotonia, hypothermia, seizure and
failure to thrive are seen. Kinky, pale, friable hair, severe
mental retardation and optic atrophy are constant features
which may appear later in infancy. Copper-histidine
50-150 μg elemental copper/kg/24 hr used in early infancy
by subcutaneous injections prevents neuropathological
changes. Wilson's disease another genetic disorder is
characterized by choreoathetosis, mental deterioration,
liver cirrhosis, and osteoporosis due to deposition of excess
copper in various tissues. Of historical importance is the
Indian childhood cirrhosis, where copper ingested with milk,
stored and boiled in brass utensils (alloy of copper and
zinc) is deposited in liver resulting into cirrhosis. Acute
copper poisoning is characterized by metallic taste, nausea,
vomiting, gastric hemorrhage, hemolytic anemia, uremia
and jaundice.
Selenium
It acts as cofactor of glutathione peroxidase which
catalyzes the breakdown of hydrogen peroxide to
oxygen. Vegetables and meat are rich sources, provided
soil contains selenium. In Keshan province of China
where soil is deficient in selenium, children, adolescents
and women of child-bearing age develop cardiomyo-
pathy and skeletal muscle myopathy (Keshan disease) and
osteoarthritis (Kashin-Beck disease). Excess of selenium
causes alopecia, abnormal nails, garlic odor to breath and
lassitude. It is used as antioxidant and for treatment of
seborrheic dermatitis.
Fluoride
Water, plant and animal food are sources of fluoride,
which are in turn dependent on content of fluoride in
Nutrition 175
the soil. It is important for structure of bone and tooth. It
prevents dental caries. When present in excess in water
and soil or ingested for longtime, they lead to calcification
of ligaments and tendons, weakness, anemia, loss of
weight and brittle bones. Mottling of teeth occur when it
is taken in excess during enamel formation (fluorosis).
This occurs when water supply contains more than 2
parts per million (ppm) of fluoride.
Magnesium
It is one of the constituents of bone and teeth. It activates
enzymes in carbohydrate metabolism and maintains
normal neuromuscular excitability. It is important intra-
cellular cation next to potassium. Deficiency is seen in
malnutrition, malabsorption, diabetes, pancreatitis and
chronic renal failure. In newborn, hypomagnesemia is
commonly associated with hypocalcemia, and
magnesium administered may restore both calcium and
magnesium to normal values. Levels of magnesium, zinc,
copper, calcium in colostrum are higher than mature milk
of full-terms. In neonates infusion of magnesium sulfate
has been used for its neuronal protective property in
perinatal asphyxia and due to its smooth muscle relaxing
action it had been used in persistent pulmonary
hypertension, acute bronchial asthma and torsade de
points in children. Hypermagnesemia, clinically is
uncommon except in neonates born to mothers who are
receiving intravenous magnesium for pre-eclampsia.
Green leafy vegetables, nuts, legumes and cereals
are dietary sources of manganese. Since it is a consti-
tuent of cytosolic superoxide dismutase and cerulo-
plasmin, it is an important antioxidant micronutrient.
Severe manganese deficiency in prenatal life causes
increase in prothrombin time and bleeding. It is low in
seizure disorders. Its excess may cause syndrome akin
to Parkinson's disease. Inhalation in large quantities can
cause asthenia, leg cramps and encephalopathy.
BIBLIOGRAPHY
1. Antia EP (Ed). Trace Elements in Clinical Dietetics and
Nutrition (3rd ed). Oxford University Press: Mumbai
1989;133-36.
2. Barness LA, John SC. Nutrition. In Behrman R, Kliegman
RM, Arvin AM (Eds). Nelsons Textbook of Pediatrics
(15th edn): WB Saunders: Philadelphia 1996;141-47.
3. Bhandari B, Gupta AP, Gupta A. Breast milk mineral
content. Indian Pediatr 1985;22:23-26.
4. Bhandari B, Mehta R, Sharda B: Hepatic and serum
copper in Indian childhood cirrhosis. Indian Pediatr
1981;18:769-73.
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Pediatrics
5. Bhandari B. Trace Elements in human health and disease.
Quaterly Med Rev 1983;34:1-31.
6. Bhaskaram P. Zinc deficiency. Indian Pediatr 1995;32:
1153-55.
7. Buist NRM, Kennaway NG, Powell BR. In: Campbell
AGM, Mcintosh N (Eds): Textbook of Pediatrics (4th
edn). Edinburgh: Churchill Livingstone 1994;1213-15.
8. Gupta AP, Bhandari B, Gupta A, et al. Mineral content
of breast milk from North Indian Mothers giving birth
to preterm and term—implications for mineral nutrition.
J Trop Pediatr 1984;30:286–88.
6.5 Child and Adolescent School
Health Education
A curriculum such as “Life Skills and Health Education”
is especially needed in developing countries like India
since there is an incerasing threat of communicable,
noncommunicable and lifestyle diseases prevalent in the
country. Lack of knowledge of diseases, preventive
health care, as well as other health issues across all
segments of society as well as absence of health and life
skills training in the Indian Education System at the
primary or secondary level makes this curriculum a dire
need.
The school-health education program was established
in 1958 with a view to stregthen younger generations.
Currently it works as a technical resource centre with
the Ministry of Education, National Centre for Educa-
tional Research and Training (NCERT), and Directorate
of Adult Education in close collaboration with the State’s
Health Education Department, and Universities.
However, none of the Indian schools has a system of
Health Education and Life Skill Curriculum practiced in
a systematically appropriate manner. Through school
based health education programs have been practiced
in the US, Norway nad China for mroe than 30 years, in
India they are being thought of being introduced in an
appropriate fashion only now.
Health Education and Life Skills Curriculum should
be designed to increases and create awareness of hygiene
and health among children right form their childhood
9. Janicki K. Drinking water and human health. In Yuregir
GT, Donma O Koyrin (Eds): Trace Elements in Health
and Disease. Qukurova Publishing: Adana 1989;21–33.
10. Prasad AS. Trace Elements in Human Health and
Disease. Academy Press: New York 1976;20.
11. Prasad AS, Fitzgerald JT, Bao B, et al. Duration of
symptoms and plasma cytokine levels in patients with
the common cold treated with Zinc acetate: A rando-
mized, double-blind placebo-controlled trial. Ann Intern
Med 2000;133:245–52.
12. Sharda B, Bhandarni B. Serum zinc in protein calorie
malnutrition. Indian Pediatr 1977;14:195.
Sushil Madan
ot inculcate positive living habits and empower them to
make informed choices about their own health. Keeping
this in view Health and life Skills Education program,
the first of its kind in India, was launched in January
2004 by Udayan Care team, which followed International
Health curriculum.
The basic objectives of this curriculum should be:
i. To promote the idea of responsibility for child’s
health by addressing comprehensive range of health
concerns amongst school children (6-19 years)
including (a) nutrition, growth and development,
(b) exercise and fitness, (c) disease prevention,
(d) alcholol, drug and tobacco use prevention,
(e) social and emotional health, (f) personal hygiene
of dental care, (g) consumer and environment
health, (h) safety measures and accidents, (i) conflict
resolution and prevention, (j) HIV- Aids and Family
Life Education.
ii. To instill life skills such as self-esteem, decision-
making, goal setting, effective communication,
stress management, character building, and sensory
motor skills, ensuring they become an integral part
of each child’s life and personality.
The approach followed should be as under:
a. Preparation of Life Skills and School Health
Curriculum manuals based on concerns prevalent in
school going children (6-19 years).
 Nutrition 177

b. Training and education to School Teachers, parents,
and social Educators via manuals, workshop, and
activity books.
c. Implementation of the Curriculum, Monitoring and
feedback
Our main health concerns which impact the primary and
secondary age group of 6-19 years are
a. Nutrition, Growth and Development
b. Personal Hygiene/Cleanliness and habits/Dental
care
c. Disease prevention and immunization
d. Exercise and fitness
e. Personality Development
f. Alcohol, Tobacco and Drug Use Prevention
g. Social, Mental and Emotional Health
h. Conflict Resolution and Violence prevention for
adolescents
i. Emergencies/Safety Measures/Prevention of
accidents
j. Consumer and Environmental Health and Climate
change
k. Family Life Education and HIV/Aids Awareness
l. New Age Health Hazards
m. Periodic Health Check up.
NUTRITION GROWTH AND DEVELOPMENT
Adequate nutritious and healthy food is important for
proper growth and development of children and
adolescents both in health and in disease.
• Offer a well balanced home cooked family diet
(Table 6.5.1). Serve a variety of textures. Avoid very
hot, icy cold or spicy food. Eating time should be a
pleasure. Any single meal should comprise of energy
foods(grains and cereals), protein foods (milk, eggs,
pulses, legumes), plenty of vegetables and fruits (rich
sources of nutrients, like vitamins and minerals and
several non-nutritional factors-fiber and phyto-
chemicals) with sparing use of refined flour, oil, sugar
and salt which will take care of prevention of lifestyle
diseases.
— Sufficient amount of milk and milk products:
Calcium is required for growth and bone
development and prevents osteoporosis. Nuts,
ragi and GLV also provide calcium.

TABLE 6.5.1: Sample meal plan

Meal time Food group Raw quantity Cooked recipe Serving

Breakfast Milk 150-200 ml Milk/coffee 1 cup

Sugar 5 gm
Cereals (dalia, chapatti, 50 gm Cottage cheese with One egg/cereal
chirwa, oats, khakra)/egg oil and tomato/egg
Panner/pulses/cheese 20 gm Salad
sprouted green gram

Tiffin One fruit 100 gm

One sandwich/Khakra and 40 gm
vegetable or tomato and chutney

Lunch Rice/Cereal/Chapati 100 gms Rice/Phulke 2 1/2 cup

Vegetables 100 gms Veg curry 1/2 cup
Pulses 20 gms Dal 1/2 cup
Veg salad 50 gms Salad 7/8 slices
Curd 50 gms Curd 1/2 cup

Snack Puffed rice/Groundnut 50 gms Milk-150 ml 1 cup

and roasted chana+ Milk

Dinner Rice/Cereal/Chapati 100 gms Rice/Phulka 1/2 cup

Vegetable 100 gms Veg curry 1/2 cup
Pulses 20 gms Dal 1/2 cup
Veg salad 50 gm Salad 7/8 Slices
Curd 50 gm 1/2 cup

*Quantity can be varied with appetite and increased with age.

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— Eat fish more frequently than meat and poultry
and limit/avoid organ meats (liver, kidney, brain
etc).
— Use more than one source of cooking oil. Limit
the use of ghee, butter and vanaspati.
— Eat foods rich in alpha linolenic acid (legumes,
green leafy vegetables, fenugreek and mustard
seeds) to provide essential fatty acids.
— Never starve the child. A child needs to eat more
during and after episodes of illness, Energy rich
cereal, pulse diets with milk and mashed
vegetables at frequent intervals help maintain
good nutritional status.
— Discourage overeating to avoid obesity, risk of
high blood pressure, high cholesterol and heart
diseases and indiscriminate dieting to prevent
malnutrition.
• Maintain food hygiene. Contamination is possible
before, during cooking service and storage of food.
— Wash vegetables/raw foods before eating, rinse
in vinegar if possible (10 ml in half liter of water).
— Avoid eating under cooked beef or pork
— Prepare, eat, fresh food as far as possible
— Keep cooked food covered until eaten
— Protect food from dust, flies, insects, etc.
— Do not use left over milk or food after half an hour
— Food can be kept in the fridge for 4-8 hours.
Refrigerated foods loose just 10% of nutrients over
a year’s time as compared to foods stored on
shelf/outside may loose 50% of nutrients.
— Consumption of unsafe foods can lead to food
poisoning / food borne diseases.
— Wear footware suitable for walking and PT
separately.
— Maintain good personal hygiene and keep the
cooking and food storage areas clean and safe.
• Conserve maximum nutrients in fruits and
vegetables.
— Consume seasonal fruits and vegetables for
vitality
— Eat a combination of colored fruits and vegetables
to provide all vitamins and minerals
— Highly colored fruits should be eaten to provide
phytochemicals and antioxidants
— Peel skin as thin as possible-most vitamins and
minerals lie just under the skin
— Wash leafy vegetables thoroughly before cutting,
never after cutting.
— Cook in minimum of water in covered vessel
— Do not throw leafy tops of cabbage, radish, carrots,
beetroot, and cauliflower. They are a rich source
of iron and calcium and a wealth of blood and
bones respectively.
• Offer safe drinking water. Unsafe water is one of the
main causes of ill health besides air pollution. Safe
water intake can reduce the burden of communicable
diseases such as diarrhea, dysentery, cholera,
typhoid, paratyphoid and Hepatitis A by 80%.
— Boiled of filtered water should be provided by
schools, rather than depend on visual cleanliness
of tap water for safety.
• Watch eating: This is crucial for children and
adolescents who are easily tempted by outside foods.
— Avoid junk foods comprising of refind sugar, flour
and saturated/transfats e.g. Friend potatoes,
burgers, colars, highly sweetened fruit juices, deep
fried tikkis, etc.
— Avoid exotic foods: They are very expensive e.g.
Quail /EMU birds as there is no benefit as
compared to the cost.
— Avoid processed foods. They contain coloring,
flavoring, and thickening agents along with
preservatives. Simple sunset yellow and tartrazine
color can cause allergy and associated symptoms
of vomiting, rashes and anaphylaxis. In addition
chances of adulteration increase.
• Avoid watching television while eating. It can cause
obesity and metabolic syndrome due to excessive
eating. US have designed a television, which works
as long as the child pedals a cycle-ergo meter. Bicycles
can be used in India.
— Offer favorite food along with new food in small
servings.
— Do not force food on the child.
— Insist on Mother / Teacher eating simultaneously.
— Avoid carbonated drinks, tea, coffee and. Horlicks
before meal like lunch at school or dinner at home.
— Involve the child in making salads, lemon drink
at home and school.
— Grate vegetables into sauces/stews/chappatis,
etc. (Demonstration to be arranged at school).
— Cut into small bits and chew each morsel 15/20
times to improve digestion.
— Continue feeding during illness and more after
illness.

PERSONAL HYGIENE/DENTAL CARE/
CLEANLINESS AND HABITS
• Simple hygiene can check deadly bacteria
• Wash hands with soap and water before preparing
and serving food-before eating or feeding-child to
wash hands after coming from school or play-after
defecation and urination.
• Keep finger nails clean and trimmed
• Wash toys before giving to child.
• Stop thumb sucking by diverting attention if present
• Give bath preferably twice a day
• Ask child to cover mouth and nose with handkerchief
while sneezing
• Take special care of eyes/nose/ears
• Vision to be checked by a doctor once a year
• Wear clean clothes everyday
• Do not spit or blow nose on the ground
• Brush teeth twice a day for at least 2-3 minutes at a
time and flossing once a day
• Rinse mouth and teeth after each meal
• Comb hair daily, prevent lice infestation
• Wash hair with shampoo at least twice a week
DISEASE PREVENTION AND IMMUNIZATION
Normally a child is admitted to school after primary
vaccination with; BCG, oral polio, HiB, Hepatitis B,
diphtheria, pertusis, tetanus, MMR, typhoid, Chicken
pox and Hepatitis A vaccine to take care of tuberculosis,
polio, DPT, HiB, HB, typhoid, chicken pox and
Hepatitis A. For adolescents refer to Table 6.5.2.
TABLE 6.5.2: Top up immunization of adolescents
Vaccine Age
1. Td Booster at 10 and 16 years
2. MMR Vaccine One dose if not given earlier
3. Hepatitis B Three doses (20 mcg) 0,1 and
6 months if not given earlier
4. Typhoid vaccine VI Polysaccharide vaccine every
3 years
5. Varicella vaccine One dose up to 13 years and
2 doses (at 4 to 8 weeks interval)
after 13 years of age if not give
earlier
6. Hepatitis A vaccine Two doses 0 and 6 months if not
given earlier
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Illnesses Make Life Short and Miserable
• Child should remain two arms away from a sick
person to avoid catching illness.
• Sick child should be told to take rest at home.
• Avoid if possible over crowded places, e.g. market/
cinema halls/buses.
• Avoid food given or handled by a sick person. Germs
come fre with the food.
• As far as possible avoid eating outside home.
• Eat home cooked food. School choldren to carry their
tiffin and water to school.
EXERCISE AND FITNESS
• The energy you need to perform your work-out comes
from two primary sources:glycogen(glucose from
carbohydrate stored in the body) and stored fat. You
usually use a combination of both, to fuel your body
when you exercise. High intensity shot-term exercise
uses glycogen as it’s energy source. Low to moderate
exercise activity spread over a longer duration utilizes
the body’s fat reserves and strenthens muscle power.
• Exercise keeps body, mind and thus health fit. Walk
to school every day. (if not too far)
• Rope skipping/Cycling/Swimming are the best
exercises for the evenings/weekends for half an hour,
preferable daily.
• Learn yoga that keeps you young forever and fit.
• Prevent illnesses like joint pain, memory loss, with
tonic exercises and mental activities.
PERSONALITY DEVELOPMENT
• Teach and prepare child and adolescent, to handle
and face the pressures pf modern day living, intense
competition, emotional challenges, rivalry, peer
pressure, etc.
• Counseling and the role of an Adolescent Psychiatrist
cannot be overemphasized over here from the very
begining which would help in the Personality
development of this child and overcoming behavior,
mental problems and Psychosomatic illnesses.
ALCOHOL, TABACCO AND
DRUG ABUSE PREVENTION
Children, adolescents in particular face:
• Commonly used drugs are tobacco, alcohol, cannabis
and brown sugar
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• Investigate if child loses temper easily while talking
to family members/students/teahcers and takes on
interest in personal grooming and shows poor
academic performance. There are:
Three stages of drug abuse
• Management: Both parents and teachers can play a
supportive role in guiding the child to realize his /
her own responsiblities and taking control of his life.
• Conduct more awareness drives and stop the
teenagers from getting into this habit including
smoking. Frequent counseling can be arranged with
school counselor.
• Universities must admit only non-alcoholics and
nonsmokers. They must have periodical check ups
to see if an adolescent starts this habit later and take
necessary action to prevent him from repeated failure
in examinations and drop out form school/college/
sports/general activities.
SOCIAL, MENTAL AND EMOTIONAL HEALTH
In India the current “high tech” age and industrial
growth has led to innumerable social changes. There is
need for more education and training before placement
for a job or entry into any profession. This coupled with
increasing migration from rural areas to big cities and
industrial towns has led to a large growing population
being pushed into a stage of uncertainity into a world of
competition and new challenges. This puts demand on
adaptive processes and further stress on the adolescent
population where increasing number of adolescent
population (13-19 years) appears to be involved in the
incidents of violence, sex offences, suicides and accidents
due to driving.
The hormonal changes adolescence lead to
heightened emotions. They become more emotional and
sensitive. They may go into fits of anger or pride without
understanding why it happens. Their own emotions
confuse the adolescents.
Many adolescents experience a sense of futility,
personal disorganization and aimlessness. They feel
inadequate, impersonalized and alienated and find it
difficult to adjust with the peer group. Such a disturbed
adolescent child needs counseling and advice. Problem
cases could show shyness, defiant behavior, bed wetting,
stammering, poor scholastic performance, drug
addiction, depression and hysterical convulsions.
Management
Proper interview with guidance and counseling would
be essential from the pediatrician and Psychiatrist for
the Psychological turmoil. Parents cannot be blamed or
labeled guilty for hte behaviour of the adolescent. They
should be assured that adolescents have behavioral
difficulties. and the same indicate stress in them, common
in this age group. Child should be convinced by parents
or rewarded if required.
Key expectations of an adolescent from parent are:
(a) Parent’s interest and help (b) Listening (c) Love and
acceptance (d) Trust and (e) Autonomy/independence.
The parents should be made aware of hte expectations
which adelescents are likely to have from them. They
should back up child where necessary which gives her/
him a feeling of love.
Adolescents resent when they perceive lack of trust
by the parents. This projects parental anxiety, fears and
guilt. Adolescents get a feeling of being respected and
loved when their parents listen to them. (Adolescents
aspire to be treated as independent individuals by their
parents. Parents should grant independence gradually
rather then all at once).
The counseling to parents should take place in an
anticipatory guidance clinic.

CONFLICT RESOLUTION AND VIOLENCE
PREVENTION FOR ADOLESCENTS
Adolescent is the period from the beginning of sexual
maturity to the completion of physical growth,
movement from concrete to formal operational abstract
thinking and reasoning. They have difficulty in
understanding others while achieving a sense of identify
formation-self, during this period of development so they
have behavior problems which revolve around parents,
peers, self, school, employment issues and health.
Adolescents who lack parental or peer support are at
risk of psychosomatic symptoms (abdominal pain/
headache) during this stressful phase. This effect is also
reflected in social behavior.
School maladjustment is one of the first symptoms
to appear in response to alteration in development and
maturation. Teacher’s perception could be an efficient
screening device in this respect who could check child
behavior problems:
a. In terms of activity
b. Social Conduct
c. School Performance
Here parents are asked to report on child behavior.
Recognize the Signals
• I want to run away from home
• I am ashamed of my marks
• I am burden on the earth
• I do not want to attend school at all
• I want to jump down from my house
• No body loves me at all
• I love to see the hanging scene in the movie “Bhagat
Singh”
• Nothing will change if I die.
• I am so angry that I feel like killing someone or myself.
• I will teach my parents a lesson.
VULNERABILITY
• Anyone can attempt suicide irrespective of their
intelligence. Each one of us can suffer form sadness/
depression and attempt suicide. However, mentally
ill are more prone to suicide but those not suffering
from the same can attempt it too. e.g. after failure in
exams or sudden discovery of a fatal illness.
In vie w of increasing violence and suicidal
tendencies amongst kids we need to build a future
strategy management for schools such as:
Nutrition 181
• Depression detection Technique: Trained teachers
and support staff of the institution can spot a child
what she/he does, words he/she says that can be
used as alert signs. They can help in treating children
and avoid untoward incidents.
• Breaking the conspiracy of silence-Children are
secretive in nature and know what can work as guide
in their own case as well as in the case of their friends.
They know who in their group talks about death, who
plays dare games, who is keen on killing and who
will not come to school tomorrow. The catch is to
break their silence.
• Triple-S Syndrome: This stands for three learning
shcools that children are subjected to these days:
School 1: Regular school; School 2: Tuition classes;
School 3: Parents at home They are instructed to obey
all the time. More space has to be given to children to
be activites, especially harmless ones, in their own
way.
All of us should learn to exercise authority in the
righteous way.
• Happy Intervention triangle: It talks about changing
the form of interaction with kids. At the tip of hte
traiangle it the macro-intervention by the principal
who can make assembly meetings at school more
lively. At one end is micro intervention by teacher in
the class or in the playground who can make
classroom activity more interactive, joyous and one
that refreshes the mind. This also works as a forum
where teahers can observe and distinguish lonely kids
from others. At another end are parents, friends,
relatives and otehrs who can spend time with the
child and observe him or her in a micro environment.
They can also report on alarming signals. This is mini
micro intervention.
• Do not challenge. Children who threaten are more
prone to attempt suicide than those who do not.
Hence do not challenge those who threaten to attempt
it.
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Counseling of Parents and Children
• Suicideal behavior can be seen in families across
generations as depression can run in families so
proper counseling is required for parents and
children.
EMERGENCY SITUATIONS/SAFETY MEASURES/
PERVENT ACCIDENTS
They are as under:
• Head and forehead injuries (Cuts/ bruises/internal)
due to fall from the terrace/balcony, while running/
playing, etc.
• Slipping from staircase to entrapment of fingers in
doors at home or in the car
• Injury to fingers by sharp items, poor quality toys
• Swallowing of hard nuts/pins/loose parts of toys/
stray items on the floor
• Burns caused by fire crackers / boiling water/tea in
the Kitchen/bathroom, etc.
• Eye and ear injuries due to use of cleaning agents,
colors use in holi, etc.
• Electrical shocks dur to open wires/sockets, etc.
• Road accidents while crossing
• Kerosene oil poisoning
• Domestic/ School accidents with fall
Epileptic Convulsion, Acute asthmatic attack, coma-
diabetic/others, Heat stroke, Diarrhea/Vomiting,
Dehydration.
Management
• Be vigilant all the time. Preventing an accident is wiser
than coping with one after the event.
• Take adequate safety measures
— Keep electrical sockets covered
— Protect sleeping children from falling off cots with
railing/side support
— Keep Kerosene/washing sode/spirit/naphthe-
lene balls/baygon, matches and medicines out of
reach.
— Avoid handling of sharp objects by children
— Put safety locks on all cabinets and drawers
— Secure refrigerator/dishwasher/stove/washing
machine/dryer/doors to avoid pinching of
fingers.
— Keep chairs/stools away from windows to ensure
safety
— Supervise in traffic/festivals and hold hands
while walking on road.
— Do not leave child in the bath alone
— Do not allow the child to swim alone
— Do not permit children to peep out of running
vehicles
— Take the child to hospital in case of emergency
immediately.
Teacher/Nurse/Mother should be trained for
immediate help and shifting to consulting room
or hospital nearby.
FAMILY LIFE EDUCATION (FLE) AND
HIV AIDS AWARENESS
There is an urgent need for informal education on
Parenting and sex education from the beginning of the
teens.
Following are the components of FLE for school
children aged 13-18 years
1. Adolescent nutrition— Action Plan for the child, Kerala
has stipulated that all girls in Kerala on completion
of 18 years should aim 45 kg weight and 145 cm height
because birth wight of an infant is hte single most
important factor that determines the mental
development of a young child. Normal birth weight
of an infant has a sure edge over the low birth weight
baby born to mothers of poor nutritional status.
2. Personal hygiene— Most of our school girls do not
drink water adequately not pass urine frequently in
school contributing towards silent urinary tract
infection, Poor toilet hygiene also needs immediate
attention. In many residential institutions for girls
proper menstrual hygiene including trimming of
public hair is not taught to them. They also need to
be made aware that some amount of vaginal
discharge and dysmenorrhea is within normal limits.
3. Understanding ones emotions— The basis of formation
of good personality which includes a clear mind and
clear body is laid during adolescence. A person with
wholesome personality is one who has strong mental,
physical and cognitive skills which enable him/her
to behave, relate to and act effectively in the family
and the society at large.
4. The formation of good personality can surely be
influenced by the family. The family stands for all
the basic human values necessary for living usefully
and meaningfully. On one side the adolescent has the
fantasy of love and sex and parents immediate
problem is of getting him admission to Professional
college. Family life education is one acceptable mode
of introducing what is essential for adolescents to
understand and appreciate.

5. Awareness on HIV/Aids – Family Life Education for
older children add young adults (13 - 21 years) should
have adequate emphasis on understanding and
appreciating one’s own sexuality by showing parts
of body, and telling hormonal changes before and
during puberty with consequences in development.
WHAT IS HIV / AIDS ?
• HIV- Human Immune Deficiency Virus infects man
alone (HIV Infects person /Carrier)
• Initially multiplies rapidly-High concentration in
blood, CSF, Semen, Vaginal fluid, lesser extent in
breast milk.
• Multiplies at a slower rate later and persists
throughout his/her lifetime.
• Impairs functional capacity of immune system.
Clinically immunodeficient (AIDS Patient)
• Is Vulnerable to TB/Pneumonia/Fungal Infection/
cancer.
MANAGEMENT
• Foster each student’s ability to introspect on his/her
own sexual feelings and needs. Without such insight
one might not know how to avoid hurting oneself or
others.
• Develop the ability to be alert and sensitive to difficult
situations where the child/student ought to think
before acting.
• An adolescent becomes aware of his own/other
people’s bodies—a child can absorb attitudes towards
sex before the questioning begins.
• Baby boys have erections and little girls have pleasant
feeling when they rub their thighs together or rub
their clitoris.
• It is important for parents and teachers to answer
children’s queries regarding sex by explaining about
the anatomy of the body, onset of adolescence like
menstruation, breast and development of sex organs
general issues and sex abuse.
• Help students to have confidence in their own
judgement and values provided by parents/teachers
who have a positive approach to sex and family life
education.
• Subjects such as high risk behavior, family planning,
unplanned children, STD, etc. should be discussed
in the context of HIV/AIDS control.
• It is important to ensure that adolescents have
knowledge with regard to sex, counseling, advice for
Nutrition 183
family planning such as contraceptive use including
condoms. A condom acts as a physical barrier and
prvents potentially infected semen or vaginal
secretions from cirect contact with the partner’s sex
organs/anus/mouth. Contraceptives like the pill/
IUD do not protect a woman from HIV infection. Thus
on educating and creating awareness youth can think
and act rationally thereby preventing tragedy of
unwanted pregnancy and staying healthy without
HIV/AIDS.
• Crucial steps for eradication and prevention of HIV/
AIDS from the face of earth, as it will not only reduce
the burden of pediatric HIV but also overall numbers
of people infected with HIV.
a. By sex education thru plays
b. Prevention of parent to child transmission
(PPTCT) of HIV infection. This vertical trans-
mission can be pregnancy associated or by breast
feeding.
c. Prevention thru transfusion of blood and blood
products. Blood should be screened for HIV.
d. Prevention of sharing of needles thru intravenous
drug users
e. Important to involve Junior colleges in the AIDS
Awareness Programs.
f. Avoid at all costs Unprotected Sexual Intercourse
Transmission takes place by physical contact.
Same is true for Syphilis and Gonorrhea.
g. Risk increases with multi-partner relationships.
h. Avoid Sex with commercial sex workers.
i. Avoid Sex at an early age.
j. Avoid sex (Man with Man).
k. HIV testing should be compulsory before
marriage for the couple.
• Poniters for Diagnosis
Rapid loss of weight
Persistent fever and cough
Pneumonia/Tb
Swellings of lymph nodes
Diarrhoea and Oral thrush
Repeated attacks of herpes
Blood tests-Elisa (antibody 2/4 months after
Infection)
PCR (Antigen)
NEW AGE HEALTH HAZARDS
• Computer hazards: Constant focusing on a particular
distance for a long period of time where eyes focus
on one point causes muscle fatigue and eye strain.
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Blinking rate drops down by a good 20-25% while
staring at a computer. Over a period of time children
tend to develop dry eyes due to this. To combat this,
it is necessary to take frequent breaks (every 30-40
minutes) where children/youth splash water on their
eyes, close their eyes for a minute and use lubricating
eye drops. To avoid Computer Vision Syndrome
(CVS) the computer screen should be below eye level.
• Television watch: There is a direct co-relation between
a digital lifestyle and putting on too many pounds. It
is critical to ration a child/youth’s television viewing
as more the television viewing results in less fat being
burnt leading to obesity
• Music blues: I Pods and other digital music players
thru head phones increase the risk of hearing loss as
they pump music directly into the ear. Anything over
80 decibels actually hurts the ear, 120 decibles leads
to instant hearing loss. It is not just the level of the
noise but also the duration. It is important to unplug
ear phones and listen to music on FM/record players
otherwise at a turned down volume or use head
phones that fit outside the ear canal.
• Cell caution: Continuous use of cell phones can lead
to hearing loss and formation of benign tumor along
the auditory nerve. Electromagnetic waves from
mobile handsets are supposed to have harmful effect
on the brain, while headphones/hands free and insert
type of devices present loud noise directly at the ear
drum level; hence prolonged use should be avoided.
• Sleepless nights: Getting sleep after watching TV is
difficult.Visual stimulation has a greater impact on
the brain than auditory stimulation. Children must
sleep for 8-9 hours at night to feel fresh next morning.
CONSUMER, ENVIRONMENTAL POLLUTION AND
CLIMATE CHANGE
Consumer has to face
1. Hidden Dangers of Indoor Pollution
2. Environmental Pollution and Climate Effects
• Hidden dangers of indoor pollution: Chemicals are added
to our food supply, used as additives, preservatives
during food processing and storage, Cosmetics, air
freshners, computers, cleaning solutions, drugs, dyes,
household paints, light switches in cars, hair spray,
insecticides, stain removers, around us eventually
result in chemicals being inside us / in the air/ water/
soil that we breathe/drink/eat decades after their use
is ceased. Some of them may but most do not
biodegrade and they need extra metabolic enregy
expenditure to complete the detoxification process.
The current level of chemicals in food, water supply,
indoor and outdoor environment lowers out
threshold of resistance to disease and alters the body’s
metabolism causing enzyme dysfunction, nutritional
deficiencies and hormonal imbalances.
• Toxins are at play in any home/work environment
in which you may find yourself with Sick building
syndrom (SBS) and cause Multiple chemical
sensitivities (MCS). It cannot be traced back to a
specific bacteria or virus. MCS results form either a
single high exposure to a particular chemical toxin
or repeated low level exposure to the thousands of
chemicals that surround us. Symptoms of MCS
include prolonged fatigue, memory difficulties,
dizziness, poor concentration, depression, anxiety,
troubled breathing, irritability, muscle and joint aches
and pains, head aches, chest pains, nausea, etc. The
list of symptoms is so large that it makes it difficult
to diagnose and differentiate from other health issues.
• Environmental pollution and climate effects: Litter on city
streets and industrial waste pollutes waterways, toxic
chemicals inthe soil and ground water as it breaks
down. Light pollution defined as excess light at night
significantly increases the risk of breast cancer in
women. It also disrupts the migration pattern and
breeding cycle of many birds and animals. Smog
made of particulate matter and smoke (from petrol,
diesel, oil, coal, cooking gas) and ground level ozone
creates serious health risks for children and adults
and causes many respiratory illnesses such as chronic
bronchitis, bronchial asthma, silicosis, etc. Outbreaks
of heat waves are expected to cause spread of
infectious diseases. Drought and floods caused by
climate change impact the whole agricultural setting
which naturally means smaller harvests. It is critical
that the youth and children are made aware of the ill
effects of climate and the warming trends to reduce
CO2 emissions and global warming.
• Understand climate Change: Check out Websites like
www.kidrgreen.org for more on this topic.
• Prevention and Management:
• Garbage management: This consists of collection,
treatment, segregation (organic and inorganic matter)
and processing of waste. Organic waste should be
returned to the earth within 24 hours. Plastic material
is separated and dealt with for recycling.

• Drainage development: The drains should be checked
and maintained by the Municipal Corporation before
the rainy season every year. There should be no
obstruction to the flow of waste on route.
• Rain water harvesting: Rain water should be conserved
on the terraces of big buildings and used for toilet
flushing and gardens. Conserve Kitchen and bath
water and reuse after treatment with oxygen for three
days.
• Energy efficiency: Low energy lighting and reduced
energy consumption products such as TV, air condi-
tioners ( with variable speed drives), CF lamps should
be used. Geysers and street lights should be switched
to solar power and solar cookers should be used for
cooking. Retrofit program can provide existing
buildings with more energy efficient products leading
to energy savings of 20-50% in the urban areas.
• Bio fuel plantation: Petrochemicals used for cars, tucks
(Petrol, diesel) should be replaced by bio fuel plan-
tation. This will be cheaper and cause less pollution
and emission reduction of CO2. Corporate Social
responsibility initiative will help largely in out
progress to mitigate global warning.
• Car free days: Increasing the use of public transport
and the usage of bicycles instead of cars will curb
greenhouse gas emissions. Apart from that, physical
activity like walking and cycling will prevent obesity
and obesity related diseases. This will lead to
improved air quality and lead to better respiratory
health.
• Green electricity: In Australia, UK, US green electricity
is being generated without the use of fossil fuels.
Wind, Solar, Ocean, Geo thermal and hydropower is
used instead which are renewable green sources and
hence do not release green house gasses in the process
of producing energy. Bio-mass produced by burning
garbage landfills/organic Kitchen waste is an
exception but the same can be countered by planting
vegetation which counters methane gases released
in this process.
• Save and plant a tree: Trees are great for absorbing CO2
from the air. Every tree you prevent from being cut,
or that you plant, and nurture till it’s grown, will serve
a life time of absorbing CO2, even while it provides
beauty and shade, shelter and food, and keeps the
soil firm and healthy. Gardening and planting trees
while helping to preserve the environment is also a
good source of exercise.
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• Offsetting CO2 emissions: We must offset out remaining
CO2 emissions using CO2 allowances or credits.
• Become resource savvy: Conserve energy at homes/
schools. Save water, save paper. Prevent waste-
Recycle, Re-use and Refuse. Do not burn waste and
compost biodegradable waste. Keep electrical
appliances in good condition-air filters on ACs clean,
fridge coils and tube lights dust free. Depend less on
artificial aids for lighting and cooling and more on
sunlight and natural ventilation.
• Youth and children to be made aware that organic
waste can be spread in thin layers not more than 5
cms in thickness and processed preferably in the
presence of plants in an area under shade.
• School Teachers should take the initiative of making
nature Clubs for the children and spread the message
of climate change and foster grass root education and
activism to prepare amore proactive population for
the future. India should be seen as a part of “Higher
as quoted by British Prime Minister Gordon Brown.
• Prevent dengue and malaria:
— Dengue and malaria are on the rise due to poor
sanitary and drainage facilities.
— Need for water storage due to interrupted water
supply by Municipal corporations.
— Extensive unplanned construction activities
— Damp living conditions
— Poor school environment
— Favorable hot and humid conditions which
facilitate mosquito breeding.
— Lethargic civil administration and lack of public
awareness have assured sustained dengue
transmission and malaria endemicity.
— Long term vector control is the need of the day by
providing good sanitary facilities, Keeping pots
covered, spraying water bodies with pesticides
and improving the living conditions of slums and
environment since no vaccine is available till date.
Children should be made to make projects on this
to increase awareness.
HEALTH CHECK UP
• Children and adolescents must have routine health
check ups by a Pediatrician for Nutrition, Growth and
Development and also be checked by ENT Specialists,
Opthalmologist for hearing, vision and dental
specialists respectively once a year. Child should also
be referred to the Pediatrician for treatment of
186
186 IAP
IAP Textbook
Textbook of
of Pediatrics
Pediatrics
physical illnesses such as diarrhea, dysentery,
pneumonia, typhoid, etc. on time.
TRAINING WORKSHOPS
Immediate need of the day is to train teachers and
supportive staff in schools both public and private with
the ultimate knowledge to spread the knowledge of
health, hygiene and life skills to primary age (6-10 years)
and family life education, HIV-AIDS and adolescent
problems to middle (11-12 years) and high school child-
ren (13-19 years). The life skills, health and curriculum
manual should be prepared in consultation with
Pediatricians, Psychiatrists. Educators and Social
Scientist. In addition simple Medical quiz should be
prepared with questions and answers which can be
discussed during question hour sessions. IAP can give
necessary support in preparation and printing of this
manual and training of teachers.
Implementation and Monitoring of the Curriculum
Teachers can teach Health and Hygiene issues along with
allied subjects. Teenage Club can be made where Family
Life Education, HIV-AIDS and Adolescent problems can
be discussed. This should work with parents, school and
community efforts in a supportive social climate. One
such successful project was carried out by Syed Amir
Group of Schools in Kolkata by the author. This can also
be carried out in conjunction with Reproductive Child
Health Program of Ministry of Health and Family
Welfare. It is important for teachers to monitor the
program and get the feedback.
CONCLUSION
Role of NGOs Creating Opportunities for Parental
Empowerment (COPE) will be the correct approach to
achieve the goals of this Curriculum along with the
parent Teacher Association.
Many programs are being carried out in School
Health Education across the world. It is critical that the
same are carried out in an orderly fashion covering all
that is required to be done according to the need of the
hour in out country. Courses pertaining to Health and
Hygiene will soon be part of the Health, Hygiene,
Immunization and Personality Development. Our
Community of Educators, Parents Students and NGOs
can work together ot create interesting, creative and
effective educational materials and follow the model of
Udayan Care if found satisfactory on monitoring.
BIBLIOGRAPHY
1. Adolescent Wellness Program by Boston Public Health,
www.bphc.org/programs.
2. Child and Adolescent School Health by School of Public
Health, sph.bjmu.educn/eng/ershao.htm.peking
University.
3. Colorado Department of Public Health and Environment:
Child, Adolescent and School Health website:
www.cdphe.state.co.us/ps/cash of 24.4.08.
4. Enhanced Health Services for High Schools,
Massachusetts Department of Public Health with Boston
Public Schools. http://www.bphc.org/programs
5. Health Action by people, Thiruvanthapuram, Published
by State Aid Cell, Thiruvanthapuram.
6. Madan S. Family Life Education for Adolescents-Why?
Indian Journal of Practical Pediatrics 1998;6:37-9.
7. Marc A Forman, William H Hetznecker, John M Dunn.
Parents as Tecahers.In Nelson’s Textbook of Pediatrics
11th Ed, W B Saunders, Philadelphia 1979;2:30:61.
8. Nair MKC. Perspectives in Adolescent Care, Editorial
IAP Journal of Practical Pediatrics. Journal of Indian
Academy of Pediatrics 1998;6:7-10.
9. National Network; Health Education to be part of School
Curriculum soon: Teena Thacker, posted online.
Wednesday, March 26, 2008.
10. New Directions in Health Education. Edited by George
Campbell, Health Education and the Environment in the
Basic School Curriculum in Norway: Arne haukness,
page 117 International Health Curriculum (overview)
Publisher: Taylor and Francis 1985.
11. Udayan Care; School Health Education, Health and life
Skills for Primary Grades. Website: www.udayancare.
org/schoolhealth_education.htm
7.1 Community Pediatrics: Shashi N Vani ................................................................................................................................................. 188
7.2 National Health Programs: Shashi N Vani , Piyush Gupta ................................................................................................................ 190
7.2.1 National Rural Health Mission (NRHM) 2005-2012: Piyush Gupta ..................................................................................... 191
7.2.2 Maternal and Child Health (MCH) Programs: Shashi N Vani ............................................................................................. 193
7.2.3 Integrated Child Development Services (ICDS) Program: BNS Walia .............................................................................. 194
7.2.4 Child Survival and Safe Motherhood (CSSM) Program: BNS Walia .................................................................................. 196
7.2.5 Reproductive and Child Health (RCH) Program: BNS Walia, Shashi N Vani .................................................................... 197
7.2.6 Integrated Management of Neonatal and Childhood Illness (IMNCI) Strategy: BNS Walia .......................................... 200
7.2.7 National Programs on Immunization: A Parthasarathy, Shashi N Vani, BNS Walia .......................................................... 200
7.2.7.1 Universal Immunization Program (UIP): KM Ganessan ..................................................................................... 200
7.2.8 Acute Respiratory Infections (ARI) Control Program: Keya Lahiri, BNS Walia, Shashi N Vani ....................................... 202
7.2.9 Control of Diarrheal Disease (CDD) Program: BNS Walia, Shashi N Vani ......................................................................... 203
7.2.10 National Leprosy Eradication Program: BNS Walia ............................................................................................................. 204
7.2.11 National Vector Borne Disease Control Program (NVBDCP): Piyush Gupta ................................................................... 206
7.2.11.1 National Malaria Control Program: BNS Walia ..................................................................................................... 206
7.2.11.2 National Filaria Control Program: BNS Walia ....................................................................................................... 207
7.2.12 National AIDS and STD Control Program: BNS Walia ......................................................................................................... 207
7.2.13 Nutrition Programs: Shashi N Vani ......................................................................................................................................... 208
7.2.14 Mid-day Meal Program: HPS Sachdev ................................................................................................................................... 209
7.2.15 Anemia Control Program: Shashi N Vani ............................................................................................................................... 209
7.2.16 Control of Vitamin A Deficiency: BNS Walia ........................................................................................................................ 210
7.2.17 National Iodine Deficiency Disorders Control Program: N Kochupillai ............................................................................. 210
7.2.18 National School Health Program: BNS Walia ....................................................................................................................... 211
7.2.19 National Cancer Control Program: BNS Walia ..................................................................................................................... 211
7.2.20 National Mental Health Program (NMHP): BNS Walia ......................................................................................................... 211
7.2.21 National Program for Control of Blindness : BNS Walia .................................................................................................... 211
7.3 Community Newborn Care: Shashi N Vani ........................................................................................................................................ 212
7.4 Under Five Clinics: Ajit Kumar ............................................................................................................................................................. 215
7.5 The Girl Child: Shanti Ghosh ............................................................................................................................................................... 218
7.6 Customs and Beliefs in Child Rearing: Anil Mokashi ...................................................................................................................... 220
7.7 International Agencies and Child Health: Shashi N Vani ................................................................................................................ 225
7.8 Adoption and Care of Orphans: RD Potdar ...................................................................................................................................... 226
188 IAP Textbook of Pediatrics
7.1 Community Pediatrics
INTRODUCTION
Pediatrics is concerned with the health of infants,
children and youth, their growth and development and
opportunities to achieve full potential as adults. Health
care of children is an essential component of pediatrics.
WHO definition of “Health” denotes a state of comp-
lete physical, mental and social wellbeing and not merely
an absence of disease or infirmity. This is very apt for a
child's health also and it should enable him/her to lead
a socially and economically productive life.
Study of pediatrics is not just the art and science of
the diagnosis and treatment of diseases, but also the
science for the prevention of diseases and promotion of
child's health. In the last few decades its scope has
expanded to include not only the health problems of an
individual child, but of all those in the community too.
Thus, the concept of community pediatrics has evolved.
DEFINITION
The term community pediatrics includes, the earlier dis-
ciplines known as public health, preventive pediatrics,
social pediatrics and community medicine. It focuses on
the health needs of the community as a whole. In the
modern concept, community pediatrics has been
effectively linked up with “primary health care”. The
foundations of the practice of community pediatrics are
based on epidemiology, biostatistics, social sciences and
organizing the health care services which include proper
planning, implementation and evaluation.
Community pediatrics includes mother and child
health care (MCH), as a very important component. It
must be remembered that mother and child's health are
interdependent on each other. Preventive pediatrics
consists of efforts to avert disease and disability, rather
than cure it.
Primary prevention: It is directed at avoiding disorders
before they begin, e.g. vaccination, clean water supply
and proper sewage disposal, etc.
Secondary prevention: It indicates recognition and
elimination of the precursors of the disease, e.g. screen-
ing programs for thyroid disorders, anemia, blindness,
etc. Screening is the search for an asymptomatic illness
in a defined population, which is usually performed for
Shashi N Vani
the purpose of treatment, but is sometimes done for
counseling or research also. Ethics demand that screening
tests should not be done, unless justified by compen-
satory benefit and that too after obtaining informed
consent.
Tertiary prevention: It indicates the measures for
amelioration or halting of the disabilities arising from
established disease, e.g. physiotherapy to prevent con-
tractures in patients with chronic neurological diseases.
Most successful primary preventive measures
require, understanding the cause, pathogenesis and the
natural history of diseases. For secondary and tertiary
prevention, however, determining the cause is not so
essential.
Many preventive measures such as tetanus immuni-
zation are effective only for the individual recipient.
Others are applied to the entire community, e.g. water
fluoridation, pulse polio immunization.
Thus, modern preventive medicine has been defined
as the art and science of health promotion, disease
prevention, disability limitation and rehabilitation. It
implies a more personal encounter between the indivi-
dual and health professional than public health.
Social medicine: It is the study of man as a social being
in his or her total environment. The focus is on the health
of the community as a whole.
Epidemiology: It is the scientific study of factors influencing
the health, disease and the control of disease in
populations, rather than in individuals.
Why Study of Community Pediatrics is Needed?
i. Vast differences exist in the child health care
problems and services among the developed and
developing nations.
ii. Maldistribution of doctors and poor doctor—patient
ratio: Approximately, 80 percent population lives
in rural and tribal areas, whereas, 80 percent of
doctors serve the remaining 20 percent population
in urban and semi-urban areas. Thus, doctors alone
cannot cope up with the demands of the child care
from difficult rural/tribal areas.
iii. Inadequate training in pediatrics for the doctors as
well as nursing and paramedical staff does not make
 Community Pediatrics 189

them feel confident to offer child care services in a
large community.
iv. Meagre allocation of budget for child care services,
improper prioritization and maldistribution of avai-
lable funds, lack of knowledge and attitude for the
effective use of available resources, general poverty,
ignorance, traditional cultural taboos/customs, etc.
are some of the other major stumbling blocks for
provision pediatric services in developing countries.
Proper training of workers and development of
community pediatrics linked with primary health care,
offers a viable alternative for improvement of child health
services in developing countries.
Stillbirth Rate (SBR)
Number of stillbirths during the year
SBR = ————————————————— × 1000
Number of live births + stillbirths
during the year
Perinatal Mortality Rate (PMR)
Number of stillbirths + infant deaths of
less than 7 days during the year
PMR = ————————————————— × 1000
Number of live births + stillbirths
during the year
Neonatal Mortality Rate (NMR)

Demographic Vital Statistics Number of infant deaths of less than

28 days during the year
Children less than 14 years of age constitute approxima- NMR = ————————————————— × 1000
tely 40 percent of total population. Women in the repro- Number of live births during the year
ductive age, i.e. between 15 and 44 years of age constitute
Age Specific Mortality Rate (ASMR)
approximately 22 percent of total population, together
they constitute about 62 to 63 percent of total population Number of deaths in a particular
which is a major vulnerable group. age group
ASMR = ——————————————— × 1000
Children less than six years age constitute approxi- Midyear population of the same
mately 17 percent of total population of which children age group
less than 1 year constitute 3 percent, children between
1 and 3 years of age group constitute approximately Under Five Mortality Rate (U5MR)—(UNICEF)
6 percent and between 3 and 6 years constitute 8 percent
Number of deaths of children less than
of the total population.
5 years age group
Infant Mortality Rate (IMR) is the most sensitive index U5MR = ———————————————— × 1000
for assessing the quality of socioeconomic development Number of live births during the year
of a community and also reflects the quality of perinatal
care available to the community. Maternal Mortality Rate (MMR)
Incidence of low birth weight infants in India is Total number of female deaths due
approximately 30 percent of total births. Vital statistics to complications of pregnancy, child-
provide an essential foundation for gauging children's birth or within 42 days of delivery from
wellbeing and the level of care, nurture and resources “Puerperal causes” in a particular area
they receive. Some of the common indicators used are during a given year
given below: MMR = ———————————————— × 1000
Total number of live births in the
Crude Birth Rate (CBR) same area and year
Number of live births during the year (ideally, the denominator should include all the deliveries
CBR = ——————––—————————— × 1000
Midyear population and abortions).

Crude Death Rate (CDR) BIBLIOGRAPHY

Number of deaths during the year
CDR = ———————————————— × 1000
Midyear population
Infant Mortality Rate (IMR)
Number of infant deaths during the year
IMR = ————————————————— × 1000
Number of live births during the year
1. Kumar A: Role of social pediatrics in the interdisciplinary
approach to community health care. Indian Journal of
Preventive and Social Medicine 1972;3.
2. Nelson Textbook of Pediatrics, (15th edn) 1996.
3. Park’s Textbook of Social and Preventive Medicine (14th
edn) 1994;327.
4. Polany L: Manual of Community Pediatrics (2nd edn),
1996.
190 IAP Textbook of Pediatrics
7.2 National Health Programs
Under the Constitution of India, the subject of health
facilities, including their planning, establishment and
administration, falls under the purview of respective
governments of states of the union. However, Govern-
ment of India has from time to time introduced National
Health Programs, which are either centrally sponsored,
i.e. part of expense is met by the Central Government,
or wholly funded by the Center. Though these programs
are addressed to health problems, diseases and condi-
tions of great national concern like family planning,
AIDS control, blindness and tuberculosis control, they
suffer from numerous deficiencies in their implemen-
tation.
i. Most states have financial constraints, matching
contributions by the state often do not materialize.
ii. The staff hired under the centrally funded schemes
and the medicines available therefrom, are often the
only ones available for the total health activities of
the health services.
iii. Most of the programs do not provide for medicines
in a form suitable for child patients. Thus, anemia
prophylaxis program offers tablet of iron and folic
acid, which are unsuitable for preschool children,
in whom the anemia is very common. Similarly,
liquid preparations of rifampin or isonicotinic acid
hydrazide are not offered in the National Tuber-
culosis Program.
iv. The criteria for inclusion as a beneficiary of the pro-
gram, often exclude children from availing of free
medicines provided in the program, e.g. sputum
positivity as a prerequisite for beneficiaries of tuber-
culosis control program, as only 10 percent children
suffering from tuberculosis show sputum positivity.
v. Staff training programs often neglects specific skills
required for handling children. This results in inade-
quate care or a complete neglect of children, e.g.
blindness control program and cancer control
program, where trained pediatric ophthalmologists
or oncologists are not employed.
vi. The vertical nature of numerous programs leads to
a set of persons performing duties related to a single
program, thus adding to transport and time costs,
so that a large part of the health budget is spent on
Shashi N Vani, Piyush Gupta
staff salaries, with little left for medicines, and sup-
plies or for other essential requirements. As soon as
the latter are exhausted, the entire work force
becomes nonfunctional.
NATIONAL HEALTH PROGRAMS
The Ministry of Health, Government of India, with the
help of Central Health Council has taken several
initiatives in launching programs aimed at controlling
or eradicating diseases which cause considerable
morbidity or mortality in India. New programs are being
added and existing ones modified, in response to
changing epidemiology of disease, host or parasites. The
important National Programs are listed below:
I. National Rural Health Mission
II. National Programs Related to Mother and
Child Care
1. Maternal and child health program (MCH)
2. Integrated child development services scheme (ICDS)
3. Child survival and safe motherhood program (CSSM)
4. Reproductive and child health program (RCH)
5. Integrated management of neonatal and childhood
illnesses (IMNCI): A strategy.
III. National Programs Related to Control of
Communicable Diseases
1. National program of immunization
2. Acute respiratory infection (ARI) control program
3. Diarrheal disease control program
4. Revised National Tuberculosis control program
(RNTCP)
5. Leprosy eradication program
6. National vector borne disease control program
(NVBDCP)
7. National AIDS control program.
IV. National Programs Related to Control of
Nutritional Deficiencies and Disorders
1. Nutritional programs
2. Mid-day meal program

3. Anemia prophylaxis program
4. Vitamin A deficiency control program
5. National iodine deficiency disorders control program.
V. National Programs Related to Control of
Noncommunicable Diseases
1. National school health program
2. National cancer control program
3. National mental health program
4. National diabetes control program
5. National program for control of blindness.
7.2.1. NATIONAL RURAL HEALTH
MISSION (NRHM) 2005-2012
Piyush Gupta
Recognizing the importance of health in the process of
economic and social development and improving the
quality of life of our citizens, the Government of India
launched the National Rural Health Mission of April 12,
2005. NRHM seeks to provide effective health care to
rural population throughout the country with special
focus on 18 states (Arunachal Pradesh, Assam, Bihar,
Chattisgarh, Himachal Pradesh, Jharkhand, Jammu &
Kashmir, Manipur, Mizoram, Meghalaya, Madhya
Pradesh, Nagaland, Orissa, Rajasthan, Sikkim, Tripura,
Uttaranchal and Uttar Pradesh) which have weak public
health indicators and/or weak infrastructure.
The mission adopts a synergistic approach by ralating
health to determinants of good health, viz., segments of
nutrition, sanitation, hygiene and safe drinking water. It
also aims at mainstreaming the Indian systems of
medicines to facilitate health care.
GOALS
The Goal of the Mission is to improve the availability of
and access to quality health care by people, especially
for those residing in rural areas, the poor, women and
children. Major targets are listed below:
• Reduction in infant mortality rate (IMR) and Maternal
mortality ratio (MMR) by 50% from existing levels in
next 7 years.
• Universal access to public health services such as
women’s health, child health, water, sanitation and
hygiene, immunization, and nutrition.
• Prevention and control of communicable and non-
communicable disease, including locally endemic
diseases.
Community Pediatrics 191
• Access to intergrated comprehensive primary health
care.
• Population stabilization, gender and demographic
balance.
• Revitalize local health traditions and mainstream
AYUSH.
• Promotion of healthy life styles.
STRATEGIES
a. Core Strategies
i. Train and enhance capacity of Panchayati Raj
Institutions (PRIs) to own, control and manage
public health services.
ii. Promote access to improve health care at house-
hold level through the female health activist
(ASHA).
iii. Health plan for each village through Village Health
Committee of the panchayat.
iv. Strengthening sub-center through an untied fund
to enable local planning and action and more multi-
purpose workers (MPWs).
v. Strengthening existing PHCs and CHCs, and
provision of 30-50 bedded CHC per lakh population
for improved curative care to a normative standard
(Indian Public Health Standards defining personnel,
equipment and management standards)
vi. Preparation and implementation of an inter-sectoral
District Health Plan prepared by the District Health
Mission, including drinking water, sanitation and
hygiene and nutrition.
vii. Integrating vertical Health and Family Welfare
programs at National, State Block, and District
levels.
viii. Technical Support to National, State and District
Health Missions for public health management.
ix. Strengthening capacities for data collection,
assessment and review for evidence-based
planning, monitoring and supervision.
x. Formulation of transparent policies for deployment
and career development of human resources for
health.
xi. Developing capacities for preventive health care at
all levels for promoting healthy life styles, reduction
in consumption of tobacco and alcohol, etc.
xii. Promoting non-profit sector particularly in under
served areas.
192 IAP Textbook of Pediatrics
b. Supplementary Strategies
i. Regulation of private sector including the informal
rural practitioners to ensure availability of quality
service to citizens at reasonable cost.
ii. Promotion of public private partnerships for
achieving public health goals.
iii. Mainstreaming AYUSH-revitalizing local health
traditions.
iv. Reorienting medical education to support rural
health issues including regulation of medical care
and medical ethics.
v. Effective and viable risk pooling and social health
insurance to provide health security to the poor by
ensuring accessible, affordable, accountable and
good quality hospital care.
c. Components
The Plan of action includes increasing public expendi-
ture on health, reducing regional imbalance in health
infrastructure, pooling resources, integration of
organizational structures, optimization of health man-
power, decentralization and district management of
health programs, community participation and
ownership of assets, induction of management and
financial personnel into district health system, and
operationalizing community health centers into
functional hospitals meeting Indian Public Health
Standards (IPHS) in each Block of the country.
The mission plans to promote access to health care to
rural household through a female health activist, ASHA.
The main components are described below:
Accredited Social Health Activists (ASHA)
Every village/large habitat will have a female Accredited
Social Health Activist (ASHA)-chosen by and account-
able to the panchayat—to act as the interface between
the community and the public health system. ASHA
would act as a bridge between the ANM and the village.
She will be an honorary volunteer, receiving perfor-
mance-based compensation for promoting universal
immunization, referral and escort services for RCH,
construction of household toilets, and other health care
delivery programs. She will facilitate preparation and
implementation of the Village Health Plan along with
Anganwadi worker, ANM, functionaries of other
Departments, and Self Help Group members, under the
leadership of the Village Health Committee of the
Panchayat. She will be given a Drug Kit containing
generic AYUSH and allopathic formulations for common
ailments.
Other Components
i. Strengthening Community Health Centers (CHC)
for first referral.
ii. Primary Health Centers (PHC) and sub-centers.
iii. Intergrate all vertical Health and Family Welfare
Programs at District and State level merge into one
common “District Health Mission” (DHM) at the
District level and the “State Health Mission” at the
State level.
iv. Guide activities of sanitation and hygiene.
v. Strengthening disease control programs.
vi. Develop guidelines for Public-Private Partnership
(PPP) in health sector and identifying areas of
partnership, which are need based, thematic and
geographic.
vii. To examine new health financing mechanisms.
viii. Reorienting Health/Medical Education to Support
Rural Health Issues.
Timelines for Major Components
i. Preparation of Village Health Plans 2006
ii. ASHA at village level (with Drug Kit) 2005-2008
iii. Upgrading of Rural Hospitals 2005-2007
iv. Operationalizing District Planning 2005-2007
v. Mobile Medical Unit at district level 2005-2008
6. Desired Outcomes of NRHM by 2012
i. Infant mortality rate reduced to 30/1000 live births.
ii. Maternal mortality ratio reduced to 100/100,000.
iii. Total fertility rate reduced to 2.1.
iv. Malaria mortality redcution rate-50% up to 2010,
additional 10% by 2012.
v. Kala-Azar mortality reduction rate: 100% by 2010
and sustaining elimination until 2012.
vi. Filaria/Microfilaria reduction rate: 70% by 2010,
80% by 2012 and elimination by 2015.
vii. Dengue mortality reduction rate : 50% by 2010 and
sustaining at that level until 2012.
viii. Japanese encephalitis mortality reduction rate: 50%
by 2010 and sustaining at that level until 2012.
ix. Cataract operation: Increasing to 46 lakh per year
until 2012.
x. Leprosy prevalence rate: Reduce from 1.8/10,000 in
2005 to less than 1/10,000 thereafter.

xi. Tuberculosis DOTS services: Maintain 85% cure rate
through entire mission period.
xii. Upgrading Community Health Centers to Indian
Public Health Standards.
xiii. Increasing utilization of First Referral Units from
less than 20 to 75%.
xiv. Engaging 250,000 female Accredited Social Health
Activists (ASHA) in 10 States.
7.2.2. MATERNAL AND CHILD
HEALTH (MCH) PROGRAMS
Shashi N Vani
Women of the reproductive age groups and children
constitute almost 60 percent of the population. The
hazards related to pregnancy and childbirth in the former
and the frequent occurrence of nutritional and infectious
disorders in the latter, makes these groups more
vulnerable to death and disease. The term “Maternal and
child health”—(MCH) refers to promotive, preventive
and curative health care activities for mothers and
children. These are eminently suited for inclusion in
primary health care.
Objectives of MCH:
i. To reduce maternal, infant and childhood morta-
lity and morbidity
ii. To promote reproductive health
iii. To promote physical and psychological develop-
ment of children and adolescents.
Policy Guidelines for Implementation of
MCH Programs
1. Effective use should be made of existing resources
and infrastructures available in the community.
2. The services should be delivered as close to the homes
of beneficiaries as possible.
3. Services for mothers and children should be delivered
in an integrated manner.
4. Child survival programs should serve as a sugar-
coating for delivery of the family planning programs
which in general, are not popular.
5. Voluntary agencies working in the area should be
involved in providing MCH services.
Details of Services Rendered in MCH Programs
The multipurpose health workers form the backbone of
this program. They are expected to:
Community Pediatrics 193
1. Record occurrence of pregnancy in their work area
on the basis of history of missed periods.
2. Screen women identified as pregnant for any of the
under mentioned ‘Risk’ factors.
i. Age less than 17 years or over 35 years
ii. Height less than 145 cm
iii. Weight less than 40 kg or more than 70 kg
iv. History of bleeding in previous pregnancy
v. History of stillbirths
vi. History of cesarean section as indicated by scar in
lower mid-abdomen
3. Identify women with moderate severe anemia.
4. Administer two doses of tetanus toxoid.
5. Provide iron and folic acid tablets to pregnant women
for a period of 180 days.
The advantage of identification of ‘at risk’ pregnan-
cies is that 80 percent of total morbidity and mortality in
the group is known to occur in the 20 percent of the
pregnant women identified to be ‘at risk’ by above
mentioned criteria.
Antenatal Care
The package of antenatal care for all pregnant women
consists of: screening for anemia, eclampsia and pre-
eclampsia and multiple pregnancies. Hemoglobin
estimation is done, blood pressure recorded and fundal
height is measured.
Mothers are advised to eat more of the foods gene-
rally consumed by them. Their breasts are examined to
exclude retracted nipples. Mother is told about what
articles are required at the time of labor and for the
newborn infant on its arrival. A dialogue is initiated
regarding spacing of further births.
Intranatal Care
The program envisages delivery of infant by a trained
birth attendant. These attendants are women belonging
to the local community, who have been trained in use of
aseptic precautions, during delivery of infant, severance
of cord and subsequent care of the cord and infant. They
are trained in suction of throat mucus and in mouth to
mouth resuscitation, if required. These workers are
trained to identify infants who are ill and require referral
to an appropriate medical institution.
Education is also imparted to mothers regarding
breastfeeding, immunizations required by the infant,
family planning and general hygiene.
194 IAP Textbook of Pediatrics
The health care of the delivered woman continues to
be supervised by the TBA at the subcenter or her house,
under the supervision of health visitor or female
multipurpose worker. Primary health care of the new-
born is also undertaken by the TBA.
Care of Children
It includes the following activities to be conducted by
the ‘female multipurpose health worker’ under the
supervision of the doctors at primary health center.
1. Monitoring of growth of children to detect faltering
of weight gain or malnutrition
2. Immunization against vaccination preventable
diseases
3. Treatment of common ailments as per the IMCI
guidelines
4. Referral of cases to health institutions
5. Implement national health programs
6. Impart health and nutrition education to community.
At Risk Children
In order to focus greater attention on children who are
at greater risk of disease or death, the concept of identi-
fying and registering ‘at risk’ children was enunciated.
‘At risk’ children include those who belong to any of the
under mentioned categories:
i. Birth weight less than 2.5 kg
ii. Twin births
iii. Weight below 50 percent of reference standard at
any age
iv. Difficulties in breastfeeding, bottle feeding started
below 6 months age or delay in giving supple-
mentary foods beyond 6 months age
v. Birth order of 4 or more
vi. Death of one or both parents
vii. Recurrent illness in child or family
Implementation of MCH Programs
Medical officer of PHC is the leader of the health team.
The services are delivered essentially through the staff
members of the PHC and subcenters comprising medical
officers, health assistants (female and male) and
multipurpose female health workers, also called as
auxiliary nurse midwives (ANM) and multipurpose male
health workers.
Trained birth attendants and village health guides
wherever available, provide support to the services. In
ICDS blocks, Anganwadi workers also help in various
MCH program tasks, especially related to detection of
malnourished children and identification of those
requiring immunization.
For every 5000 population in rural area and 3000
population in tribal area, there is a subcenter where MCH
clinics/immunization clinics are conducted on one or
more fixed days in a month. Home visits are done by
health workers according to a planned schedule. For
every such 5 or 6 subcenters totalling a population of
about 30,000, there is a primary health center (PHC)
where medical officer and health assistants conduct
curative services as well as MCH and other preventive
and promotive services.
In the recent years, for every one lakh population, an
upgraded PHC known as community health center
(CHC) has been established where some additional
health care services like anesthesia, dentistry and
pathology are made available.
Under the child survival and safe motherhood
(CSSM) program in selected districts with approximately
five lakhs population, one first referral unit (FRU) is
created where there is provision of a surgeon, an
obstetrician, a pediatrician, and an anesthetist along with
facilities of blood transfusion and operations. More
complex cases are sent either to district hospital or the
nearest teaching hospital attached to a medical college.
BIBLIOGRAPHY
1. Manual for orientation of ANM and supervisors—Repro-
ductive child health, Dept. of Family Welfare, Ministry
of Health and Family Welfare, Govt. of India, 1996.
2. Monograph on integrated training on national programs
for mother and child development. CTC-ICDS, Dept. of
Woman and Child Development, Govt. of India, 1992.
3. National Plan of Action a committment to the child, Dept.
of Woman and Child Development, Govt. of India, 1992.
4. Park’s Textbook of Preventive and Social Medicine (14th
edn) 1994.
5. Polany L: Manual of Community Pediatrics (2nd edn).
1996.
7.2.3 INTEGRATED CHILD DEVELOPMENT
SERVICES (ICDS) PROGRAM
BNS Walia
The ICDS was launched in 1975 in 33 community
development (CD) blocks of the country and has now

spread to more than 4000 CD blocks. The objectives of
the scheme are outlined below:
i. To improve the nutritional and health status of
children in the age group of 0 to 6 years.
ii. To lay sound foundation of psychological, physical
and social development of the child.
iii. To reduce morbidity, mortality, malnutrition and
school drop-out rates.
iv. To impart nutrition and health education to mothers
for making them more competent in looking after
nutrition and health needs of children.
The scheme is focused for the benefit of preschool
children, and pregnant and lactating women in the
reproductive age group (15-44 years), as they constitute
most vulnerable sections of population with higher
morbidity and mortality rates. Also, foundations of health
and psychological development are laid in the first six
years of life. It is, therefore, important to utilize scarce
financial resources on this segment of population. The
package of services provided by the ICDS scheme is given
below. The expectant and lactating women are offered
health check-ups immunization against tetanus,
nutritional supplements, nutrition and health education.
Recently, health check-ups of adolescent girls have also
been included in the program. Children below the age of
36 months, are given health check-up, immunization and
nutrition supplements, whereas children between the
ages of 36 to 72 months also receive nonformal preschool
education, in addition to the above mentioned
services. The immunizations given to children include
BCG, DPT, oral poliomyelitis and measles vaccine.
Children aged five or more, also receive a booster dose of
diphtheria-tetanus toxoid. Expectant mothers receive 2
doses of tetanus toxoid during the gestation period.
In a country where almost half the population is living
below the poverty line, it is not surprising that pregnant
women and preschool children are not receiving their
caloric requirements. Though the problem is rampant in
houses of poverty stricken and landless children of Dalit
and tribal communities, it is by no means uncommon
even in well to do families, because of ignorance of proper
weaning methods for infants and preschool children. The
nutritional supplements, aim at meeting the gap of about
300 to 400 calories found in the diet of average
preschooler. These are provided in the form of preproces-
Community Pediatrics 195
sed or semiprocessed foods or foods prepared on the spot
from locally available foodstuffs. Children are also
administered a dose of 200,000 international units of
vitamin A every 6 months. Iron and folic acid are also
offered for prophylaxis of anemia. Pregnant women and
nursing mothers are also given iron and folic acid tablets.
Health check-up of children includes, the record of
weight for identification of malnourished children, who
receive special attention. Antenatal care of pregnant
women and postnatal care of nursing mothers and care
of newborn infants is carried out by the female multi-
purpose worker of the area, under the supervision of the
health visitor. The Anganwadi worker helps them in
organization of the immunization program by
identifying children who require to be immunized and
informing families about date, time and venue where
the immunizations may be obtained.
The administrative unit for the location of an ICDS
project is a community development block in the rural
areas, a tribal development block in the tribal areas and
a slum in the urban areas.
An Anganwadi is established for a population of 1000
in rural and urban areas and 700 in tribal areas. The
Anganwadi is run by an Anganwadi worker. For a
population of 100,000 in a community development
block, 100 Anganwadi workers are employed on a part
time basis. Their work is supervised by 4 to 5 female
supervisors. The overall charge of the ICDS work in a
CD block is administered by child development project
officer (CDPO), who establishes Anganwadi centers,
maintains their supply lines, monitors the program,
arranges training programs and reports to State
Governments.
The project is monitored on the basis of monthly
reports sent by Anganwadi worker, as well as by inde-
pendent teams of the Planning Commission. Numerous
benefits of the project are reported. These include raising
immunization and vitamin A coverage reduction in
prevalence of malnutrition, reduction in incidence of low
birth weight and reduction in infant and preschool
mortality.
BIBLIOGRAPHY
1. Monograph on Integrated Training on National
Programs for Mother and Child Development CTC-ICDS,
Dept. of Women and Child Development GOI, 1990.
196 IAP Textbook of Pediatrics
7.2.4 CHILD SURVIVAL AND SAFE
MOTHERHOOD (CSSM) PROGRAM
BNS Walia
This program was initiated in 1992. It is yet another
excercise, of renaming old programs which have existed
for several years, and repacking them with a new name.
The different components of the program are:
Advice on Breastfeeding
The topic of breastfeeding is discussed in detail in
Chapter 3 and 5. Information and education by para-
medical staff and the birth attendants regarding
breastfeeding to prospective mothers is the only contri-
bution of this program.
Care of the Newborn Infant
The main aim of child survival program is to reduce
infant mortality. Since neonatal deaths constitute almost
half of the infant mortality, it is necessary to pay attention
to such measures as they may reduce mortality. A well-
thought, low cost program for the newborn infants has,
therefore, been approved for implementation though it
has yet to start functioning all over the country. A major
lacuna is the inadequate training of birth attendants and
provision of supply of sterile equipment to them.
The strategy is to:
i. Provide antenatal care to all pregnant women
ii. Ensure safe delivery services
iii. Provide basic care to all neonates
iv. Identify and refer these neonates, who are at risk.
The package of antenatal services consists of: (a)
advice on nutrition and prevention of anemia with iron
and folic acid, (b) tetanus immunization and early
identification of “Pregnant women at risk” so that their
labor may be conducted at a referral center.
Resuscitation
If the infant fails to cry within 15 to 20 seconds, i.e. time
taken to wipe his body and wrap him in a clean cloth,
steps should be initiated for resuscitation. They may
include clearing his throat with mucus extractor, assisted
with a ventilation bag and mask or mouth to mouth
breathing. If bag and mask are not available, take care to
blow only the air in your blown up cheek, into the infant’s
lung. If in spite of above described measures, the infant’s
heart rate remains below 60/min, an external cardiac
massage is recommended.
It is hoped that every birth shall one day be attended
by a trained birth attendant, who will cut the cord with
a sterile blade and tie it 2.5 inches from the base with a
clean twine. Supplies of cord kits can be locally assembled
and sterilized at PHC for free distribution to birth
attendants. The neonate must be protected from catching
a child by avoiding a bath, keeping the infant well-
wrapped in the mother’s cot and keeping the room warm.
A normal infant is put to mother’s breast within an hour
of birth. No other food or water is required to be given.
Infections are the cause of a large proportion of deaths
in neonates. These can be considerably reduced by
ensuring cleanliness in delivery room, training staff in
technique of handwashing, use of sterile instruments for
cord cutting, not permitting persons who have skin or
respiratory infection to handle the infant, and not
allowing relatives to handle or feed the infant.
A dose of oral polio vaccine and BCG should be
administered to the infant, within the first week of life.
Low Birth Weight Infants
Almost 25 to 30 percent of neonates in many developing
countries, have birth weight less than 2500 gram. Weight
of neonates can be recorded by ordinary spring balances,
which are cheap and easy to carry. A red tape applied at
1800 gram mark can point to an illiterate TBA, the need
for referral whereas an orange colored tape at 2500 gram
may be used to alert the TBA to LBW of infant. The TBA
and other workers in PHC should be familiarized with
clinical features which indicate severe illness and referral
to the PHC. These are failure to feed, abdominal
distention, imperforate anus, hypothermia, failure to pass
urine for 48 hours afterbirth, fast breathing or periods of
stoppage of breathing, convulsions and jaundice reaching
up to umbilicus.
Pregnant Women
Essential Care for All
• Register by 12 to 16 weeks
• Antenatal check-up at least 3 times
• Immunize with TT
• Give IFA—Large tablets to all, i.e. 1 tablet a day for
100 days
• Treat those with clinical anemia: 2 tablets a day for
100 days

• Deworm with mebendazole during 2nd/3rd
trimester, in areas where prevalence rates of hook-
worm infestation are high.
• Safe and clean delivery services.
• Prepare the woman for exclusive breastfeeding and
timely weaning.
• Postnatal care, including advice and services for limi-
ting and spacing births.
Early Detection of Complications
• Clinical examination to detect anemia
• Bleeding indicating APH (before labor) or PPH (after
delivery)
• Weight gain of more than 3 kg in a month and systolic
BP of 140 mm Hg or more or diastolic BP of 90 mm
Hg or more
• Fever 39°C and above after delivery or after abortion
• Prolonged or obstructed labor (labor pains for more
than 12 hours).
Emergency Care for those who need it
• Early identification of obstetric emergencies
• Provide initial management and refer to identified
referral units
• Use fastest available mode of transport.
Women in the Reproductive Age Group
• Counseling on:
— Optimal timing and spacing of birth
— Small family norms
— Use and choice of contraceptives
• Information on availability of:
— Medical termination of pregnancy (MTP) services
and
— Intrauterine devices (IUD) and sterilization
services
• Provide family planning services.
BIBLIOGRAPHY
1. Manual for orientation of ANM and supervisors—
Reproductive and Child Health Dept. of Family Welfare,
Ministry of Health and Family Welfare GOI, 1996.
2. Modules of CSSM MCH division, Ministry of Health and
Family welfare, 1994.
Community Pediatrics 197
7.2.5 REPRODUCTIVE AND CHILD
HEALTH (RCH) PROGRAM
BNS Walia, Shashi N Vani
The National Family Welfare Program has been renamed
in 1997, as the Reproductive and Child Health (RCH)
Program. The program envisages that men and women
make informed choices, receive counseling for respon-
sible and health sexuality, and avail of services for
prevention of unwanted pregnancy, safe abortion and
maternity care. Also health services shall continue to be
provided, pertaining to child survival and prevention
and treatment of diseases of reproductive tract in women.
An important shift in the goals of new program is from
the malady of “targetitis” to providing a range of quality
services instead. The package of essential reproductive
health services recommended for implementation
includes:
i. Prevention and management of unwanted preg-
nancy
ii. Services to promote safe motherhood
iii. Provision of services to promote child survival
iv. Nutrition supplements for vulnerable groups
v. Prevention and treatment of reproductive tract
infections and sexually transmitted infection
vi. Reproductive health survey for adolescents
vii. Information and counseling for health and sexuality
viii. Availability of a referral system.
The additional services to be provided by the
revamped program, would necessitate retraining of staff,
and make available the equipment and supplies, super-
vision and support and adequate financing to make the
implementation of program, a reality.
RCH II has since been launched in 2004 with
improved strategies based on the experience gained in
the implementation of RCH I.
Contraception
Access to wider range of choices of contraceptives is well-
known to improve contraceptive use. Service providers
are expected to help clients make decisions for selecting
contraceptives that are most suitable for them. Reversible
methods of contraception are not being used to the extent
that they are desired. Safety and freedom from morbidity
caused by the method selected would ensure its
198 IAP Textbook of Pediatrics
continued use and satisfied clients would then become
the spokes person for the program. Contraindications to
IUD insertion must be respected and patient be given
immediate medical attention, in case of any adverse
reaction.
Efforts should be made to encourage vasectomy in
preference to tubectomy, as it is a safer procedure.
Counseling of men should be carried out to dispel their
fears and anxieties regarding vasectomy.
Provision of services for medical termination of
pregnancy and safe abortion services for unwanted
pregnancies at the primary health center level, could help
to reduce illegal abortions and maternal deaths
therefrom.
Antenatal services should be provided at every clinic
and dispensary. During home visits, health workers
should identify women who have missed periods, and
once pregnancy is confirmed, at least 3 to 4 antenatal
examinations should be carried out to detect anemia,
preeclampsia, malpresentation and infection.
Advice on breastfeeding, personal hygiene, nutrition
and immunizations should be given. In the postpartum
period, family planning methods should be discussed
with the parturient lady.
Safe Delivery Services
More than 75 percent deliveries in India take place at
home, and majority of these are conducted by traditional
birth attendants. It is impossible to replace them, and
therefore, it would be worthwhile to train them to do a
clean delivery, identify pregnant women at risk,
recognize the indications for referral. Their training must
also include guidance on breastfeeding, resuscitation of
newborn and identification of danger signals in newborn
infants. Repeated training programs and continued
supervision would be required to attain desirable
standards of performance.
Postpartum Services
This program should offer services for detection and
management of infection and hemorrhage, nutrition
advice, and counseling on breastfeeding. Advice on
family planning or tubectomy if offerred during this
period, is more likely to be accepted. Timely referral and
transport should be arranged, if clinical condition
demands.
Child Survival Services
Almost, half the total deaths in children occur in the first
year of life. Prevention of infectious diseases by vaccines,
and of diarrhea and malnutrition have helped to reduce
the postneonatal mortality. Further reduction in infant
mortality rates can be expected to occur only by reduction
in prenatal and neonatal mortality. For this purpose,
better training of birth attendants and female
multipurpose workers in the care of neonates, cord care,
resuscitation, prevention of chilling of baby, identifica-
tion of congenital anomalies and danger signals, would
enable referral of cases for hospitalization. Upgrading
of facilities for neonatal care at community health centers,
subdivisional hospitals and district hospitals would be
required. The pattern adopted by the Tamil Nadu state
is quite effective, without being expensive. The
resurgence of sexually transmitted diseases, may indicate
routine prophylaxis for gonococcal infection in districts,
where gonorrhea is prevalent.
Nutrition Supplements for Pregnant and
Lactating Women
These programs have been established under the
Integrated Child Development Services at the village
level, in almost half the community development blocks
in the country and benefit pregnant and lactating
women. There is need for expanding this program to
include the undernourished adolescent girls, who
should also receive iron and folic acid, in view of the
high prevalence of anemia in young women of rural
areas. Prevention and treatment of reproductive tract
infections (RTI) can affect not only women’s health, but
also the outcome of delivery, child survival and HIV
transmission. Reproductive tract infections provide a
useful entry point for introduction of family planning
methods to the patients. The idea of integration of the
program of detection and treatment of RTI in the enlar-
ged reproductive health program is, therefore, based
on sound reasoning. The need for additional supplies
and training of staff for acquisition of certain additional
skills is essential for proper implementation of the
program.
Efforts at reduction of infectious morbidity related to
RTI, should include prophylaxis against gonococcal
ophthalmia, detection and treatment of maternal syphilis
and hepatitis B immunization.
 Community Pediatrics 199
Chart 7.2.5.1
200 IAP Textbook of Pediatrics
BIBLIOGRAPHY
1. Manual for orientation of ANM and supervisors—
Reproductive and Child Health Dept. of Family Welfare,
Ministry of Health and Family Welfare GOI, 1996.
2. Pachauri S: Defining a Reproductive Health Package for
India. South East Asia Regional Working Papers No. 4,
1995.
7.2.6 INTEGRATED MANAGEMENT OF
NEONATAL AND CHILDHOOD
ILLNESS (IMNCI)-STRATEGY
BNS Walia
About 2 million infants and young children die annually
all over the world. The tragedy is that almost 70 percent
deaths are caused by common, easily treatable illnesses
like diarrhea, pneumonia, malaria, measles and malnut-
rition. Majority of such patient, residing in rural area or
slum areas first come to the attention of auxiliary health
workers. It is envisaged that if these workers could be
trained in the skills required to identify and treat the
above named illnesses, the morbidity and mortality cau-
sed by these illnesses could be considerably reduced.
The WHO has coordinated these efforts and prepared
training materials and guidelines and undertaken train-
ing courses which are appropriate for use by workers of
first level outpatient health facility in developing
countries. In addition, a course has been developed to
improve drug supply situation in these facilities.
The IMNCI guidelines are based on simple clinical
signs, which have been identified as most sensitive and
specific in arriving at a clinical diagnosis, without
laboratory tests. The guidelines are presented as wall
charts in the clinics or as booklets which can serve as
handy manuals to guide the health workers.
Methodology of IMNCI
Depending on a child’s age, IMNCI guidelines focus on
neonates, infants, and children upto 5 years of age. The
treatment guidelines are broadly described under the age
categories: (i) young infants upto 2 months of age; and
(ii) children age 2 months-5 years. The health worker
follows the steps of case management process as
described below:
i. Assess the young infant/child;
ii. Classify the illness;
iii. Identify treatment;
iv. Treat the young child/infant;
v. Counsel the mother; and
vi. Provide follow-up care.
A summary of this case management is presented as
color-coded charts. Chart 7.2.5.1 provides a page of these
charts. Each illness is then classified according to the color
coding, i.e. green, yellow or pink. Those in the green
classification are managed at home, those in the yellow
can be treated at the out-patient health facility while those
in pink classification need urgent referral.
If referral is decided upon, urgent treatment is given
before sending the patient away. Mothers of patients are
taught how to administer oral drugs at home, and to
increase fluid intake during diarrhea or fever. Mother is
also informed regarding which signs should be regarded
as of serious importance and should make her return to
clinic immediately and when a routine visit may be made.
Mothers are given appropriate feeding instructions and
follow-up instructions for the relevant clinical condition.
Substantial evidence has been gathered by now
regarding the effectiveness of the IMNCI approach in
reduction of childhood mortality and in improving child
care at family and community level.
The question is sometimes asked as to what is new in
this program as some of the programs like ARI and
control of diarrheal diseases did exist earlier. What is new
really, is the way the health worker is to be conveyed
this information. The guidelines help to ensures high
quality coordinated child health services. In most
developing countries, health care programs for children
include nothing more than immunization. Adoption of
this program by governments of developing countries
gives hope that the children shall survive as a result of
such efforts from the common killer diseases to benefit
from immunizations.
BIBLIOGRAPHY
1. Gove S. Integrated management of childhood illness by
outpatient health workers: Technical basis and overview.
Bulletin of the World Health Org 1997;75(suppl 1):7–16.
2. Lembrechts, Bryce J, Orinder U. Integrated management
of childhood illness, a summary of first experience. Bull
WHO. 1999;77(7):582–93.
7.2.7 NATIONAL PROGRAMS ON
IMMUNIZATION
A Parthasarathy, Shashi N Vani, BNS Walia
7.2.7.1 UNIVERSAL IMMUNIZATION
PROGRAM (UIP)
KM Ganessan
Immunization is regarded as the greatest success story
of the 20th century. The global immunization coverage

has increased to over 85 percent not only in the develo-
ped countries, but also in developing countries through
successful organization of National Immunization
Programs and adoption of National Immunization
Schedules. The success gained through the 20th century,
will pave the way for introduction of several newer
vaccines in the 21st century, in the National Immuni-
zation Schedules of the respective countries.
HISTORICAL PERSPECTIVES
At the global level, the first ever organized immuniza-
tion program, was instituted in the year 1974, under the
caption “Expanded Program on Immunization” (EPI) by
the World Health Organization (WHO). India adopted
EPI in 1978. While BCG, DPT, OPV, and measles for
children under five years of age and TT for pregnant
women were the targeted antigens adopted at the global
level under EPI in 1974, India adopted BCG, DPT and
Typhoid immunization in 1978 and later on, OPV in 1979.
In order to achieve certain time bound specific goals,
Universal Immunization Programs (UIP) was launched
in 1985 as an off-shoot of (EPI) with the targeted
beneficiaries, viz. Infants under one year for BCG, DPT,
OPV and measles coverage children at 1½ years for DPT
and OPV Booster, children at 5 for DT and children at 10
and 16 as also pregnant women for TT. Subsequently,
Children's Vaccine Initiative (CVI) was launched at the
global level in 1991 with the objectives of improving the
quality of vaccine, exploring newer production
technologies, discovering newer vaccines and possibly
to finally develop a single vaccine vehicle incorporating
several antigens. The global program on vaccine and
immunization (GPV) was launched in 1993, at the global
level with the objective of sustaining high coverage and
developing a good global surveillance network for
vaccine preventable diseases, and evolve eradication
strategies. In India the success of UIP resulted in the
launch of child survival and safe motherhood (CSSM)
programs in 1992 and the reproductive and child health
(RCH) program in 1997, incorporating immunization as
one of the major components of the program.
The UIP Objectives
Universal coverage of all infants, under 5 children,
children at 10 and 16 as also pregnant women with the
recommended antigens as per the national immuniza-
tion, schedule was the aim of the Universal
Immunization Program (UIP).
Community Pediatrics 201
The objectives are:
• To increase immunization coverage
• To improve the quality of service
• To achieve self-sufficiency in vaccine production
• To train health personnel
• To supply cold chain equipment and establish a good
surveillance network
• To ensure districtwise monitoring.
The National Immunization Schedule
An epidemiologically relevant, immunologically appro-
priate, technically feasible, socioculturally acceptable and
economically viable National Immunization Schedule
was evolved as the minimum needs program (MNP)
for universal coverage of children and pregnant
women.
Achievements of UIP
High Coverage and Decline in VPDs
Annually 25 million infants and pregnant women have
been reached out. The overall immunization coverage
have gone up to nearly 90 percent for all antigens. Over
80 percent decline have been achieved for the targeted
diseases, viz. neonatal tetanus, diphtheria, pertussis,
poliomyelitis and measles.
Self-sufficiency in Vaccines
Over 21,854 PHC's and 1,32,730 subcenters are rendering
immunization services in rural area. 1500 lakh doses of
OPV, 1200 lakh doses of DPT, 1200 lakh doses of TT,
290 lakh doses of DT, 550 lakh doses of BCG and 330
lakh doses of measles vaccines are freely available
annually.
Cold Chain System
To preserve all vaccines at +2°C to + 8°C, the following
cold chain equipments have been supplied.
• Ice Lined Refrigerators (ILR) to PHC's along with
vaccine carriers (+ 2°C to + 8°C) with temperature
monitoring
• Walk in coolers with temperature monitoring for state
level storage
• Freezers with temperature monitoring at district
stores (–20°C)
• Walk in freezers with temperature monitoring for
large states (–20°C).
202 IAP Textbook of Pediatrics
Dial thermometers have been supplied to monitor ILR
temperature. The quality of cold chain is monitored by
testing oral polio vaccine samples selected randomly
from the field. For this purpose, a new network of testing
laboratories have been setup.
Surveillance of VPDs
Effective surveillance network have also been esta-
blished. The PHCs act as primary reporting units and
medical college hospitals and other major hospitals are
acting as sentinel centers. Monthly reporting including
“0” reporting by the reporting units is mandatory.
Towards polio eradication strategy acute flaccid paralysis
(AFP) surveillance has been intensified through the
National Polio Surveillance Project (NPSP) through
WHO Surveillance and Assistance Surveillance Medical
Officers. Each state has got a state level immunization
officer. District immunization officers monitor the entire
program supervising the district and PHC level ope-
ration.
Targets Achieved
Neonatal tetanus elimination has been achieved by many
states. Reduction in number of cases and deaths due to
measles has since been achieved by 1992 onwards. Polio
eradication is expected to be achieved in very near future.
Pulse Polio Immunization carried out from 1995 to
2007 annually have covered over 15 crores of children
under 5, with additional doses of OPV on National
Immunization Days.
The good infrastructure established under UIP has
helped to carry out the UIP plus program namely the
CSSM. The success of CSSM has paved the way for CSSM
plus namely the Reproductive and Child Health Program
(RCH). A good rapport has been built up, with parents
and pregnant women resulting in good demand
generation. Awareness on cold chain maintenance has
increased. Sustaining high coverage has become
mandatory. Self-sufficiency of vaccine production has
encouraged introduction of newer vaccines like MMR
and Hepatitis B in the UIP in coming years. VPD eradi-
cation has become a reality. The Information Education
and Communication, (IEC) system has become effective.
The success of the program has resulted in saving an
estimated 16.8 lakh lives annually.
The current progress in UIP is the development and
implantation of a mid-term stategic (Multi-Year Plan-
MYP) with definite goals, milestones and indicators to
measure the coverage and progress, with a provision for
necessary mid-course corrections. A National Technical
Advisory Group (NTAG) was formed in August 2003.
Based on its recommendations in 2002, the Government
of India has developed our MYP for 2004 to 09.
Achievement of five specific objectives of India
Immunization Policy: availing opportunities to introduce
vaccines (like MAR/AR, JE and Hepatitis B) and to
produce an opportunity to expand wherever feasible
with other public health interventions of maternal and
child care.
BIBLIOGRAPHY
1. Basu RN: Chalenges in the final stage of polio eradication:
Ind J Ped 71: Aprl 2004:339–40.
2. Biswal P: Universal immunization programme: Reduce
material 10th NCCPF meeting, New Delhi, 30th Apl 2004.
3. Ghosh A: Status of UIP in the Country. Report on
National Consultation meet on prevention of Hepatitis
B in children: NIPCCD 1998;21–25.
4. John TJ, Parthasarathy A, Bhave SY: Historical Aspects
of Global Immunization Programs: IAP Guide book on
Immunization 1996;11–12.
5. Sokhey J: National Immunization Program: Frontiers in
Social Pediatrics AK Patwari, HPs Sachdev (Eds). Jaypee
Brothers Medical Publishers (P) Ltd., New Delhi
1998;253–65.
7.2.8 ACUTE RESPIRATORY INFECTIONS
(ARI) CONTROL PROGRAM
Keya Lahiri, BNS Walia, Shashi N Vani
Acute respiratory infections are a major cause of infant
and childhood mortality, contributing 20 to 30 percent
of the total deaths in children below 5 years of age and
15 to 30 percent of total deaths in children.
Prevalence
Patients suffering from ARI constitute 22 to 66 percent
of all pediatric outpatient cases and 12 to 45 percent of
all indoor admissions. In the urban set up, children under
the age of 5 years suffer 3 to 5 episodes of ARI in a year.
Amongst rural children, the morbidity is slightly lower.
Mortality due to ARI is higher amongst small-for-date
infants, the premature, the malnourished and when it
occurs in association with measles or pertussis.

ARI Control Program
The guidelines devised by the World Health Organi-
zation for prevention and treatment of ARI are based on
the premise that diagnosis of ARI is possible by
paramedical workers and that treatment with orally
administered antimicrobial agents is safe and effective.
The WHO protocol puts forward two signs as the
“entry criteria” for a possible diagnosis of pneumonia.
These are cough and difficult breathing. Presence of fever
is not essential for diagnosis. Infants under
3 months are categorized as a separate group, because
in them the gram-negative bacteria predominance as the
cause and the disease is more liable to take a serious
course. Patients belonging to this age group are treated
with antibiotics parenterally in the form of a combination
ampicillin 25 to 50 mg/kg/day and gentamicin 5.0 mg/
kg/day for a period of 7 to 10 days.
Presence of any of the under mentioned signs is
indicative of severe illness.
1. Respiratory rate more than 60/min
2. Chest indrawing in the absence of nose block.
3. Infant has stopped accepting feeds
4. Abnormally sleepy or difficult to wake
5. Hypothermia
6. Convulsions
Children aged between 3 months and 5 years: The
common causative organisms are gram-positive, e.g.
Strept. pneumoniae. Fast breathing has been noted to be a
better predictor of pneumonia than auscultatory findings.
Fast breathing is defined as respiratory rate more than
40/min in children above 1 year of age and more than
50/min in children between the ages of 3 to 12 months.
TABLE 7.2.8.1: Clinical assessment and management of acute respiratory infection
Clinical signs Classification
I Not able to drink or central cyanosis Very severe pneumonia
present
II Chest indrawing Severe pneumonia
No cyanosis
Able to drink
III Resp. rate over 40/min Pneumonia
No chest indrawing
IV No fast breathing No pneumonia
No chest indrawing
Feeding well
Community Pediatrics 203
Presence of chest indrawing indicates serious respiratory
tract involvement.
The categorization of a case as one of pneumonia and
its severity is summarized in the Table 7.2.8.1.
BIBLIOGRAPHY
1. Basic Principles of Control of Acute Respiratory
Infections in Children in Developing Countries; a Joint
WHO / UNICEF Statement, WHO, Geneva 1986.
2. Intergrated Management of Childhood Illness: Global
status of implemention, August 1998 WHO, UNICEF,
1998.
3. Management of childhood illness is developing coun-
tries: Rationale for an integrated strategy. WHO,
UNICEF, 1998.
4. The Management of Acute Respiratory Infections in
Children: Practical Guidelines for Outpatient Care,
WHO, Geneva, 1995.
5. The role of IMCI in improving family and community
practices to support child health and development.
WHO, UNICEF 1998.
6. World Health Organization: Case Management of Acute
Respiratory Infections in Children in Developing
Countries. Document WHO/RSD/85, 15.
7.2.9 CONTROL OF DIARRHEAL DISEASE
(CDD) PROGRAM
BNS Walia, Shashi N Vani
Diarrhea is the cause of almost one-fourth of deaths in
preschool children. The experience of scientific workers
who treated cases of cholera in camps of Bangladesh
refugees in 1971 with a mortality rate of less than one
percent, provided ample proof of the effectiveness of this
Treatment
Admit / refer oxygen IV chloramphenicol
25 mg/kg/day Assess twice daily
Admit / refer
IV Penicillin 25000 units/kg/dose, 6 hourly.
Assess once daily.
Oral cotrimoxazol 5–8 mg/kg of TMP
+ 25 mg/kg/SMZ. Amoxicillin/Ampicillin
25–50 mg/kg/day.
Assess once in 2 days.
Treat like URI
Ask mother to return if chest
indrawing or increased respiratory rate occurs.
204 IAP Textbook of Pediatrics
low cost intervention in reduction of childhood mortality
caused by dehydration in diarrheal disease. Treatment
of dehydration caused by diarrhea was therefore
included in the child survival program with the following
objectives: to reduce diarrhea related deaths in children
under the age of 5 years by 30 percent by 1995 and by
70 percent by year 2000 AD. The strategy adopted was:
i. To train medical and other health personnel in
standard case management of diarrhea.
ii. Promote standard case management practices
amongst private practitioners.
iii. Instruct mothers in home management of diarrhea
and recognition of signs which signal immediate
medical care.
iv. Make available the oral rehydration salts (ORS)
packets free of cost, at government health facilities
at first and later through the public distribution
system.
The rational treatment of diarrhea consists in pre-
vention of dehydration in a case of diarrhea by oral
rehydration therapy, using oral rehydration salts. The
composition of ORS is given below:
Chemical Quantity to be used in grams
Sodium chloride (IP) 3.5 gm
Sodium citrate (IP) 2.9 gm
Potassium chloride 1.5 gm
Glucose (IP) 20.0 gm
A sachet containing the above contents is dissolved
in 1 liter of water and is kept in a clean utensil. 150 to
200 ml of solution is administered, each time a stool is
passed, depending upon whether the stool is small or
large, and upon the age of the child.
Some of ORS packets available in the market
containing a higher content of glucose, though intended
to make the solution tastier, are liable to worsen diarrhea
by osmotic effect of the sugar and therefore, should be
avoided. In case, ORS packet is not available, oral
rehydration therapy can be carried out by a home-made
solution, constituted as follows:
Weight Household measure
(gm)
Common salt 3.5 3/4th of a teaspoon
Baking soda 2.5 1/2 teaspoon
Cane sugar 40 8 level teaspoon (not
heaped)
Lemon one (Supplies potassium)
Kindly note, that when cane sugar is used in place of
glucose, double the quantity of sugar is used. Other home
available solutions for prevention of dehydration, can
also be administered. These include rice water, dal water,
butter milk, soups and coconut milk. A pinch of salt is
added to each helping of 300 ml of these fluids.
Sweetened aerated drinks, fruit juices or sweetened tea
may worsen the diarrhea by their osmotic effect, and
should therefore be avoided.
Breastfeeding should be continued. If stool characte-
ristics of the patient resemble that of lactose intolerance,
milk to be fed could be diluted with equal quantity of
water for 3 to 4 days. Others should continue to have
undiluted feeds before discharge from the PHC. The
mother should be given a few packets of ORS and
demonstrated, how to reconstitute it into a solution for
administration.
Patients who are diagnosed to be having dysentery,
are given cotrimoxazole in addition to ORS. In case of
unsatisfactory response, nalidixic acid is given for five
days. Occurrence of amebic dysentery is uncommon in
children and there is little justification for adding
metronidazole to the treatment of a dysentery case on a
routine basis.
Any program for diarrheal disease control must
include provision of potable water. Parents must also be
educated regarding storage of water and foods in clean
utensils, continuance of breastfeeding, using only freshly
prepared weaning foods and thorough washing of hands
with soap before handling foods.
7.2.10 NATIONAL LEPROSY ERADICATION
PROGRAM
BNS Walia
The National Leprosy Control Program was launched
in 1955, as a centrally aided scheme. Its focus was on
rural areas of high and moderate endemicity. In 1969 to
70, the scheme was converted into a centrally sponsored
program.
In 1981, guided by the fact, that large variations still
existed in the prevalence of the disease in different states,
the Ministry of Health and Family Welfare constituted a
working group of experts in leprosy to devise a new
strategy for eradication of leprosy. The recommendations
of the working group included conversion of the National
Leprosy Control Program into a time bound National
 Community Pediatrics 205

Leprosy Eradication Program, with specific goal to arrest TABLE 7.2.10.1: Multidrug therapy (MDT)
the disease activity in all leprosy cases, by 2000 AD and regimen for leprosy
screening of pre-school children and youth for early Phase Drug Dose Administration
detection of cases. A National Leprosy Eradication
MULTI BACILLARY CASES
Commission under the chairmanship of the Union
Intensive phase
Minister for Health and Family Welfare for formulation for 14 days Rifampicin 60 mg daily
of policies, and the National Leprosy Eradication Board Clofazimine 100 mg daily
under the chairmanship of the Union Health Secretary, Dapsone 100 mg daily supervised
were constituted for monitoring the activities of the Rifampicin 600 mg once
program. a month
Continuation phase
A Deputy Director General, Health Services was
(for at least Clofazimine 300 mg once
given the charge of planning and implementing the 2 years) a month supervised
programs at the Government of India level. At the state 50 mg daily unsupervised
level, the program is supervised by a senior officer in Dapsone 100 mg daily unsupervised
the Directorate of Health Services. One district leprosy
PAUCI-BACILLARY CASES (PB)
officer had been provided for districts where leprosy was
Continuation phase
highly endemic, and one per two or three districts where (minimum for 6 months)
it was of moderate endemicity. The field activities have Rifampicin 600 mg once
been conducted by leprosy control units which serve a a month supervised
population of 4-500,000 and comprise one medical Dapsone 100 mg daily unsupervised
officer, 4 nonmedical assistants and 20 paramedical
workers. found to be safe and effective as judged by decrease in
Survey, Education and Training (SET) centers were prevalence rate of cases, decline in detection rate of new
established for each population unit of about 25,000. cases, and decline in deformity rates. In the 7th-five-year
These units are located at the primary health center and plan, sample survey cum assessment units were created
one paramedical worker is assigned to each center. It is in the states, for survey purposes so that the reported
hoped that once the prevalence rates in leprosy-endemic data under NLEP is validated by an independent
districts fall below 1 per 1000 population, the vertical authority.
leprosy eradication program would be abolished and its District leprosy societies have been formed in
functions would be taken over by the primary health every district under the chairmanship of the Deputy
center staff. Commissioner. Each district is provided with a mobile
In the urban areas, the program is run under the leprosy treatment unit for visits to leper’s colonies for
urban leprosy centers, which look after a population of supervision of treatment and periodic surveys.
50,000/70,000 and are attached to a neighborhood
dispensary or hospital. Rehabilitation
Reconstructive surgical facilities have been developed Rehabilitation of leprosy patient included physical, social
at several hospitals. Operational manuals and guides and vocational rehabilitation. Physical rehabilitation
have been written and distributed to workers to ensure involves, the care of ulcers, correction of deformities and
delivery of services of a uniform quality. physiotherapy. Numerous leprosy rehabilitation units,
A WHO study group on chemotherapy of leprosy in reconstructive surgery units and hospital wards have
1981, recommended the use of combined chemothe- been established for rehabilitation of patients with
rapeutic regimens for the treatment of all multibacillary deformities. Voluntary organizations are playing a major
and paucibacillary patients. The former type constitute role in the rehabilitation field, with the guidance and
about 25 percent of the total cases in India. financial assistance of Ministry of Social Welfare and
The multidrug therapy (MDT) regimen followed several international agencies. More institutions for
under the program is given in Table 7.2.10.1. vocational training of patients are required as economic,
All the antileprosy drugs are supplied free of cost to independence is the best safeguard against social
patients from Central Government Funds. MDT has been rejection.
206 IAP Textbook of Pediatrics
Health Education
The stigma of leprosy as a punishment for past sins, is
deeply ingrained in the Indian psyche. The notion that
leprosy is an infectious disease, which is completely
curable by available medicines without any residual
deformity, if treated at an early stage has to be propagated
widely. This is essential in order to correct the prejudices
and misconceptions of the public, as well as give the
sufferers a hope of cure, which is essential for continuing
the treatment for prolonged periods.
Research in leprosy is being promoted by ICMR and
Department of Science and Technology and is mainly
focused on trial of new treatment regimens and field trials
of vaccines for prevention of the disease.
7.2.11 NATIONAL VECTOR-BORNE
DISEASE CONTROL PROGRAM
(NVBDCP)
Piyush Gupta
National Vector-Borne Disease Control Program
(NVBDCP) initiated in 2003-04 includes the erstwhile
National Anti Malaria Program (NAMP), National Filaria
Control Program (NFCP) and Kala-azar Control
Program, and also includes programs for control of
Japanese Encephalitis (JE) and Dengue/Dengue
Hemorrhagic Fever (DHF).
7.2.11.1 NATIONAL MALARIA CONTROL
PROGRAM
BNS Walia
National Malaria Control Program has been functioning
since 1958. An expert committee recommended a revised
strategy for control of malaria which was implemented
in 1995 to 96. Special attention is to be paid to tribal areas,
epidemic prone areas and development project areas. The
seven North Eastern States having high incidence of
falciparum malaria is to be provided, with 100 percent
assistance for malaria control. In remaining states, the
program is to be operated as centrally sponsored scheme
with 50 percent funding to be contributed by the state.
Nonavailability of state contribution could result in short
falls in spray operations, decline in slide examinations
and incomplete treatment of the cases.
The objective of the program is to bring down malaria
transmission to a level, where it ceases to be a health
problem. Thereafter, PHC staff must maintain it.
PHC is the focal point of all antimalaria acitivites,
which include epidemiological surveillance by staff,
laboratory examination of blood smears of fever cases,
administration of chloroquine to all patients running
fever by health workers, spraying and antilarval
operations, surveillance, radical treatment of malaria
positive cases, and improvement of the environment.
Strategies of malaria control should include the
undermentioned essential steps: (1) survey and moni-
toring of incidence of malaria, and (2) use of residual
insecticide spray. The vector for filaria, Japanese B
encephalitis being the same as that of malaria and the
vector of filaria being amenable to the same insecticides
as the mosquito, the control activities against these
diseases should be integrated with the Malaria Eradica-
tion Program to avoid duplication in efforts and
expenses. The use of Japanese B encephalitis (JE) vaccine
in the areas prone to this disease has resulted in
considerable decrease in the number of reported cases
and deaths due to this disease.
The existing guidelines for vector-borne diseases
control are summarized below:
i. Spraying with appropriate insecticide in areas with
annual parasite index (API) of two or more in the
last three years.
ii. Spraying BHC in districts reporting 100 or more
cases of Japanese B encephalitis, in any year during
the last decade.
iii. Spraying DDT in PHCs reporting 10 or more cases
of kala-azar, in anyone of the last three years.
iv. Continuation of antilarval operations.
v. In addition, malathion fogging is to be undertaken
whenever an outbreak of JE or malaria is encounte-
red.
The PHC doctor should plan intervention measures
for transmission control in a methodical fashion. The
exercise involves ascertainment of period of trans-
mission, the vectors responsible for it, monthly
infant parasite rates, characteristics of breeding
places and susceptibility status to insecticides.
Transmission control measures include:
a. Indoor residual spray
b. Indoor/outdoor fogging
c. Antilarval measures, using chemical larvicides,
biocides, fish, fungi or nematodes.
d. Personal protection measures like bednets,
impregnated bednets, use of repellents and
gauze screening of house, should be undertaken.
 Community Pediatrics 207

Only human or mixed dwellings should be 7.2.12 NATIONAL AIDS AND STD
sprayed. The formula for calculation of insecti- CONTROL PROGRAM
cide requirement is given below:
BNS Walia
Name of Preparation of Area to be Dosage per
insecticide suspension covered sqm The first few cases of AIDS were described in USA in
DDT 50% WP 1 kg/10 liter 500 sqm 1 gm 1983. In India, the first AIDS case was recorded in 1986.
BHC 50% WP 1.5 kg/10 liter 500 sqm 200 mg The disease has spread rapidly since last 10 years. It is
Malathion 25% 2.0 kg/10 liter 250 sqm 2.0 gm feared that, if the same rate of spread continues, by 2000
WP AD, India might be home to 5 million of the infected
Deltamethrin individuals.
2.5% WP 400 gm/10 liter 500 sqm 20 mg
In response to this grave challenge, the Government
The district malaria officers should supervise the of India established the National AIDS Control Program
spraying operations. in 1987, under the National AIDS Control Organization
New problems are emerging as a result of resis- (NACO) in the Ministry of Health, Government of India.
tance of mosquitoes to insecticides. The parasites The National AIDS Committee (NAC) and a multi-
are becoming resistant to common inexpensive sectoral committee under the chairmanship of the
drugs. There is increased breeding of parasite at Minister of Health and Family Welfare and the Secretary,
places where irrigation and other development Health respectively coordinate the various activities of
projects are being implemented and migration of the program.
malaria infected population is faster and more Similar committees have been established in all states
frequent. in the form of empowered committees, state AIDS cells
Newer strategies such as biodegradable insecti- and state technical advisory committees. The latter advises
cides and impregnated nets shall be introduced, on the technical aspects of program implementation. The
depending upon availability and affordability. NACO has established a national HIV sentinel
vi. Information, education and communication acti- surveillance system consisting of (i) surveillance of HIV
vities regarding the mode of spread and infection as indicated by serum positivity (ii) surveillance
prevention of vector-borne diseases, require to be of AIDS cases, showing clinical signs and symptoms.
carried out on a regular basis. Surveillance of cases suffering from AIDS is now the
responsibility of all medical institutions who refer
suspected cases to the hospitals for establishing the
BIBLIOGRAPHY
diagnosis and refer them to the public health authori-
1. Training Module for Medical Officers of Primary Health ties. The surveillance reports are sent to the states every
Center. Part I: Directorate of National Malaria Eradication month and to NACO for purposes of monitoring the
Program, Ministry of Health, Govt. of India, 1996.
program of the AIDS. Disease control activities are tar-
getted at the three main modes of spread, which include:
7.2.11.2 NATIONAL FILARIA CONTROL PROGRAM i. sexual activity with multiple partners.
ii. self injection of intravenous drugs by addicts.
BNS Walia
iii. transfusion of HIV infected blood.
The scheme has an operational component managed by The first two components which constitute risk
the district malaria team and the PHC staff. The research behaviors are tackled by information, education and
and training component is controlled by the Director, communication strategies, using media campaigns and
National Institute of Communicable Disease. The personal contacts.
strategy of filaria control consists of: Counseling services are provided to those who have
• Antilarval measures undertaken periodically. already acquired HIV positive status or AIDS, so that
• Administration of chemotherapeutic agents for they receive proper care and do not continue spreading
eradication of parasites in the host. the disease. Since other sexually transmissible diseases
208 IAP Textbook of Pediatrics
are also spread by the same behavior which leads to
spread of HIV infection; and presence of STD in an
individual increases the risk of his/her acquiring HIV
infection manifold, all the STD clinics in the country have
thus been strengthened. The diagnosis and treatment of
STD based on syndromic approach is being introduced
at PHC level. The AIDS control cell is conducting training
programs for paramedical workers and general practi-
tioners, in order to enhance their capability for effective
STD diagnosis and treatment and for counseling.
An important component of the program is, making
available good quality condoms at reasonable prices.
HIV infected blood, causes about one-tenth of all HIV
infections in developing countries. These are totally
preventable. Encouragement of voluntary blood dona-
tion, total stoppage of sale of blood, testing of blood for
syphilis, HIV, hepatitis B and C and malaria have been
made mandatory for all blood banks. Test kits for these
infections are supplied by NACO to the blood banks.
Licensing of all blood banks in the country by the Drug
Controller, Govt. of India has been enforced. State blood
transfusion councils have been set up in all states of the
union, to supervise safe blood transfusion programs.
Numerous international donor agencies are involved
in providing financial resources, test materials and
technical know-how for the program. Non-governmen-
tal voluntary organizations are playing an important role
in the prevention and control activities initiated by
NACO.
Zonal blood testing centers have been established all
over the country, these centers receive blood samples from
affiliated blood banks and after testing samples for HIV
communicate the results to the blood banks. HIV positive
blood is discarded. Central assistance of money and
equipment is being given to states to upgrade blood bank
services. Teaching facilities for short-term training in
blood banking techniques and for training programs
leading to MD degree in blood transfusion, immuno-
hematology are being established. 31 blood component
separation units are being set up in the country, in blood
banks which process more than 10000 units of blood
annually.
The entire program is monitored by officials
belonging to NACO by periodic visits to zonal blood
testing centers and district blood banks.
BIBLIOGRAPHY
1. National AIDS Control Program, India, Country
Scenerio, An Update, Document prepared by NACO,
Ministry of Health and Family Welfare, 1994.
7.2.13 NUTRITION PROGRAMS
Shashi N Vani
Malnutrition is a multifaceted problem. Pregnant and
lactating women and children are at a higher risk for
undernutrition. Economically weaker sections of the
society, i.e. the rural, tribal and urban slums, are worst
affected by malnutrition.
A number of surveys and research studies have
recorded a high incidence of diet related deficiency
diseases. Common diseases due to undernutrition in
community are as follows:
• Protein energy malnutrition
• Nutritional anemia
• Nutritional blindness
• Iodine deficiency disorders (IDD)
Other disorders due to deficiency of B group vitamins
and trace elements are also not uncommon.
It is established that nutrition, immunity and infec-
tion are inter-related. Malnutrition alters immuno-
competence and thus increases the risk of infection while
repeated infections tend to precipitate malnutrition,
particularly in those cases, when the nutrient intake is
marginally inadequate.
The problem of protein energy malnutrition is being
managed with the help of the following programs which
provide supplementary calories and proteins to the
beneficiaries.
Special Nutrition Program (SNP)
The main features of this program are as follows:
• Children below 6 years of age are to be provided with
300 calories and 10 grams of proteins per child per
day.
• Expectant and nursing mothers shall receive 500
calories and 20 grams of proteins, and severely
malnourished children 600 calories and 20 grams of
proteins, respectively.
• Supply of vitamin A, iron and folic acid (IFA) tablets
in the last trimester of pregnancy.
Nowadays majority of beneficiaries have been
transferred to ICDS.
Integrated Child Development Services (ICDS) is one
of the largest supplementary nutritional programs of the
world for children less than 6 years age group and
pregnant and lactating women. Details of ICDS are
discussed later on.
Other major nutritional programs are:
• Wheat-based supplementary nutrition program
(WNP)

• Tamil Nadu Integrated Nutrition Project (TINP)
similar in concept to ICDS.
• World Food Program (WFP)
• Mid-day Meals Program (MDM)
7.2.14 MID-DAY MEAL PROGRAM
HPS Sachdev
The Midday Meal Program (MDMP), also known as the
‘Noon meal program’, was started in 1962–63. Recently,
in 1995, the Government of India modified this country
wide program of nutrition support to children in primary
schools (Classes I to V).
The stated objective of the modified MDMP are:
(i) To raise the nutritional status of primary school
children, particularly those belonging to low socio-
economic groups; (ii) To improve attendance and
enrolment in schools, (iii) To prevent dropouts from
primary school. The beneficiaries of this program are
children attending primary school (6 to 11 years of age).
Children belonging to backward classes, scheduled caste
and scheduled tribe families are given priority.
The MDMP was started initially as a “centrally spon-
sored” scheme of the Government of India. However,
presently it is implemented by the State Governments
and central assistance is provided. To begin with
Employment Assurance Scheme (EAS) blocks with low
female literacy rates were included and all the districts
with District Primary Education Program (DPEP) were
given priority for implementation of scheme. One of the
school teachers on a primary school is designated as the
‘Organizer’ and is given responsibility for the implemen-
tation of the scheme.
Under the present program, the nutritional support
could be either in the form of provision of a hot meal, of
which the food grain components is 100g per child per
day for 200 school days or equivalent precooked food or
through the supply of 5 kg of wheat/rice per month per
child in a family for 10 months. The beneficiary, to be
eligible, has to attend school for 20 days in a month. The
supplementary nutrition given to each beneficiary
provides 300 calories and 8 to 12 g protein/day.
Only one or two studies have shown that the scheme
has resulted in some nutritional improvement of
beneficiaries. However, no significant improvement in
school enrolment/attendance had been documented.
Community Pediatrics 209
The major bottlenecks in implementation of scheme
include frequent interruptions in the supply of raw
materials, low budget allocation per beneficiary, lack of
effective monitoring and supervision, resulting in
pilferage in the channels of distribution and wrong
identification of beneficiaries. It is also possible that
adequate amount of food offered is denied at home to
children, who receive nutrition supplements at school.
BIBLIOGRAPHY
1. Kapil U, Bhanthi T, Nayar D: Nutrition Intervention
Programs for Promotion of Mother and Child Health in
India. Indian Practitioner 1996;1:27–44.
2. Schemes of the Department of Women and Child
Development. A Synopsis. Department of Women and
Child Development, Ministry of Human Resource
Development, Government of India 1991;26–7.
7.2.15 ANEMIA CONTROL PROGRAM
Shashi N Vani
Poor absorption of iron from cereal diets, low iron
intakes, and hookworm infestations are the important
causes of high incidence of anemia in children and to
some extent in pregnant, lactating women. Anemia due
to iron and folic acid deficiency is known to affect up to
50 percent of Indian women in the low income group in
the second half of pregnancy, 40 to 60 percent of
preschoolers and 25 to 30 percent of women in child
bearing age. Nearly 10 percent of maternal deaths in
India are attributable to anemia.
National Nutritional Anemia Control Program
(NNACP) covers pregnant women, nursing mothers,
women acceptors to terminal methods and IUD. Target
is to cover 50 percent of total pregnant/lactating category
of women and 25 percent acceptors of terminal methods
and IUD.
Fifty percent children in age group of one to five years
have also been included in the program.
Recommended daily dose of iron and folic acid (IFA)
tablets is as follows:
Adult women: 60 mg elemental iron (equivalent to 180
mg ferrous sulfate) + 0.5 mg folic acid.
Children: 20 mg elemental iron (equivalent to 60 mg
ferrous sulfate) + 0.1 mg folic acid.
210 IAP Textbook of Pediatrics
If the preschool children cannot swallow the tablets,
2 ml liquid should be given. Antianemia drugs are
inexpensive and distribution logistics are simpler. Iron
plus folic acid tablets should be advised for regular daily
dose, during the last trimester of pregnancy. Nausea may
occur as side effect in some cases. Two tablets/day for
three months is the normal dose given to the mothers.
Supplementation of folic acid to iron preparations
increases the birth weight of infants by 100 to 200 gm.
7.2.16 CONTROL OF VITAMIN-A
DEFICIENCY
BNS Walia
Deficiency of vitamin-A in diet can present as night
blindness, xerosis or keratomalacia, leading to loss of
sight in one or both the eyes. Vitamin-A deficiency is
reported to cause 10 percent of the cases of blindness in
India. The goal of the program was to prevent vitamin-
A associated blindness by the year 2000 AD. However,
it is clear that we have not achieved it.
Strategy
Since vitamin-A is capable of being stored in the liver,
from where it is released into the plasma, it is possible to
build-up stores of vitamin-A in the liver by administering
a dose of 200,000 IU of the vitamin at 6 monthly intervals.
All children between the ages of 9 months of 3 years are
administered 2 ml of vitamin-A concentrate, by
paramedical workers in the rural and slum communities,
either when they visit the health facility or at home
during the multipurpose worker’s home visit. Other
measures which prevent vitamin-A deficiency are:
a. Promotion of breastfeeding and feeding of colostrum.
b. Encourage the intake of green leafy vegetable and
yellow colored fruits.
c. Increase of coverage with measles vaccine, as an
attack of measles depletes vitamin-A stores.
Special attention is given to the program in areas
where some cases of xerosis or night blindness have been
detected, in areas of country with famine conditions and
during measles outbreaks. Children suffering from
cholestatic jaundice are also more liable to develop
keratomalacia. Mothers should be encouraged to
improve food intake of their children during illness and
for a few weeks after recovery.
7.2.17 NATIONAL IODINE DEFICIENCY
DISORDERS CONTROL PROGRAM
N Kochupillai
The National Goiter Control Program (NGCP) was
initiated in the sixties. The program then had the objec-
tive of surveying goiter prone regions of the country for
prevalence of endemic goiter and initiating iodation of
salt, in areas found to be endemic for goiter.
Kochupillai et al using a filter paper, cord blood spot
based strategy, showed strikingly high incidence of
neonatal chemical hypothyroidism (NCH) of 100 per
thousand births (10%) in the Tarai districts of UP. Further
studies revealed, high prevalence of cretinous and
subcretinous levels of developmental damage to the brain
of children in these regions. These findings made the
government include salt iodation in the 20 point program
of the Prime Minister in 1984. Compulsory iodation of
edible salt was introduced in UP in 1987, which resulted
in remarkable decline in incidence of NCH after
successful salt iodation in UP. Subsequent studies
conducted under the aegies of ICMR in 14 randomly
selected districts of the country, showed that endemic
goiter was widely distributed in the whole of the country
and not restricted to the Himalayan belt. Thereupon, the
Central Council for Health, approved a national policy
of universal iodation of edible salt all over India, to
eradicate nutritional iodine deficiency and related mental
retardation in the country.
The IDD control program has three components:
1. Initial survey to identify endemic areas.
2. Supply of iodized salt to the identified areas.
3. Resurvey after 5 years of continuous supply of
iodized salt to assess impact of the measures.
The district administration has been given the
responsibility of advocacy, policy implementation and
monitoring. A goiter control cell in the Salt Commis-
sioner’s organization monitors the operations of
production of iodized salt, its quality and distribution.
BIBLIOGRAPHY
1. Epidemiological survey of endemic goiter and endemic
cretinism. An ICMR TOSA force study. ICMR Publication
1989.
2. Kochupillai N, Godbole MM, Pandav CS, Karmarkar
MG, Ahuja MMS. Int Jr Med Res 1984;80:293–99.
3. Kochupillai N, Pandav CS, Godbole MM, Mehta M,
Ahuja MMS: Bull WHO 1986;64:547–51.

7.2.18 NATIONAL SCHOOL HEALTH
PROGRAM
BNS Walia
A beginning was made on this program in 1996 by
undertaking examination of school pupils, by camp
approach during 3 days on two consecutive months every
year. Doctors, dentists, teachers and paramedical workers
from the state health services were deployed for the
purpose. Students requiring specific interventions were
referred to nearby dispensaries/hospitals for treatment.
The program could be made more efficient by better
record keeping, and follow-up; by local area health
workers to ensure that the diseases/disabilities detected
during school health examinations, receive due medical
attention.
7.2.19 NATIONAL CANCER CONTROL
PROGRAM
BNS Walia
This program was initiated in 1985, with the main
objectives of:
• Prevention of tobacco related cancer.
• Prevention of cancer of uterine cervix.
• Strengthening of diagnostic and treatment equipment
for cancer at medical colleges and major hospitals.
Many regional cancer hospitals have been opened.
IEC activities emphasize on avoiding the chewing of
tobacco, pan masala and, self-palpation of breasts and
reporting to nearest dispensary for examination, in case
of symptoms referable to reproductive tract.
7.2.20 NATIONAL MENTAL HEALTH
PROGRAM (NMHP)
BNS Walia
It was launched during the 7th five-year plan, with a
small financial outlay. Not much was accomplished. The
objective of program included:
• Provision of mental health services at district level.
• Improvement of facilities in mental hospitals.
• Training of trainers of PHC personnel in mental
health.
• Program for substance use disorders.
Community Pediatrics 211
7.2.21 NATIONAL PROGRAM FOR
CONTROL OF BLINDNESS
BNS Walia
The first organized efforts to control blindness at national
level commenced with the launching of National
Program for Trachoma Control (NPTC) in 1963. A
meeting of Central Council of Health and Family Welfare
held in 1975 resolved that “one of the basic human rights
was the right to see and therefore, it had to be ensured
that no citizen goes blind”. Following this the NPTC was
renamed as the National Program for Prevention of
Visual Impairment and Control of Blindness in 1976.
Objectives of the Program
The strategy evolved for prevention of control of
blindness included:
• Dissemination of information about eye care.
• Augmentation of ophthalmic services so that eye care
is promptly availed off.
• Establishment of a permanent infrastructure of
community oriented eye health care.
Management
National Blindness Control Program is cent percent
centrally sponsored program. Organizational structure
of the National Program consists of:
i. National Program Management Cell.
ii. State Program Cells.
iii. District Blindness Control Society looking after the
work in district exists in few districts at present
but is expected to be set up in all districts.
The National level cell is managed by the Directorate
General of Health Services, Ministry of Health and
Family Welfare. It was two divisions. The Technical
Division is headed by Deputy Director General (DDG)
and the Administrative division is headed by an
Additional Secretary level officer. At the State level, State
Program Officer is supervised by the State Director of
Health Services under the overall charge of the State
Health Secretary.
The State Central Mobile Units allocated to
Ophthalmology Departments of Medical Colleges, report
to the Director of Medical Education. The training of
paramedical ophthalmic assistants is carried out in
designated medical colleges.
212 IAP Textbook of Pediatrics
The District Blindness Control Society is formed
as per society registration act. It is headed by the
Dy. Commissioner. It coordinates the work of blindness
control in the district.
Achievements
At the tertiary level, regional institutes of ophthalmo-
logy and the apex institute, i.e. Dr RP Center for
Ophthalmic Sciences, at New Delhi, have been estab-
lished. Many medical colleges have been upgraded and
designated as training centers for paramedical
ophthalmic assistants. Eye banks have been set up in
government and nongovernmental sector.
At secondary level, district hospitals have been equip-
ped for ophthalmic services by providing ophthalmic
7.3 Community Newborn Care
IMPORTANCE OF NEWBORN CARE IN INDIA
The Infant Mortality Rate is a sensitive indicator of socio
economic development of a country. IMR has two distinct
components viz. the neonatal mortality (deaths during
first month of life) and postneonatal mortality (deaths
from 1 month up to 12 months of life). Most of the decline
in IMR has been due to reduction in the postneonatal
mortality. This has been possible because of success of
programs like Universal Immunization Program, control
of deaths due to diarrhoeal diseases and acute respiratory
infections (pneumonia). After impressive reductions in
1970 and 80s, the decline in IMR has not been very
noticeable. This is a cause for concern. For further
reduction in IMR measures to reduce neonatal mortality
must be undertaken in a big way.
India faces the biggest newborn health challenge
of any country in the world.
Of the total global burden, India has:
20% of total births
30% of total neonatal deaths
40% of still births
40% of low birth weight infants
25 of maternal deaths
This is the highest for any country in the world.
In India, 260 lakh babies are born every year of which
equipment and manpower. District Blindness Control
Societies have successfully implemented projects in the
pilot districts, in which they had set up.
At the primary level, the services are provided by
the primary health centers equipped with ophthalmic
equipment and posting of paramedical ophthalmic
assistants.
There has been a sustained rise in the cataract
operations and IOL implantation.
Resources
The program has been receiving assistance from Danish
International Development Agency (DANIDA), the
World Bank and the Overseas Development Adminis-
tration of UK.
Shashi N Vani
12 lakhs die within first four weeks of life. It is estimated
that one newborn dies every two minutes in India. Of
the total births in India about 30% are low birth weight
babies. Amongst the low birth weight babies in India,
2/ are full term but small for date babies, majority of
3
whom can be saved by simple measures. Remaining 1/3
are preterm babies and many of whom will need special
and intensive care.
ESSENTIAL NEWBORN CARE AND
NATIONAL HEALTH PROGRAMS OF INDIA
Newborn health was recognized as priority in the early
1990s. For the first time in India, it was introduced in the
National health program as a part of CSSM (Safe
Motherhood and Child Survival) program in 1992 at the
conclusion of UIP (Universal Immunization Program).
It was continued as a part of RCH (Reproductive and
Child Health) program. Since 1997, Government of India
has also incorporated Newborn care into India’s
adaptation of Integrated Management of Childhood
Illnesses (IMNCI training program) which devoted 50%
of overall training time to the care of newborn and young
infants. Its implementation strategy incorporates home
visits for preventive and promotive newborn care by
AWWs and ANMs. Neonatal health is recognized as the

key to child survival in the RCH program phase II (2005
to 2010).
Through RCH II and IMNCI a lot of efforts are being
made to improve newborn care at community level along
with the care at institution level.
SPECIAL ISSUES OF NEWBORN HEALTH IN INDIA
• Majority of newborns are delivered at home and often
by untrained traditional birth attendants (> 60%).
• There is wide state to state variation in neonatal
mortality rates and the related parameters. Kerala has
NMR as low as 10 whereas Orissa has NMR of around
70.
• There are many other inequalities also in terms of
Urban Rural mortality rates, rich and poor mortality
rates, facilities available for the newborn care in terms
of quality and quantity, rate of institutional deliveries
and availability of skilled and properly equipped
attendants at the time of birth.
• Incidence of Low Birth Weight babies is very high in
India. Low birth weight babies constitute 75% of
neonatal mortality and 50% of total infant mortality.
• A lot of traditional and cultural practices of newborn
care are prevalent in our country influencing neonatal
survival in several aspects (beneficial, harmful as well
as harmless practices).
• Within the neonatal period, 2/3 of deaths occur
during the first week of life, especially in first hour
and day of life.
• Leading cause of neonatal mortality are sepsis
(bacterial infections causing septicemia, pneumonia
and meningitis), births asphyxia and prematurity.
First week deaths are mostly caused by asphyxia and
prematurity. Thereafter sepsis is the leading cause.
• Other important adverse factors contributing to poor
neonatal outcome include poor nutrition and health
status of mothers and the future mothers (girl child
and adolescent girls) and lack of proper care during
pregnancy, childbirth and thereafter.
LEVEL OF NEWBORN CARE
Basic Care (Level I)
Almost 80 to 85% of neonates in our community require
only simple basic care which includes clean and safe
delivery by a skilled and properly equipped birth
attendant, basic resuscitation including drying,
Community Pediatrics 213
positioning, suction of mouth and nose if secretions are
present and even use of bag and mask for positive
pressure ventilation, measures to provide adequate
warmth and maintain warm chain, early and exclusive
breast feeding for first six months of life, infection
prevention measures like strict hand washing before
handling the neonate, aspective cord care, eye care, etc.
and management of minor problems. All these are
included in essential newborn care. This level of care can
be offered in health care facility including PHC, CHC,
FRU and other hospitals and also at home. All the
functionaries with proper orientation and simple skills can
offer this level of care. Mothers can also offer this level of
care with the support from AWWs and ANMs of their area.
Special Care (Level II)
About 10 to 12% of newborns require special care in the
form of oxygen therapy, advanced neonatal resuscitation
including endotracheal intubation, intravenous fluids,
medications including antibiotics, phototherapy,
exchange transfusion, close supervision and monitoring
in a hospital. Such care is possible in district level
hospitals as well as medical college hospitals and private
centres of pediatricians. These level II are centers are
necessary to take care of majority of referrals from level I.
Intensive Care (Level III)
Only about 3 to 5% of newborns require highly sophisti-
cated, technology dependant intensive care including
continuous electronic monitoring, mechanical ventila-
tion, arterial blood gases and such investigative facilities.
Specially trained neonatologists and nurses offer such
care in selected centers.
SOME SPECIAL ASPECTS OF COMMUNITY
NEWBORN CARE IN INDIA
The Problem of Low Birth Weight Babies
Irrespective of primary causes of deaths, over 2/3 of
neonatal deaths occur among babies born with birth
weight < 2500 grams, i.e. LBW babies. As mentioned
earlier incidence of LBW babies in India is the highest in
the world. There are several sociocultural reasons apart
from medical reasons for such high incidence of LBW
babies. They include poor nutritional status of women
in general and pregnant and lactating mothers in
particular, hypertension, anemia, malaria, other chronic
214 IAP Textbook of Pediatrics
infections like tuberculosis, tobacco abuse, poverty,
illiteracy, pregnancy at a very young age, short inter
pregnancy intervals poor antenatal care, lack of rest, etc.
All these need to be addressed in the programs related
to care of newborn in community.
A few simple interventions are very useful for the
care of LBW infants in resource constraint areas.
Kangaroo Mother Care (KMC) is one such important
method. Stabilized Low Birth Weight babies are
undressed fully except diapers, cap, socks and mittens
and put directly with their abdomen on mother’s chest
so that direct skin to skin contact is achieved. The baby
gets adequate warmth from mother and also has better
weight gain because of augmented breast feeding. Baby
feels much secure and has steady heart rate and
respirations. Incidence of acquired infections, hypogly-
cemia and apneic attacks is much less. Thus KMC has
several advantages and is a comprehensive method of
care of LBW babies in community. With some training,
community health workers have found it very useful for
the care of weak, low birth weight babies. KMC has been
found useful in the care of very sick babies in intensive
care set up in developed countries also. Other family
members can also support the mother in giving KMC to
baby. Through RCH and IMNCI program KMC training
has been taken up in a big way and is being easily
accepted by mothers, family members as well as
community workers.
Feeding Low Birth Weight Babies with
Expressed Breast Milk from Mother
This is another simple and useful modality of rearing
these weak babies in our community. This training is
also given to the community workers. In summary, care
of the newborn in community is gradually gaining its
due importance in national health programs like RCH
phase II and IMNCI in our country. The main objective
is to achieve NMR of < 20 by the year 2010 as against
the current national average level of 38 and help achieve
IMR < 30 by year 2010, the Millennium Development
Goal.
It is proposed to improve the knowledge and skills
of all the levels of health care functionaries involved in
newborn care in our country and also to achieve change
in behavior and practices of the community members
for better standards of newborn care.
THRUST AREAS IN NATIONAL PROGRAMS
Care of the Girl Child
• Improve nutrition
• Vaccinations
• Education
• Respect in the family without any gender discrimi-
nation
• Discourage selective female feticide and even neglect
of the girl child and infanticide.
Care of the Adolescent Girls
• Improve nutrition
• Prevention and control of anemia
• Attention to personal hygiene
• No early marriages, i.e. before the age of 18 years
• No motherhood before the age of 21 years.
Care during Pregnancy
• Good nutrition throughout pregnancy
• Early registration of pregnancy
• Regular ante natal check up, minimum of three (one
check up in each trimester) can be more also
• Prophylaxis for anemia and tetanus
• Detection of high risk and at risk pregnancies and
early start of management
• Preparing for institutional deliveries/skilled birth
attendant well in advance
• Birth preparedness with needed delivery kits, clean
linen, money, arrangement for vehicles for traveling
to hospitals in emergencies, prior information
regarding nearby referral hospitals.
Care during Delivery
• Prefer institutional deliveries
• One independent skilled attendant to take care of the
newborn immediately after birth
• Adopt five cleans at the time of delivery (clean hands,
clean surface, clean tie, clean cut and clean cord)
• Prompt resuscitation of the baby whenever required
• Early skin to skin contact and warm chain main-
tenance. Avoid early bath to baby
• Start breast feeding as early as possible preferably
within an hour of birth
• To take all the measures to prevent infections
including thorough hand washing and handling the
baby

• Examination of the baby and detection of congenital
defects requiring immediate attention
• Detection of high risk cases and primary management
and safe transferal when required to a higher center
of newborn care.
Care during Postnatal Period
• Warmth
• Proper breast feeding with correct technique
• Prevention of infections
• Early detection of danger signals like refusal to take
feeds, not doing well, cold to touch, abnormal look
and behavior suggesting convulsions, jaundice,
7.4 Under Five Clinics
One of the most encouraging signs of out times is the
awakening of the public to the needs and rights of
children. The year 1959 ushered in a new era in child
welfare. To meet the special needs of the child, United
Nations adopted on 20th November 1959, the
“Declaration of the Rights of Children”, the Government
of India adopted a National Policy for children in August
1974. The policy declares that:
“It shall be the aim of the state to provide adequate
services to children, both before and after birth and
through the period of growth, to ensure their full physical
mental and social development. These shall progressively
increase the scope of such services so that, within a
reasonable time all the children in the country enjoy
optimum conditions for their balanced growth”.
Under five mortality is an important indicator of the
quality of health care. The under five mortality rate has
reduced from 109.3 to 94.9 per 1000 live births. Similarly,
the neonatal mortality rate for India has declined from
48.6 to 43.1 per 1000 live births and the infant mortality
rate has declined from 78.5 to 70 per 1000 lives
births.However, the national goal of decreasing the infant
mortality rate to 60 per 1000 live births still remains to
be achieved. Hence, the importance of schemes like
Under Five Clinics in both the rural and urban areas-
more so, in the slums of the urban areas.
Community Pediatrics 215
cyanosis, pallor, umbilical infections, pustules
conjunctivitis, loose stools, etc.
• Suitable primary care
• Safe transferal when required to higher centers
• Vaccinations: BCG, zero dose oral polio vaccine and
wherever available Hepatitis “B”.
Care during Follow up
• Exclusive breast feeding for first six months
• Routing vaccinations as per national immunization
schedule
• Growth monitoring
• Neuro developmental and neuro sensory assessment.
Ajit Kumar
Children between 0-4 years constitute about 12.6
percent of the total population. Mortality in the age group
of 1 to 4 years is about 1 percent, the major causes being
preventable diseases like malnutrition, diarrhea,
dehydration, infectious diseases (like dephtheria,
measles, tuberculosis, pertussis, tetanus and polio) and
infestations.
For child growth care and development in the age
group of 0-5 years various strategies have been used,
singly or in combination for the betterment of their
health, nutritional status, psychological development and
also their education. A country’s future human resources
development is determined on the basis of the develop-
ment indices like infant mortality, morbidity, prevalence
of disability, living conditions and education of children,
especially the under fives.
WHAT ARE UNDER FIVE CLINICS?
Ensuring child health is an investment for the future. It
embraces various aspects of comprehensive child care
with emphasis on preventive, social and cultural aspects
of child life. Total child care in its own environment is
the concept of under five clinics. These clinics offer
curative, preventive and promotive health services
within the resources available involving nonprofessional
auxilaries, paramedical personnel, undergraduates,
216 IAP Textbook of Pediatrics
postgraduates. It is economical and reaches large number
of children in the community.
Under five clinics focus on the downward extension
of its services ot under five children and emphasizes early
identification of developmental delay in infants below
two years by Anganwaadi workers and organize
interventional programs by trained PHC medical staff.
The Under Five Clinic and ICDS programs are for the
people and by the people with the existing staff-both
medical and paramedical.
AIMS, OBJECTIVES AND SERVICES IN
UNDER FIVE CLINICS
Preventive Care
1. Immunization to cover 7 major preventable diseases
2. Nutritional services
3. Health care and treatment of illness
4. Oral rehydration in diarrheal and dehydration
5. Family planning—advocating small family size
6. Growth monitoring—road to health cards
7. Health education and guidance.
Curative Services
Early diagnosis and treatment of acute and chronic
diseases and disorders of growth and development and
minor investigations.
Referral Services
Early detection and referral to a hospital.
The services in Under Five Clinics are rendered by
the PHC health team. The aim is that the clinics should
be self generating, utilizing local resources. Clinics should
be run at minimum expenses. The main brunt of the
clinics in on ANM and the multipurpose workers in the
PHC.
WEEKLY UNDER FIVE CLINICS
Every child between 0-5 years in the area is registered
and given a weight card. Children have to be registered,
weighted, examined by a doctor, immunized nutrition
advice given and supplementary nutrition given.
Children are referred to the hospital whenever required.
IMMUNIZATION
This is to prevent and protect vulnerable children from
common preventable diseases like tuberculosis,
diphtheria, pertussis, tetanus, polio, hepatitis and
measles. Immunization schedule as recommended by
Indian Academy of Pediatrics should be followed.
NUTRITIONAL SERVICES
Nutrition is one of the major problems in developing
countries. Most of the children in pre-school age group
suffer from Protein Calorie Malnutrition—more of caloric
deficiency than protein. It was founded by ICMR that
on an average, a preschooler lacks about 300 calories a
day. This is not only due to poverty but also due to
ignorance, local beliefs, customs and taboos. It is essential
to educate the community in using locally available cheap
vegetable protein in their diets. A protein packet formula
was devised by National Institute of Nutrition to meet
the needs of the children. These protein packets contain:
1. Bengal gram or any cereal
2. Wheat or jawar
3. Groundnut or any pulses
4. Sugar or any pulses
It weights 70 grams and gives about 300 calories. The
inclusion of these locally available vegetable proteins
brings down the cost. The most important aspect of these
packets is that they not only cure mild to moderate cases
of PCM but also serve as a practical method of nutrition
education to the mothers in the community. ANM plays
a major role in nutrition education. Anemia, PCM, rickets,
Vitamin A deficiency and nutritional blindness are
common in the age group, hence can be corrected in
Under Five Clinics. Vitamin A can be given as prophy-
laxis. Health Checkups help in identifying “at risk”
children.
ORAL REHYDRATION
In developing countries a preschooler has at least 2 to 6
episodes of diarrhea in a year. Every episode leads to
dehydration and lowering of nutritional levels. The ANM
can teach the benefit of oral rehydration which helps in
the reduction of deaths due to dehydration.
FAMILY PLANNING
About 60 percent of malnutrition can be wiped out if the
family number is restricted to 2 children with a gap of
three years in successive pregnancies. This can be
impressed to the mother in the Under Five Clinics. It is
important to gain the confidence of the mothers for infant
survial if we have to embark on successful family
planning at a larger scale.

HEALTH EDUCATION
It is the involvement of mothers in all programs of the
Under Five Clinics that can help in better upbringing of
children with regard to prevention, early diagnosis,
treatment of malnutrition, correction of dehydration by
ORS, vitamin A supplementation and immunization to
protect children under the ages of five from the seven
most common and preventable diseases.
GROWTH MONITORING
Use of growth charts – “road to health” cards help in
identifying diseases in early stages, status of the child
regarding immunization, growth and nutritional levels.
Weight should be checked at monthly intervals during
first year, every two months during the second year and
every three months thereafter upto the age of 5 – 6 years.
The growth curve helps in early diagnosis of growth
failure and its etiology.
ENVIRONMENTAL SANITATION
Environmetal sanitation goes with the overall develop-
ment of the community which is important in total child
care. Good roads, clean drinking water, closed drainage
helps in proper growth of the child. Poverty,
substandard housing, overcrowding, inadequate water
sanitation and sewage disposal facilities and related
environmental risks and insecurity characteristic of a
slum has a great impact on the survival and quality of
life of the urban poor children especially below the five
years group. The lack of safe water and sanitation
facilities increases the risk of intestinal infections and
parasitic diseases among children under five. Acute
respiratory infections, gastroenteritis measles, PCM and
malaria are the five major causes of 70 percent of under
five mortality.
Community Pediatrics 217
ROLE OF UNDERGRADUATES IN
UNDER FIVE CLINICS
The doctor should be aware of the morbidity pattern and
local problems of children in a country. Medical students
should be exposed and made aware of the local disease
pattern to help in early diagnosis, referral and manage-
ment. Undergraduates can play a major role in the proper
upbringing and health education programs, immuni-
zation programmes and also ones related to personal
hygiene, deworming, vitamin a prophylaxis and
maintaining road to health charts. Undergraduates
during their posting in social and preventive medicine
and pediatrics should be exposed to various preventive
pediatric programs. The undergraduates can help in the
early diagnosis of malnutrition, dehydration and in
educating the mothers in the use of locally available
vegetable proteins, use of oral rehydration, supplemen-
tary nutrition, and importance of immunization and
monitoring of growth of the child.
CONCLUSION
Under five clinics can run within the existing resources
and hence should be established in all the PHC centers
in the country to bring down the high mortality and
morbidity in children. This indirectly helps in the
successful implementation of family planning programs
in our country as a security of the surviving children is a
prerequisite for smaller sized families.
BIBLIOGRAPHY
1. Health Care of Children, Under Five Voluntary Health
Association of India: New Delhi.
2. Mathur YC, Reddy YR. Social Pediatrics in Hyderabad.
The Bombay Hospital Journal 1973;15:55-57.
3. Mathur YC. Experience with weight charts at primary
health centers. Indian Pediatrics 1975;12:101.
4. Mathur YC. Under Five Clinics-Institute of Child Health.
Indian Pediatrics 1975;12.
5. National Family Health Survey-3, 2005-2006.
6. The State of the World Children 2008, UNICEF.
218 IAP Textbook of Pediatrics

7.5 The Girl Child

Shanti Ghosh

Sex ratio is a good indicator of the status of girls and In 1994, the Central Government passed the Prenatal
women in a society. According to the census of India Diagnostic Technique Regulation and Prevention of
2001, the sex ratio stands at 933, which is an improve- Misuse Act. This is referred to as the PNDT Act. The law
ment over the figure of 927 in the 1991 census. The has many loopholes. Government laboratories and clinics
country has witnessed an overall reduction in the sex are monitored much more closely than private labora-
ratio from 972 in 1901 to 933 in 2001. There are consi- tories and clinics. Genetics tests are monitored much
derable variations in the male to female ratio from one more closely than ultrasound tests. In spite of the ban
state to another. Kerala has a sex ratio of 1058, the highest imposed by the PNDT Act, many doctors continue to
in India. Changes in sex ratio in major states are communicate the sex of the fetus to parents. The Act has
summarized in Table 7.5.1. not had any impact on the spread of sex selective abor-
tions and this has become a socially accepted practice.
During the 1980s sex selective abortions spread to the
TABLE 7.5.1: Changes in sex ratio in states rural areas. It is estimated that more than 100,000 sex
year selective abortions are performed annually in India and
1991 2001 this may be an underestimate. This problem seems to be
more in Punjab, Haryana, Delhi and Maharashtra but is
Uttar Pradesh 938 898
prevalent in every part of India. Punjab has one of the
Bihar 1061 921
highest sex ratio at birth in the world. This may be related
Andhra Pradesh 985 978
to lack of women’s autonomy. Women tend to have more
Madhya Pradesh 972 920 autonomy in the South than in the North of India. The
Maharashtra 978 922 percentage of mothers undergoing ultrasound
West Bengal 945 934 examination or amniocentesis was 22 percent in Punjab,
Tamil Nadu 1044 986 19 percent in Haryana, 42 percent in Delhi and 31 percent
Rajasthan 905 922 in Maharashtra. This again may be an underestimate as
Karnataka 983 964 there are no reliable records.
Orissa 1037 972 Sex selective abortion is a two-step process involving
Jharkhand 1032 941 an initial determination of sex of the fetus followed by
abortion if the fetus is a female. Hoardings (Invest Rs
Punjab 832 874
500 now and save Rs 50,000 later), posters, and billboards
Gujarat 954 921
openly canvass for sex determination and abortion.
Kerala 1004 1058
The percentage of mothers undergoing ultrasound
Assam 919 932 examination or amniocentesis was 22 percent in Punjab,
Haryana 867 861 19 percent in Haryana, 42 percent in Delhi and 31 percent
Uttaranchal 936 964
in Maharashtra.
Chhattisgarh 985 990
Punjab (874), Haryana (861) have the worst sex ratio
Earlier data not available as the states were created only while Tamil Nadu (986), Chhattisgarh (990) and Kerala
recently.
(1058) are at the other end of the spectrum. The sex ratio
in the 0 to 6 age group, which was 945 in 1991, has
Of the 18 states mentioned above, sex ratio has declined to 927 in 2001.
deteriorated in 12 states. The maximum improvement is According to the 2001 census, there were 49 districts
in Kerala (1036 in 1991) and in Uttar Pradesh (876 in where for every 1000 male children aged 0 to 6 years
1991). there were less than 850 female children (Table 7.5.2).
 Community Pediatrics 219

TABLE 7.5.2: Sex ratio of population for all age groups and TABLE 7.5.3: Estimated death rates for
for 0-6 years age group 1981–2001 children 0-4 years old
Year Total Male Female
1981 1991 2001
All 0-6 All 0-6 All 0-6 India 22.5 21.0 24.1
ages years ages years ages years Andhra Pradesh 18.1 17.8 18.4
Bihar 22.9 21.2 24.8
All India 935 971 927 945 933 927
Gujarat 19.6 18.5 20.9
Himachal 973 971 976 951 970 897
Haryana 22.4 19.4 26.2
Pradesh
Himachal Pradesh 16.7 14.1 19.7
Haryana 870 902 865 879 861 820
Madhya Pradesh 32.6 31.6 33.7
Punjab 879 908 882 875 874 793
Maharashtra 12.7 11.2 14.3
Rajasthan 923 954 910 916 922 909
Orissa 29.0 28.7 29.4
Gujarat 942 947 934 928 921 878 Punjab 16.8 15.9 17.9
Maharashtra 937 956 934 945 922 917 Rajasthan 27.7 27.3 33.8
Uttar Pradesh 29.6 25.3 34.5
A majority of these districts were located in Punjab,
Haryana and Gujarat.
In a recently completed study in Mehsana district in TABLE 7.5.4: Mortality rates (1998-1999)
Gujarat and Kurukshetra district in Haryana, it was Male Female
observed that the last births had a stronger pre-
ponderance of boys than all other births. Among the Neonatal 50.7 44.6

women who belonged to upper castes, whose families
were landed and who were literate there were more than
246 males for every 100 girls in the last births. This was
obviously due to sex-selective abortions.
Infanticide too has been reported from some districts
in the past but there is no authentic report recently. One
reason for the declining sex ratio also appears to be the
paradox of development characterized by smaller family
size and culturally determined notions of sex preference.
A study conducted in Madhya Pradesh and Rajasthan
(Bhind and Morena district) revealed that out of a sex
ratio of 837 at birth, the sex ratio of existing children 0 to
6 years was 500.
Estimated death rates for children 0 to 4 years by sex
and residence according to sample registration scheme,
1998 are given in Table 7.5.3. Female rates are higher in
every state.
Mortality rates for females are higher from post-
neonatal period onwards (Table 7.5.4).
At birth, there is a feeling of being let down and
disappointment if the child is a girl. There are no beaming
relatives or friends. There is discrimination in various
ways—food, attention, new clothes, outings, etc.
Schooling is considered unnecessary for the girl as she is
supposed to occupy herself with household chores and
looking after the younger sibling. There is subtle
Postneonatal 24.2 26.6
Infant 74.8 71.1
Child 74.8 71.1
Under 5 mortality 97.9 105.2
discrimination even among the well off families mainly
about the quality of education, access to higher education
and taking up a profession, etc. The aim is to get the girl
married as soon as possible. A large number of girls get
married before the legal age at marriage.
The menace of dowry has increased tremendously
often leading to disharmony, cruelty and even death.
Demands go on for years after marriage.
Historically it would seem natural for the Vedic
Aryans to have a son preference because a pastoral
society of warriors needed men for protection of the race
and survival in a new country, yet Vedic literature does
not bemoan the birth of a girl child. In fact, special
mantras exist in the Rig Veda, the recitation of which is
supposed to lead to the birth of a girl child who will grow
up to be a learned lady. The position of the girl child
seems to have deteriorated after the first millennia,
especially in the North Indian states due to a change in
political equations. Early marriage, low status in
220 IAP Textbook of Pediatrics

marriage due to widespread polygamy and practice of
seclusion among upper class women became rampant.
Access to education was also limited. Though the
Constitution and a vast body of legislation has promoted
gender equality, the status of the girl child continues to
be low. One indication is the low sex ratio of women.
Even though literacy rates have increased substan-
tially, there is a vast difference between male (75.85) and
female (54.16) literacy. Kerala (90%) and Mizoram (88%)
have the highest literacy rates for women. Neither
education nor affluence have brought about any
significant change in the attitude towards the value of
women. In 1998-99, only 53.3 percent boys and 34.2
percent girls completed lower primary education, while
figures for upper primary were 35.6 percent and 19.7
percent respectively.
There are innumerable reports of trafficking in girls
for sexual activities, prostitution, etc. The unscrupulous
men (even women) and parents are partners in this crime
for sake of a little money.
It is a tragedy indeed that in a country where
innumerable goddesses are worshipped, the life of a girl
child today seems to be on discount.
BIBLIOGRAPHY
1. Census of India 2001.
2. Ghosh S. The girl child. Indian Pediatr 1986,23:120-22.
3. Jejeebhoy SG. Women’s autonomy in rural India: Its
dimensions, determinants and the influence of context
in fertility termination in South Asia. In Sathar ZA,
Phillips JF (Eds). Oxford, Oxford University Press, 2001.
4. Visaria L. Sex selective abortions in the States of Gujarat
and Haryana: Some Empirical Evidence. Health Watch
Trust, New Delhi, 2001.

7.6 Customs and Beliefs in Child Rearing

Anil Mokashi

INTRODUCTION 2. Infant feeding

Custom is something people do and belief is What they 3. Diseases: causes and treatment
think. We Know why a child falls sick and what to do if 4. Child rearing
he falls sick. The mother is not likely to know it. She will 5. Women’s health
believe the disease is caused by different reason. So she PRIME MESSAGES
wants to treat him in a way that her custom says. Unless
we teach her the right way of treating him, she is bound A. Encourage useful customs.
B. Allow harmless customs.
to follow a neighbor’s advice. It is important to know
C. Discourage harmful customs.
what people ‘think’ and ‘do’ for illnesses. The disease
have colloquial names. Unless you know them, you can EXPLANATION
not talk with the mother. So find out local names for the
diseases. Changing customs is more important as it A. Encourage Useful Customs
directly reflects on children. Changing beliefs is not so 1. For first pregnancy and delivery the pregnant lady
important. Some customs are useful, some are harmful, goes to her mother’s place where she gets adequate
while some are harmless. We should encourage useful diet, rest and attention.
customs; discourage harmful customs and allow 2. Rooming in of a mother and baby in an isolated
harmless ones. Here we will just enlist the customs. Every room avoids neonatal infections and helps
community has its own customs and you will have to developing the bond.
prepare your own list while trying to change what the 3. Honey and warm water is a natural way of relieving
mothers do. neonatal constipation.
Five groups of customs are particularly important for 4. Breast feeding till he is two years old bridges the
the health of children. ‘food gap’.
1. pregnancy and childbirth: delivery, newborn, cord 5. Soaked biscuits are used as a weaning food. Biscuits
and placenta. are available in every small village, are ready to feed

and very much socially acceptable they are hygienic
too.
6. When a child gets cold. Muscus is sucked out from
nose using a dropper or a cotton wick.
7. Warm milk with tamaring to cure sore throat.
8. Household medicines like tulas, honey, ginger,
lemon for common cold are much safer and useful
than antihistaminic, antibiotic and steroid drugs.
9. Honey, ghee, groundnuts are fed to ‘bring out
measles’.
10. An abscess is fomented with warm cloth.
11. Burnt bread is fed for poisoning.
12. Hand washing before eating is hygienic.
13. Feet washing by adults before entering the house is
good for infants crawling over the floor.
14. Naming ceremony on 12th day helps the child
identify with his name and develop personality.
15. Celebrations of the ‘naming ceremony’ are done in
6th month. It avoids handling, kissing by guests in
newborn period.
16. First food ceremony at the age of 6 months.
17. Oil Massage improves weight gain length, peri-
pheral blood flow, induces postmassage sleep,
prevents skin infection.,
18. Wrapping the baby to keep warm has reduced the
morbidity and mortality. Baby’s linen should be soft
cotton material with good absorptive properties.
B. Allow Harmless Customs
1. Burning or burying a placenta.
2. Fallen stump of umbilical cord is preserved for
religious purpose.
3. A religious garland of wooden sticks for jaundice.
4. A garlic garland for cough and cold.
5. Ear drops for otitis media.
6. Goat’s milk eye drops for conjunctivitis.
7. Human milk eye drops for conjunctivitis.
8. Ears are pricked with a religious ceremony; to cure
neck glands.
9. Religious ear pricking in Hindus.
10. Religious nose pricking in girls.
11. Religious circumcision in Muslims.
12. To prevent or cure ‘teething troubles’ a ‘copper
plate’ dental band is worn around neck; herb
‘dikamali’ is applied over gums, homeopathic
tablets are used in nearly every household.
13. Owa Water is fed or an adult blow air on child’s
abdomen after chewing ‘owa’ (cumin seeds) to cure
abdominal colic.
Community Pediatrics 221
14. Some (pimpli) herbs are boiled with milk to make
the milk more digestible.
15. To help the child with delayed speech development,
a guava, half eaten by a parrot is fed in a belief that
he will start talking like a ‘parrot’.
16. Milk is boiledin silver vessel with a golden ring in it
and fedas a brain tonic.
17. An abdominal binder for newborns is supposed to
protect their soft abdomen from ‘distending’.
18. The fifth female child in a row of females was named
‘Nakusa’ , meaning ‘unwanted’.
C. Discourage Harmful Customs
1. After birth the baby is in wet liquor, blood soaked
cloth, loosing heat, getting cold. It is wrong practice
to neglect her once she cries.
2. Child bathing soon after is a common practice,
leading to a significant drop in baby’s temperature.
After birth keep the baby at 28 to 30 degree room
temperature.
3. Newborn is given vigorous massage before bath. It
is unnecessary and may be harmful. Fractures are
reported.
4. A practice of fuming herbs over burning coal may
be harmful and invite respiratory irritation.
5. Fomenting a newborn with burning coal below his
bed in summer months is harmful.
6. Swollen breasts of a newborn are squeezed and
massaged to express the milk resulting in more
swelling and infection.
7. Umbilical cord is cut by using razor blade, Knife or
crush with stones. Ash, cowdung, blacksoil, woolen
tape is used as an applicant on the cord stump. All
these practices may lead to sepsis or tetanus.
8. Mother and baby are isolated in an ill-ventilated
darkroom.
9. Home delivery with the help of ‘experienced lady’
is a standard practice and hospital delivery is
considered as an ‘expensive fad’.
10. Oil is instilled in nose, ears, eyes, and anus in an
attempt to lubricate the machinery.
11. Kajal is rubbed ‘in’ the eyes.
12. Very hot water is used for bathing the baby.
13. Colostrum is thrown considering it harmful.
14. First feed is not given till ‘milk flows’ It starves the
child and delays milk secretion. The prelacteal feeds
with honey, sugar water glucose water is given.
There is no need.
222 IAP Textbook of Pediatrics
15. Breast-feeding is discontinued if lactating mother
suffers from tuberculosis, typhoid or fever.
16. Night breast-feed is not allowed to prevent ‘colic’.
17. Undiluted milk is not given in first year as it is
supposed to cause ‘liver disease’ and glands in
child’s abdomen.
18. Milk is given in very dilute form to cure the infantile
constipation and to make it ‘digestibel’;resulting in
marasmus.
19. A whisky bottle or gripewater bottle with a dirty
nipple is used as a feeding bottle. It is most unhy-
gienic thing put in infant’s mouth.
20. Whenever the feeding bottle is offered. Its nipple is
wiped with pallu of the sari the lady wears.
21. A poor mother of a marasmic child purchases the
costly milk powder tin in good faith to make her
child strong and gives it in a very dilute form so
that tin lasts till next month’s salary day.
22. Three hourly feeding schedule adjusting the child
according to clock. He should be fed on demand.
23. Many mothers give one breast at one feeding on
advice of elderly experienced relative.
24. First food ceremony at 10 months of age. It is too
later for weaning.
25. Mother stop breast feeding after 5-10 minutes in an
attempt to avoid sore nipples.
26. Child is not given food till he eats with his hands.
27. Removing muddus: Back of a marasmic child is
rubbed. The hair gets rolled with the dirt. When this
rolled hair is put in water it gets unwind and moves
in water. This is explained as removing of ‘Muddus’
a colloquial name for Rickets.
28. An abscess is covered with oil, beetle-nut leaf or
tamarind.
29. Teething is considered to cause many illnesses.
People do self mediation and overdose of
vitamin D, Doctors advice. Vitamin D when mother
asks for a medicine.
30. Self medication with dangerous drugs, Balguti and
lead poisoning.
31. Improper medication spoon. It should be a 5 ml
spoon.
32. Blind faith in injections.
33. Immunization is avoided for the fear of ‘fever’ gland’
at the site or getting polio.
34. Household things like saffron, cowdung, lime, ink
is applied on BCG scar.
35. Presuming at various sites for various illnesses are
caused by not able to digest the food, food is
withheld till the child is cured.
36. Branding at various sites for various illnesses is a
very popular custom. For convulsions they brand
on temples, breathlessness they brand on abdomen.
37. Blaming daughter-in-law’s diet for neonatal
problems and restricting her food intake is a very
popular practice.
38. Breast milk is withheld when infant gets ‘diarrhea’.
Many doctors overdiagnose breast-milk intolerance.
39. Vomiting and watery loose motions are managed
by with-holding water.
40. Anterior fontanel is covered with oil and beetle-nut
leaf, diverting attention from oral fluids in a child
with dehydration.
41. Purgatives are used to cure diarrhea, in an attempt
to cleanse the bowel.
42. A child on IV fluids is kept ‘nil by mouth’ may be
because in older days, doctors practiced ‘nil by
mouth for 1-2 days’.
43. A child with high fever is wrapped in wollens to
prevent ‘cold’.
44. A child with ‘measles’ is customarily not ‘taken to a
doctor’. The complications remain unattended and
take their toll.
45. Society demands injections for suppressing or
bringing out measles. May be because many doctors
‘provide’ placebo injections on demand.
46. Typhoid and jaundice are the disease that attract
strict food restrictions from the society. It might be
sometimes difficult to overcome the resistance to ‘eat
well’ eat small and eat frequent’ advice. A discussion
may bring out a long list of ‘allowed’ food items
that are nutritious. We should encourage the
‘allowed list’ than to discourage ‘not allowed’ list.
47. Hot foamentation is given to a child with measles
to ‘bring’ measles out’. He may get overheated,
dehydrated, even get skin burns in the process.
48. It is presumed that it is good for the child to ‘have
measles’. Many parents point out ‘failures of measles
vaccine’ as reason for not giving it.
49. Oily and fatty food items are prohibited as they are
supposed to cause cough and many illnesses.
50. Religious ceremony with sacrifice of animals,
money, food to cure a sick child diverts the attention
from real problem. The belief and custom continues

as many self limiting diseases get cured giving a
credit to the ceremony.
51. Wounds including operation wounds are des-
perately protected form water as it is supposed to
cause sepsis in the wound. The custom is universal
including educated and rich class. Important of
washing the wounds with soap and water prevent
sepsis needs to be informed to the society.
52. An abscess is allowed to burst by itself or punctured
by a sewing needle. People are afraid of incision and
drainage. They do not want to spend money. They
want home cure for abscess.
53. Boils are squeezed to express pus.
54. The wounds are covered with dirty cloth bandages.
Society is found of bandaging. In children, bandages
get soaked and become dirty and are a source of
infection.
55. A plethora of things are applied on wounds as a
home remedy. The harmful things include ink,
cowdung, saffron, tea powder, cow’s urine, human
urine, wet soil.
56. Warm belladona strip (adhesive) is applied over an
abscess in an attempt to ‘ripen’ it. It is supposed to
be all the treatment that is required.
57. Children, with primary complex are not allowed to
mix-up with ‘normal’ children. Their feeding
utensils are Kept’separate’. It is too much of the un-
necessary psychological strain for the child.
58. Frequent change of doctors for a child with
tuberculosis is harmful, as there is likelihood of
irregular medication and frequent change of drugs.
59. A fractured limb is massaged by a quack.
60. Vomiting is induced to bring out swallowed
kerosene.
61. Religious healers are popular for the cure of a snake
bite, scorpion bite or dog bite with ‘occassional’
disastrous results.
62. Unconcious or convulsing child is offered water as
an emergency treatment.
63. Opening of a lockjaw during convulsions receiveds
top priority unnecessarily, leaving other important
steps uncared for.
64. Eyes with foreign body, conjunctivitis are cleaned
by ‘experts’ with tongue!
65. Household medicines used as eye drops are
harmful. Kajal is harmful.
66. Hot oil is used as ear drops for questionable earache,
may lead to deafness.
Community Pediatrics 223
67. Hairpin is the most commonly used instrument to
remove wax from ears.
68. Leeches are allowed to suck ‘faulty blood’ from
edematous parts and enlarged spleen.
69. Edematous parts are branded with hot coins.
70. Seasonal fruits are blamed for causing seasonal
illnesses.
71. For child who is late is walking or has a limb para-
lysis, heavy silver or copper rings are used as
therapeutic ornaments.
72. Child is buried upto waist in waste-refuge to cure
pollomyelitis or paralysis.
73. In a sophisticated rich family an infant is wrapped
in clean, ironed long drawsheets in a neat bundle.
He looses the freedom and gets delayed physical
milestones as he is physically restrained from
developing!
74. Opium is used as a tranquilizer routinely, addicting
or killing him in the process.
75. Alcohol containing gripe-water is used as ‘child
sleeps well!’
76. Abdomen is massaged to cure his ‘Colic’
77. An infant who cries too much is declared by an
experienced lady to have a ‘Neck sprain.’ To remove
the sprain he is put in a cotton sling and revolved
around the operator. Or a sitting operator puts the
child prone on her extended legs. Fixes the head
between two great toes and stretches the cervical
vertebrae. It is an horrible sight to watch.
78. Primary teeth are never cleaned as a custom.
79. Tonics are used for weight gain as a deep rooted
custom.
80. Female children are neglected and discriminated at
all possible occassions.
81. Fallen stump of umbilical cord is preserved. It is
used as a medicine in the form of a paste when the
baby cries with ‘abdominal colic’ or gets ‘dental
problems’ or breathlessness.
82. A male child is reared with long hair and braids for
5 to 7 years till his first ‘mundan’ is done at a sacred
place in front of family deity. It creates identity crisis
and child has to face humiliating situations amongst
peers.
83. Very strict discipline for a child is harmful for his
psychological development.
84. Overprotection and pampering are customs run for
generations.
85. Severe punishment for minor mistakes to ‘teach him
lesson’ is harmful.
224 IAP Textbook of Pediatrics
86. Allowing him to have his way to avoid his temper
tantrums is a faulty child raring practice
87. Destructive behavior of a child is neglected
presuming that he will calm down as he grows up.
88. Hydrocele of a new born is massaged presuming
that his leg must have been pulled by the elder sib.
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1. Adair SM. Pacifier use in children: A review of recent
literature, pediatr. Dent 2003;25(5):449-58.
2. Aggarwal KN, Gopta A, Pushakaran R, Bhargava SK,
Faridi MM, Prabhu MK. Effect of massage and use of oil
on growth, blood flow, sleep pattern in infants. Acta Ped
2002;91(5):546-54.
3. Ahamad FU, Rahaman ME, Alam MS. Prelacteal
feedings; Influencing factors and relationship to
establishment of Lactation. Bangladesh Med Res Counc
Bull 1996;22(2):60-64.
4. Ali AR, Smales OR, Aslam M. Surma and lead Poisoning.
Br Med J 1978;2(6142):915-16.
5. Bang AT, Bang RA, Baitule SB, Reddy MH, Deshmukh
MD. Effect of home based neonatal care and management
of sepsis on neonatal mortality:Field trial in rural India.
Lancet 1999;354(9194):1955-61.
6. Bennett J, Azhar N, Rahim F, Kamil S, Traverso H, Killgore
G, Boring J. Further observations on ghee as a risk factor
for neonatal tetanus. Int J Epidimol 1995; 24(3);243-47.
7. Charles V, Charlex Sx. Strong influence of tradition on
child rearing practices in India. trrop. Geogr Med 1979;
31(3):459-63
8. Darmstadt GL, Mao-Qiang M, Chie Saha SK, Ziboh V A,
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in developing countries. PMID: 12113324 (pubmed index
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Conjunctival and Lachrymal sac pigmentation by Kohl
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10. Iyenger SD, Bhakoo ON. Prevention of neonatal
hypothermia in villages.Roles of domiciliary care taker.
Acta Pediatr 1992;81(11):859-63.
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Two? Editorial Indian Pediatr 2001;38(4)327-31.
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delivery care on neonatal body temperature. Ind J Med
Res 2000;112:212-17.
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L Hoir, France Berend, Plotz. Risk of ancient practices in
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15. Katiyar GP, Agarwal DK, Tripathi AM, Agarwal KN.
Feeding practices in Varanasi district. Indian Pediatrics
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16. Kumari S, Saili A, Jain S, Bhargava U, Gandhi G, Seth P.
Maternal Attitude Practices in initiation of newborn
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7.7 International Agencies and Child Health
7.7.1 WORLD HEALTH ORGANIZATION (WHO)
• It is a specialized, nonpolitical, health agency of the
United Nations, with headquarters in Geneva.
• 7th April is celebrated every year as “World Health
Day”.
• A world health day theme is chosen every year to
focus attention on an aspect of public health.
Objectives
The objective of WHO is “the attainment by all the
peoples of the highest level of health” which is set out in
the preamble of the constitution. The current objective
of WHO is “the attainment by all people of the world by
the year 2000 AD of a level of health that will permit
them to lead a socially and economically productive life
also known as “Health for all by 2000 AD.” The preamble
of the constitution states: “Health is a state of complete
physical, mental and social wellbeing, and not merely
the absence of disease or infirmity. The enjoyment of the
highest attainable standard of health is one of the
fundamental rights of every human being without being
discriminated on the basis of race, religion, political belief,
economic and social condition.
The health of all people is fundamental to the attain-
ment of peace and security and is dependent upon the
fullest cooperation of individuals and states.
The achievement of any state in the promotion and
protection of health is of a value to all. Unequal develop-
ment in different countries in the promotion of health
and control of diseases, especially communicable
diseases, is a common danger. Healthy development of
a child is of basic importance. The ability to live
harmoniously in a changing total environment is
essential to such development.
The extension of the benefits of medical, psychological
and related knowledge to all people, is essential for the
fullest attainment of health. Informed opinion and active
cooperation on the part of the public are of the utmost
importance, in the improvement of the health of the
people. Government has the responsibility for the health
of its people, which can be fulfilled, only by the provision
of adequate health and social measures.”
Community Pediatrics 225
Shashi N Vani
The WHO is unique among the unspecialized agen-
cies in that it has its own constitution, own governing
bodies, own membership and own budget. It is part of,
but not a subordinate to the United Nations.
7.7.2 UNICEF (UNITED NATIONS INTERNATIONAL
CHILDREN’S EMERGENCY FUND)
UNICEF is one of the specialized agencies of the United
Nations, established in 1946. In 1953, the general assembly
gave it a new name, “UN Children's Fund” but retained
the initials, UNICEF. In the early years, UNICEF and
WHO worked together on urgent problems such as
malaria, tuberculosis and venereal diseases. Later it
covered such fields as maternal and child health,
nutrition, environmental sanitation, health centers and
health education and programs which would directly, or
indirectly benefit child's health.
Greater attention is being given to the concept of the
“Whole Child”, meaning that assistance should
henceforth be geared not only to health and nutrition,
but also to their long-term personnel development and
to the development of the countries in which they live.
Content of Services
a. Child health
b. Child nutrition
c. Family and child welfare
d. Education formal and nonformal
In short, UNICEF activities cover programs assisting
in child survival, protection and development; inter-
ventions like immunization, improved infant feeding
practices, child growth monitoring, home- based diarrhea
management, drinking water, environmental sanitation,
birth spacing, education of girls and income generating
activities for women.
Promotion of ORS in diarrhea, family planning, safe
motherhood, awareness of the means to prevent AIDS
amongst youth and health workers, access to correct ARI
cases at all health care centers.
Nutrition
• Reduction of severe and moderate malnutrition.
226 IAP Textbook of Pediatrics
• Vitamin A prophylaxis
• Iodisation of salt in totality, for human consump-
tion
• Exclusive breastfeeding up to four months of age and
eighty percent of hospitals becoming “Baby
Friendly”.
Water and sanitation Provision of safe and clean drin-
king water and sanitary disposl of excreta. Eradication
of guinea worm disease.
Education Providing primary education to all children.
Child labor Reduction and elimination of child labor
and provision for their welfare and education.
Endorsement of the convention on the rights of the
child.
Care of the girl child Eliminating female foeticide, and
infanticide, reducing early age of marriage, and ensuring
that girls go to school.
7.8 Adoption and Care of Orphans
DEFINITION
Adoption is essentially a social process by which the
reciprocal need of childless parents and an orphan (or
parent—deprived) child is satisfied. Legally it may be
defined as “Transfer of rights and responsibilities
concerning the child from biological or birth parents to
the adoptive parents irrevocably”.
Adoption is also an instrument through which one
can ensure the following important children’s rights
accepted by the United Nations, Convention of Rights
of Children and the world community at large. These
are:
1. Inherent right to life survival and development,
2. Right to name and nationality
3. Child’s interest being always a primary consideration
4. Special protection from physical harm and neglect,
5. No discrimination through universal brotherhood,
6. Social security through education, employment and
earning, and
BIBLIOGRAPHY
1. Arneil GC: Pediatrics Education around the world.
International Child Health 1997;1:29.
2. Forfar's Textbook of Pediatrics (3rd ed), 1984.
3. Manual for orientation of ANM and supervisors—
Reproductive and Child Health Dept. of Family Welfare,
Ministry of Health and Family Welfare GOI, 1996.
4. Modules of CSSM MCH division, Ministry of Health and
Family welfare, 1994.
5. Monograph on Integrated Training on National Pro-
grammes for Mother and Child Development CTC-ICDS,
Dept of Women and Child Development GOI, 1990.
6. National plan of Action, A commitment to the child.
Dept. of Women and child Development GOI, 1992.
7. Nelson Textbook of Pediatrics, (14th ed), 1991.
8. Park's Textbook of Preventive and Social Medicine (14th
ed) 1994.
9. Polany L: Manual of Community Pediatrics (2nd ed),
1996.
10. The Progress of Indian States, UNICEF, 1997.
11. The Progress of Nations, UNICEF, 1997.
12. The State of World's Children UNICEF, 1997.
RD Potdar
7. Special attention to disabled children.
Considering the above definition and objectives,
adoptions could be divided into various types like intra-
family adoptions, single parent adoptions, adoption of
older children, adoption of disabled or “Special needs”
children and intercountry adoptions.
Whatever the type it is always prudent not to do it
secretly (by feigning pregnancy) but do it properly within
the law of the country. Since the emotional, psycho-
logical, social and legal consequences of adoption are far
reaching in nature it must be conducted in a very open
and supportive environment. Parents should be strongly
advised not to arrange private or secret adoptions
through hospitals and medical practitioners directly.
Adoption must always be done through an institute
which has been recognised as a “Fit Person Institute” by
the Central Government. In all states of India there are
many orphanages and adoption agencies recognized in
this manner.

Laws
In India, two laws govern the process of adoption. First,
”The Hindu Adoption and Maintenance Act 1956”
governs all Hindus adopting children and the second,
”The Guardians and Wards Act of 1890” governing
adoptions by parents who are not Hindus by religion. In
intercountry adoptions children are given for adoption
under the ”The Guardians and Wards Act of 1890” in
foster care till they are finally adopted according to the
law of the country of adoptive parents.
Every doctor should be conversant with the process
of adoption, be able to and should advise any prospective
adoptive parents on all aspects of adoption. The doctor
can help in all the following standard steps of adoption
process always using sympathy and empathy at all
stages.
Making up a Decision to Adopt
“Childless couples who are involuntarily childless have
a desire for parenthood combined with complex set of
emotions ranging from guilt of infertility to apprehen-
sions to fears related to the social status, family accep-
tance and reactions of decision to adopt, unforeseen
elements of taking home a child-borne by parents not
known and their own capabilities regarding coping up
with a new challenge in life.
Preparation for Adoption
Preparation for adoption, mentally, physically, procedure
and documentwise: The ideal age difference between at
least one parent and the baby to be adoptive should be
not more than forty years so that they have enough time
and physical strength on their side to look after the baby
till it becomes a young adult and legally a major. Parents
should be equipped with the following documents viz.
marriage certificate, proof of age, income certificate and
bank balance and property certificates (if any), Doctor’s
certificate regarding their health and also their infertility
status, references and photographs when they go to apply
for a baby for adoption.
Preadoption Counseling and
Home Study Preparation
This is done by the social worker of the agency and
consists of social and family background of both parents,
current marital and family relationships, attitudes and
Community Pediatrics 227
motivation towards infertility, childlessness and adop-
tion, anxieties regarding child’s illegitimacy, social and
genetic background, sharing the fact of adoption with
family and the child, parenting experience, aspirations
and financial capabilities, recommendations of their
friends and referees.
Choosing a Child, Medical Screening and Certifying
the “Fit for Adoption” Report
While it is true that “Choosing” can imply a bias of an
arbitrary and discriminatory selection or rejection, in the
Indian context it should be left to the social worker to
place a child who is near compatible to adoptive parents
in looks, color of the eyes and complexion. This is likely
to ensure better adjustment and integration of the baby
in the new family and society.
While doing the medical screening for fitness the
doctor should remember that this baby should be
examined and certified fit, normal or otherwise in the
context of the situational background that the baby may
have suffered physical, nutritional and emotional
deprivation in the recent past.
Clinical examination consists of identification data,
anthropometry, systemic examination, detection of any
gross deficiency disorders and overt or covert anomalies
and their correctability potential, clinical clues to
metabolic disorders if observed and physical and mental
milestones evaluation. Standard investigations which are
expected to be done are, hemogram, urinalysis,
tuberculin test, X-ray chest, stool examination for
parasites, tests for VDRL, HIV, Hepatitis B,TORCH titers
and any other indicated tests with special reference to
hypothyroidism, hemolytic anemia, chromosomal
anomalies, and metabolic screening tests for mental
retardation like phenylketonuria, galactosemia,
aminoaciduria, etc.
The entire exercise should be a balanced one to ensure
welfare and maintain interest of both the baby and the
adoptive parents with a little more tilt towards child’s
interest since the child is a totally dependent being.
Medical Care of the Orphans and
Adopted Babies
Vast majority of orphans who go for adoption after one
month of their age and those who were not abandoned
immediately after a hospital delivery are highly vulner-
able to sepsis, malnutrition, frequent attacks of acute
228 IAP Textbook of Pediatrics
respiratory and gastrointestinal and skin infections. They
may be frankly marasmic and lack immunity increasing
the incidence of morbidity and mortality amongst them.
In the management of sick orphans three actions are of
utmost importance. First is Immunization against
Hepatitis B in addition to standard schedule, second is
the Urgency of action when even slightly sick and the
third is Early use of higher antibiotics even if prima facie it
may appear an irrational and expensive proposition. By
introducing simple inputs such as IV fluids, oxygen
therapy and higher antibiotic therapy in the Orphanage
itself prior to transferring to a big hospital a large number
of such babies can be saved. Apart from this the care of
orphans and adopted babies should be like any other
normal baby.
In postadoption care, in addition to problems of
general health and standard immunization schedule, an
extra eye should be kept on feeding and sleep patterns,
motor development pattern, speech and language
development which may appear delayed for some time
initially. Advice of patience and perseverance is usually
very rewarding in most cases.
Follow-up and Postadoption Counseling
Follow-up after adoption is necessary for advice and care
in the following crisis situations which are likely to arise
in some of the babies:
1. Sudden change crises, where the baby may (and
parents) may take long time to cope up with the
suddenness of change in environment, climate, living
conditions, language, noise level, food styles and
surrounding strange faces resulting into different
types of reactions like anxiety, rejection or aggression
or any combinations of these.
2. Behavior crisis is likely manifest after first few years
and may be as a result of pampering and overpro-
tection (or even a covert rejection) by one or both
parents and other family members. There may be a
considerable delay in detection and management of
likely behavior problems due to the unwillingness of
the parents to seek interventions by adopting an
attitude of “keeping all in the family”. Such problems
may become worse in adolescence if not tackled
earlier.
3. Communication and identity crisis may come up at any
age if the child’s sense of security is not well ensured
by the parents and immediate family members. This
problem is more likely to come up in intercountry
adoptions because of the obvious difference in skin
color.
4. Crisis of assimilation is likely to occur in intercountry
adoptions in a small number of cases where the young
adults may face discrimination in getting jobs,
married, etc.
Every doctor must be aware of these problems and
be able to either counsel the family himself or convince
and refer them to the appropriate agencies.
Encouraging, Insisting and Helping the Parents
Encouraging, insisting and helping the parents to tell the
child about his or her adoption is most vital postadoptive
follow-up actions. Every child who is adopted must be
told that he or she is adopted by the parents themselves
howsoever it may appear difficult for them. When a child
comes to know the fact from sources other than his
parents, it can cause such a severe trauma (of betrayal or
breach of trust) that it might even ruin relations between
the parents and the child forever totally defeating the
very objective for which the adoption was undertaken
in the first place. Later the age of the child when the
trauma happens, worse are the consequences for the
parents. It is therefore necessary and appropriate to
encourage all adoptive parents to tell the child as early
in life as possible when the child can comprehend the
concept of biological and adoptive parenthood. If done
between the ages of six to ten years most children take
into their stride and future problems can be averted.
8.1. Child Abuse and Neglect: Meenakshi N Mehta ................................................................................................................................... 230
8.2. Child Labor: Meenakshi N Mehta, SR Banerjee .................................................................................................................................... 244
230 IAP Textbook of Pediatrics
8.1 Child Abuse and Neglect
We are guilty of many errors and many faults
But our worst crime is abandoning the children
Neglecting the fountain of life,
Many of the things we need can wait
The child cannot.
Right now, is the time his bones are being formed
His blood is being made and
His senses are being developed
To him, we cannot answer
‘Tomorrow’ as his name is ‘Today’
Gabriala Mistral
[Noble Laureate poet, Chile]
India may be feeling proud with its booming economy,
decreasing IMR and birth rate and increasing life
expectancy. All these prevent death, but not necessarily
improve the quality of life, particularly those of infants
and children. Similarly the new medical interventions
and better diagnostic techniques although have brought
about reduction in mortality the morbidity rates are high
and continue to rise. As per 2006 year’s UNDP Human
Development Report, India has misplaced priorities, i.e.
Indian Government spends on defence almost same as
that on education and more than double on health. Even,
when government does allocate funds, there is no
guarantee that it reaches the intended beneficiaries, the
health and education benefits do not percolate down to
the most needy and the poor. As per the last NFHS –
Survey [NFHS-3-2006], only 35% of men and 22% of
women complete 10 years of education; percentage of
malnourished children was 46%, 38% were stunted and
44% were routinely immunized. Out of 35 million Indian
children only 46% girls and 66% boys complete education
in rural areas, while in urban India 44% girls and 20%
boys drop out of schools. We have largest number of
malnourished children, kids affected by AIDS, Street
children and children out of school. About 60 million
children are engaged in labor, around 12-15 million are
bonded workers and one third of the 60 million children
are employed in households, hotels, dhabas, eateries,
food joints, hostels, clubs, tea stalls, and spas despite the
government ban for employment of children under
Meenakshi N Mehta
14 years from october 2006. Our underprivileged children
are denied food, security, education shelter, health, even
right to live and social status and most important love
the feeling of being wanted. Contrary to India being
signatory to the Rights of Children, a sizable number of
our children from disadvantaged background suffer
quietly from deprivation, exploitation, and abuse. Child
abuse – physical, sexual, emotional or even economic is
an unconscionable crime. Regrettably, it is a bitter truth
that is rarely acknowledged in India.
Furthermore, children in all societies, in the process
of their normal upbringing are often neglected, mal-
treated, abused intentionally or otherwise by their
parents, guardians or caretakers. The norms of child
rearing differ culturally with wide differences between
conservative and advanced societies. Although child
abuse is not a new phenomenon it has been the subject
of serious concern during the recent years. Child abuse
and neglect is a significant community problem of
enormous gravity. However, the problem is more serious
in nations with economic restraints, chiefly because of
socioeconomic reasons and illiteracy. In addition children
living in especially difficult and endangered
circumstances such as street children, refugees, children
in armed conflicts and disabled children are particularly
vulnerable to abuse and exploitation. The sale, abduction
and trafficking of children across borders is increasing.
These children are at a very high risk of abuse and
need our attention yet there is no possible means of
prevention.
THE ISSUE
The forms and dynamics of child abuse have undergone
major changes in the new millennium, adding multi-
faceted dimensions, complexities and challenges. The
problem of child abuse and the web of its human rights
violation embrace some of the most critical aspects of
the worst forms of child exploitation and abuse on the
international human rights agenda. These complexities
include changing attitudes, social orientation, contexts
and regional dimensions of the problem.

CONCEPT, DEFINITION, NOMENCLATURE
Sir Henry Kempe suggested the term ‘Battered Baby
Syndrome’ for injuries resulting from child abuse. In 1962
the American Academy of Pediatrics used this to focus
the attention of physicians on unexplained fractures and
other manifestations of severe physical abuse of children.
Since then the definition of child abuse and neglect [CAN]
has been broadened to include any problem resulting from
lack of reasonable care and protection of child and
adolescents by their parents, guardians or caretakers.
There are varying views on the definitions of child abuse.
There are those who make a distinctive between ‘child
abuse’ and ‘child neglect’ and there are others who do
make such a distinction. All too often one finds such terms
as ‘child battering’, ’child neglect, ‘child abuse’, child
maltreatment’, and ‘physical abuse’ being used by
different authors to refer to the same or very similar
occurrence.
According to Patricia Howland, the distinction
between child abuse and neglect lies primarily in the
element of deliberateness. Child abuse connotes parents’
active and usually intentional behavior which causes
physical injury to the child, whereas child neglect refers
to passive indifference to the child and an inability to carry
out the expected roles of parenthood. A comprehensive
definition of child abuse and neglect was given by the
United States Congress when it declared that the term
child abuse and neglect includes, the physical and mental
injuries, sexual abuse and exploitation, negligent
treatment or maltreatment of child under the age of
eighteen or the age specified by the child protection law of
the state in question, by a person {including any employee
of a residential facility or any staff person providing out
of home care} who is responsible for the child’s health or
welfare is harmed or threatened thereby, as determined in
accordance with regulations prescribed by the secretary.
In the broad sense most researchers and authorities agree
on the basic issue of child abuse resulting from parental
misuse or exploitation of the rights of parents and other
guardians to control and discipline children under their
care and which are detrimental to the child’s health and
well-being.
Today ‘child abuse’ does not only refer to physical
abuse, sexual abuse and trafficking; it adds many
dimensions of violation of basic human rights of a child.
It is an outcome of a set of interrelated, familial, social,
Child Abuse, Neglect and Child Labor 231
psychological and economic factors. These factors and
processes create a complex nexus between exploitation,
neglect and abuse as part of the larger perspective of
violation of child rights.
Other terms suggested for child abuse are ‘Silverman’s
syndrome,’ ‘illegitimate child syndrome,’ ‘Parental
dysfuntion,’ etc. A new term ‘Nonaccidental injury,’ [NAI],
and child maltreatment, intentional or otherwise is now
well recognized.
EPIDEMIOLOGY AND INCIDENCE
In the developed countries of the west, the incidence of the
battered child ranged from 250 to 300 cases reported per
1 million populations. In its 2008 report, the state of
world’s children, United Nations Children Fund [UNICEF]
has estimated that about 100 million children around the
world are forced to live wholly or partially on the streets,
although reliable figures are particularly impossible to
calculate. Many such children are among the 300 million
who are subjected to exploitation, violence, and abuse
around the world. Most street children were found in poor
countries in Africa, Asia, Latin America and the Middle
East and also in parts of Eastern Europe and former Soviet
Union; although the actual number of street children in
each region is unknown. The problem can be judged from
social indicators such as primary education, school
enrollment and prevalence of child labour; compared to
SubSaharan Africa where 40% of girls and 36% of boys
are not enrolled in primary education, and 35% of children
between 5 to 14 years are drafted into labour force, partly
or wholly, in South Asia the corresponding figures are 9%
of girls, 16% of boys and 13% of children are obliged to
work.
In India the first case of battered baby syndrome was
described in 1967, and subsequently sporadic cases have
been reported in Indian literature. Moreover, till recently
there used to be lack of general awareness of CAN in its
wider perspective. For all practical purposes, it did not
exist except for scattered cases of physical abuse. The last
15 to 20 years have witnessed the changing trends of this
concept and scientific studies by Indian workers on the
various aspects.
In India, although the problem of child abuse is less
thought and recognized, in reality it continues to grow in
alarming proportions. Besides the health care providers
and professionals including the pediatricians are either
232 IAP Textbook of Pediatrics
ignorant or have a general lack of sensitivity to the issues
of child abuse. Child abuse reporting is not mandatory in
India like many other countries. The majority of child
deaths in India, especially in nonurban areas are not
reported, investigated leave aside autopsied leading to
difficulties in knowing the precise number of deaths due
to child abuse. Besides the incidence of child abuse
amongst the child deaths represents only the tip of iceberg;
the much wider and albeit bigger incidence of child abuse
is widely prevalent within the families- in disciplining
the children, gender bias and discrimination for girls and
cultural practices of female foeticide and infanticide, girl
child marriage. Further, the vicious cycle of poor
pregnancy- maternal ill-health, high maternal mortality,
low birth weight babies, higher neonatal and infant
mortality, as well as out of family set up like institutions,
orphanages, street children, migrant children and
children of construction workers, child labourers from
organized and unorganized sectors, child prostitutes, war
refugees, trafficked children, kidnapped children and so
and so forth—in short wherever there are children and
wherever there are adults to exploit them.
To generate awareness and to focus attention on the
issue of child abuse and exploitation in India, a
nationwide world’s largest ever, prospective study was
commissioned by the Government of India, Ministry of
Women and Child Development in association with
UNICEF and Save The Children Fund and carried out by
the NGO –‘PRAYAS’, Delhi. The report was released in
April 2007. The study was multicentric, involved 13 states
including Delhi, Maharashtra, Rajasthan, Uttar Pradesh,
Kerala, Goa and Madhya Pradesh, covered 17000 children,
teachers and NGOs. The findings are shocking, 2/3rds of
children were physically abused, 71% were beaten, 29%
of these needed medical attention and 56% had bled from
assault; 89% by parents, 65% kids at school underwent
corporal punishment. More than 53% of Indian kids were
sexually abused, almost 22% faced severe sexual abuse,
and 6% sexually assaulted.; in 50% of these cases the
abusers were known to the child or were in a position of
trust and responsibility, and most children did not report
the matter to any one. Younger children [5-12 years] faced
higher levels of abuse and in the backdrop of the ‘Nithari’
killings and sexual abuse of children in Delhi; the issue of
children’s safety is of great concern. Of the children
interviewed, 80% faced emotional abuse and
discrimination like denial of education to girls and 5%
had to resort to substance abuse to cope up with being
beaten regularly. The sexual abuse ranged from severe,
such as rape, violent sexual assault to milder forms as
molestation, fondling or forcible kissing, inappropriate
touch or exposure to pornography. As the constitution of
the sample surveyed consisted of children at home, school
children, those in institutional care, child labourers, street
dwellers, the incidence of abuse varied according to their
background, as we know the economic and the social
outcasts were twice condemned. Sexual abuse in children
was highest -31% in children at work, followed by 22% in
institutional care and 13% in family environment. In the
same study from Chennai, The Tulir Centre for Prevention
and Treatment of Sexual Abuse, revealed that one out of
every two boys school going, compared to 2 out of 5 girls
not necessarily going to school are sexually abused. Most
often senior boy or senior classmate is the abuser and
school toilet is the common place for abuse. The degree
and type of sexual abuse varied, milder in primary section
- touching and exposing private parts to most severe in
senior/secondary section- forced sex and even
homosexuality. The study also separately interviewed
2324 young adults between 18 to 24 years, half of whom
reported being physically or sexually abused as children.
There were similarities to physical abuse in that the
offending parents, have frequently been emotionally
deprived or abused in their own childhood. As regards
sexual abuse in the girls, mothers would know what is
going on and yet collude by avoidance, for either being
scared of the abuser being at the position of trust,
responsibility /boss at work, or from the same family or
being afraid of social stigma. This often led to repeat abuse
and escalation of abuse.
FACTORS LEADING TO CHILD ABUSE
Recent research on child abuse has tended to move away
from considering the influence of a single factor such as
personality disorder or mental illness and poverty towards
looking at the effect of a whole group of predisposing or “
risk “ factors. Child abuse can happen in any family, at all
levels of society. Child abuse usually takes place in the
home, not in public settings. It occurs over a period of
time, and is usually not an isolated incident. Health and
community services identified that most abused other than
child sexual abuse occurs in families to which some or the
following apply.5 Though the exact etiology of child abuse
is not known, it is thought to be due to interaction of 3

primary factors - sociocultural beliefs, the child’s and
parental factors.
Sociocultural Factors
There is a wide variation in sociocultural beliefs of the
developing and developed world. Some issues which are
prevalent only in certain regions of the world like Asia,
and high population density areas, leading to higher
incidence of child labour, and child sexual exploitation.
Similarly political instability and other internal
disturbances including conditions of insurgency and
weak implementation of legal provisions leading to break
down of families creating major problems, with
increasing number of child soldiers, refugee children,
trafficked children, and children on the streets. However
despite these situational differences, the basic factors
leading to child abuse are:
1. Values and norms of discipline and physical
punishment.
2. Family structure – number of members in family, joint
or nuclear family system, socioeconomic status, etc.
3. Family and situational stresses – poverty, illiteracy,
unemployment, alcohol abuse, isolation, poor
housing, caste system and landlessness.
4. Parent-child relationship, punitive child rearing style,
excess or unwanted children, role reversal
5. Lack of economic opportunities, rural urban
migration.
Child Producing Stresses
1. Mentally retarded, physically handicapped, disabled,
deformed or chronically ill
2. Hyperactive and behaviorally different, strong willed
children
3. Temperamental [Difficult]
4. Too many children, girl babies, premature infants,
foster child, boys twice more common than girls to
be victims of physical abuse.
Parent Producing Stresses
1. Low self esteem.
2. Depression.
3. Unhappy childhood experiences – neglected or abused
as a child, emotionally deprived
4. Parental substance abuse
5. Character disorder or psychiatric illness.
Child Abuse, Neglect and Child Labor 233
6. Disappointment over the sex of the infant.
7. Ignorance of child rearing, unrealistic expectations.
8. Violence among adult family members.
PREDICTIONS
However, in addition to above factors there are situations
where child abuse is likely and can be predicted and thus
giving a warning. In assessing whether children are likely
to be abused it is useful to consider separately factors
relating to the parents, the child, and their social
conditions. If parents have certain personality
characteristics or have already demonstrated their capacity
to assault children and their child is difficult or
unrewarding, there is a strong possibility of injury being
triggered by any social crisis. The following have been
found to correlate with ill-treatment later in life.
The Parents
a. Young mother under the age of 18 years, is more likely
to maltreat her child.
b. Who were abused or have experienced family
disruption in their childhood
c. Lack family support and are unreasonably fearful of
caring for their child.
d. Have unreasonable expectations of their baby and treat
him as a much older child.
e. Have poor impulse control.
f. May be generally rigid or authoritarian; for example
the incidence of abuse is greater in some strict religious
groups and in the families of military personnel.
g. One, usually the father may be aggressively psycho-
pathic and assault others within and without his
family. About 5% of abusing parents fall into this
category, and a similar proportion are psychiatrically
ill.
The Child
a. Was unwanted and there may have been denial of
pregnancy, requests for abortion or talk of adoption
b. Was separated from mother at birth, for example,
because of prematurity, and his/her initial attachment
to the mother was prevented or interrupted.
c. Is disappointing either because of a defect or because
the child of opposite sex was wanted.
234 IAP Textbook of Pediatrics
d. Is hyperactive by day and troublesome/cries at night.
e. Is difficult because of illness
f. Is different from rest of the family
g. Girls are 3 times more likely than boys to be victims.
Social Factors
a. Crisis relating to housing, disconnection of services,
lack of safe water, hygiene, sanitation, unhealthy
environment.
b. Loss of work. chronic unemployment increases the
likelihood of abuse by fathers .
c. Poverty and economic crisis
d. Loneliness or isolation of mothers when partners have
left or are working away from home.
e. Marital crisis and new liaisons, step children are at
increased risk.
f. Unwanted pregnancy.
g. Harmful traditional practices like child marriages,
caste system, and child forced to work to support
family income, girl child discrimination/gender bias,
Devdasi tradition
Many families have some of the stresses listed, but
yet, one cannot identify in our social set up, all the social
stresses that precipitate or trigger child abuse or
maltreatment. It is worth remembering that child abuse
results from a series of stresses that impinge on parents
and children and new risk factors may operate for any
individual family which must be assessed at the clinical
level. Only by understanding the social, familial,
psychological concomitants of child abuse, the pediat-
rician can form a comprehensive opinion and manage-
ment plan.
CLINICAL MANIFESTATIONS
The presence of a single symptom or sign does not prove
that a child has been abused. Several symptoms together
or patterns of symptoms developing over a time indicate
that something is wrong, and the possibility of child
abuse and/ or neglect should be considered. One should
always be vigilant to the possibility of child abuse. In
extreme cases abuse can even kill the child. Regarding
sexual abuse boys and girls react differently. Boys who
have been abused get scared, do not share the traumatic
experience with anyone, for the fear of being considered
less of a man, and this can lead to revictimization. Boys
may turn extrovert, or at times violent. Vice versa girls
who are abused may feel self-destructive, may feel guilty.
Dealing with abuse is a lifelong struggle. Occasionally a
boy who has been abused grows to be anxious, lacks
confidence and self-esteem, is irritable, impulsive,
antisocial, prone to depression and has problem forming
trusting long term relationships. Worst he himself may
become abuser.
The forms of child abuse and neglect [CAN] may take
a variety of manifestations [Table 8.1.1]. The clinical
features of CAN vary from mild and insignificant to severe
the former may go unreported but suspicion is aroused
when they are recurrent. Rarely grave injuries are inflicted
and may prove fatal.
Munchausen’s Syndrome by Proxy
It is a manifestation of fabricated illness usually created
by an adult—a parent/guardian, in a child which may
mimic a real illness, with an objective of drawing attention
of medical personnel and in turn getting self importance.
This condition has to be diagnosed by eliminating real
illnesses and having a strong suspicion of such an entity.
Although rare, timely vigilance is worthwhile, as it may
turn fatal before it is diagnosed and due care is given in
time. An example of one such case encountered by the
author is illustrated here (Fig. 8.1.13).
A 5 year old boy son of a rich farmer from Jalgaon-
town from Maharashtra, was brought by his father, to
LTMG Hospital, Sion, Mumbai, for history of
haemetemesis for about 7 days. On enquiry and on
physical examination nothing significant to account for
hemetemesis was found. He was not pale or sick. Liver
and/or spleen were not palpable, Pedal edema, and ascitis
or icterus were absent. All the investigations to find the
cause of hemetemesis, were normal. While under
observation for 15 days, he did not have hemetemesis even
once, although the father continued to complain about
the same. On insisting to save the vomitus, the father
showed a red colored liquid resembling blood, in a bottle.
None of the ward staff, or adjacent patients’ relatives had
witnessed the patient actually vomit. As the red liquid on
close examination did not seem to be blood, we sent the
same liquid for chemical analysis. On analysis by the
forensic laboratory, the red liquid was detected to be
‘sindoor powder {used by women to apply on forehead,
as a sign of marital status] dissolved in water The father
was interrogated and after much persuation, he accepted
to have fabricated the illness in the child. He was helped
by the psychiatrist before discharging the patient, to avoid
 Child Abuse, Neglect and Child Labor 235

TABLE 8.1.1: Forms of child abuse and neglect

1. Physical: Cuts, bruises, haematomas, fracture, head injury, visceral injury, burns, ophthalmic injury, blunt trauma, injury due to slapping,
pushing, squeezing, kicking, shaking, -‘shaken baby syndrome’ [Figs 8.1.1 to 8.1.7.]
2. Nutritional: Failure to thrive, marasmus, stunting, deprivation of varying severity [Figs 8.1.8 and 8.1.12]
3. Sexual: (a) Rape, inscest, fondling, pornography, prostitution, involvement in sex related activities, exhibitionism, coercion (b) Female
foeticideand infanticide, Neglect of girl child and female discrimination – deprivation from food, education, clothing, entertainment, love
and social status, early girl child marriage [Fig. 8.1.9]
4. Behavioral : Wariness of adult contact, aggressiveness/withdrawl, apprehension when other children or adults cry shout, prefers to
stay away from home as much as possible, excessive compliance, attaching readily to strangers, frequent absenteeism and unwillingness
to go to school, not reporting injury to parents or giving inappropriate explanation of an injury.
5. Emotional: Humiliation, depression, extremely low self esteem, passive, withdrawn, tearful, apathetic, aggressive or demanding
behavior, constant high anxiety, poor social and interpersonal skills, persistent habit disorders such as sucking, biting, or rocking,
self destructive behavior, and unexplained academic delays, comparision with siblings /other children, girl child neglect/discrimination
6. Nonaccidental poisoning: e.g. Opium.
7. Abandonment/ desertion
8. Substance abuse: Drugs which alleviate mood or create illusions, happiness, e.g. Cocaine, Marijuana, etc. and alcohol and allied
substances, [Fig. 8.1.10.]
9. Medical Neglect: By the professionals and health care personnel dealing with the medical management of the child and if neglected
could be potentially fatal.
10. Exploitation:
Sexual: Children used for prostitution/sex related trade, pornography and allied abuses -trafficked children, devdasis, etc.
Entertainment: Use of children as jockeys for camel race in the gulf countries, street dancing and street shows/games – with
nondomesticated animals-monkeys, bears, elephants, camels, snakes etc., rope walking, pole climbing, making pyramids for
religious celebrations, fire jumping, or fire swallowing, in circus or marine activities.
Social Benefits: Use of children by schools, orphanages, NGOs, etc. for formal welcome programs, in rallies in parades, making
children wait in extreme hot or cold weather for long hours without provision of drinking water, toilet facilities.
Political: For wars, for party propaganda during elections, etc.
Labour: both in organized/unorganized sectors- for industries like carpet, lock, glass, fireworks, tin, cigarette watch, gunpowder,
chemical dye, bullet and explosives manufacturing and storage, as street children for unorganized sundry jobs on the teastalls, eateries,
food joints, liquor bars, small clubs /Matka dens, garages, roadside peddlers selling all sorts of articles, newspaper vendors, in railways,
on the vending machines, selling cinema /lottery tickets, cards.
Kidnapping: Use of kidnapped children for begging, as hooligans, for thefts stealing, house breaking, gambling and similar antisocial
activities [Fig. 8.1.11]
Trafficking of children: For various antisocial activities-namely slavery, prostitution, and sex related trades, domestic and industrial
labour, war, smuggling, entertainment, etc.
11. Neglect: For food, protection, housing, education, health, and medical problems, entertainment, family bonding most being loved, being
wanted, girl child neglect.
12. Miscellaneous: Manchaunsen’s Syndrome by Proxy [Fig. 8.1.13]

repetition of this incident or fabricating other serious
illness associated with high morbidity and mortality.
DIAGNOSIS
Abuse may not be an obvious diagnosis at an initial
consultation. The likelihood of CAN should be considered
in all cases of injuries in childhood, as well as in unusual
or bizarre circumstances. A careful history and detailed
examination of the child is essential. Parents who inflict
injuries on their children may seek medical attention at
different hospitals/health care facilities and give
misleading information so that a history of the previous
injury is not available, or deliberately hidden, so that abuse
is not suspected. Occasionally neighbours or friends may
provide useful information Children are often unable to
describe the events, especially when the parents are
present, but may give valuable details when questioned
separately. This is only possible when the abused child is
236 IAP Textbook of Pediatrics

Figure 8.1.1: Found by police with multiple injuries of left

upper limb, neck and scalp

Figure 8.1.4: Raja, found abandoned on railway station,

was numb, lost within himself, after months started gradually
talking, would repeat what was talked to him. Later rehabili-
tated through remand home—Mumbai

Figure 8.1.2: Rat litre marks on back as a result of baby

abandoned in garbage

Figure 8.1.3: Neonate deserted in cradle Figure 8.1.5: 32 weeks (old) newborn—abandoned in
in orphanage (abandoned) railway compartment and brought by police to the hosptial
 Child Abuse, Neglect and Child Labor 237

Figure 8.1.6: Kali—unknown girl deserted in the pediatric ward Figure 8.1.8: 16-day-old brought for loose-motions in
in an unconscious state in 1981. Later rehabilitated through marasmic condition disserted in orphanage cradle
remand home—Mumbai

Figure 8.1.7: Multiple congenital anomalies—

abandoned in garbage

of age and understanding or in a proper physical state to

narrate the incidence The problem is difficult and
complicated when the victim is an infant or a toddler,
dazed, drowsy or unconscious, or emotionally scared or
in a state of shock to reveal anything. Children rarely lie
about abuse. They may however retract an allegation of
abuse in the face of disbelief and denial. In CAN the
physical findings are often at variance with those expected
from the history. The features are often bizarre and do not
confirm or match with the manifestations of a known
Figure 8.1.9: Female achondroplasia—
raped by father’s employer
disease or disorder. Besides evidence of physical abuse,
special attempts should be made to look out for evidence
of other forms of abuse, i.e. sexual, nutritional, behavioral
or emotional abuse as well as various forms of exploitation.
Appropriate radiological investigations are carried out,
238 IAP Textbook of Pediatrics

Figure 8.1.12: Neglected child—psychiatric mother could not

and did not feed the baby who became marasmic

Figure 8.1.10: 9-10 year old girl brought

in alcoholic coma

Figure 8.1.11: Kidnapped, tortured and forcibly employed for Figure 8.1.13: Patient of Munchausan’s
begging by Gundas—antisocial workers syndrome by proxy

whenever there is reasonable suspicion of CAN.
Considerable experience is required to handle these
problems, and the senior staff members should be promptly
consulted. Reporting to the law enforcement agencies is
essential, depending on the local situations.
EFFECTS OF CHILD ABUSE/NEGLECT
Child neglect can have severe deleterious short and long
term effects on children’s cognitive, socioemotional and
behavioral development. The immediate effects are often
noticeable, whereas some effects manifest late and unless
related to previous abuse, are difficult to be attributed to
the abuse in the past. These delayed effects include low
I.Q., motor problems, hyperactivity, physical defects,
increased intensity to reactions, less social responsibility,
poor impulse control, aggression, marked anxiety
feelings of rebellion and so on. Neglect occurring early
in life is particularly detrimental to subsequent
development. Relative to physically abused children,
neglected children have more cognitive and academic
deficits, may feel worthless, social withdrawal and
limited peer interactions and internalizing as opposed
to externalizing problems. Child abuse breaks down
child’s trust in his/her family members. There is a strong
correlation between child abuse and later crime – drug
abuse, poor social and marital adjustment and sexual
difficulties. Some of these problems may not have arisen
if these adults had not been abused as children. Abusive
behaviors are transmitted to next generation and child
abuse victims, may have permanent emotional and
mental scars of past abuse.
MANAGEMENT
The management obviously depends on diagnosis and
type of abuse. Physical injuries and abnormalities are
appropriately treated. More often than not the affected
child is never taken to a police or a physician or a
caretaker agency. Occasionally the police bring the child
found by them abandoned and hence there is no assess to
any history or family background. Illegitimate babies are
almost always disserted.
Not all abandoned babies or those found by police
survive. Even after the treatment of immediate cause,
rehabilitation on long term basis if not impossible, is
extremely difficult. It is time the existence of child sexual
abuse in India, is acknowledged and accorded the
seriousness it deserves. The nationwide GOI –Ministry
Child Abuse, Neglect and Child Labor 239
study makes important recommendations including
legislative and policy changes, setting up outreach and
support services and advocacy. Though well-intentioned,
the suggestions will translate into little change in ground
reality unless there are specific interventions aimed at
diverse groups. The argument for the inclusion of sex
education in the school curriculum should be reinforced,
instead of the child getting half hazard and wrong
information and ideas about sex from his peers and
roadside cheap literature. Adults in India including the
politicians and policymakers need to grow up and
abandon their ingrained squeamishness about sexual
discourse for the sake of a healthy society. Child labor,
homelessness, and low education – both low school
enrollment and high school dropout are unpardonable
mass crimes. It is the responsibility of government and
civil society to pull out all stops and deal with them on
priority basis. The management of CAN per se is
extremely complex and difficult. Whenever possible, the
child should be rehabilitated in his own family. The
parents and other family members need support and
counseling and no one else is best suited for this, than
their own family physician, if they have one.
Unfortunately amongst the poorer sections of society,
where the problem of CAN is high, due to socioeconomic
constraints, difficulty in assess to any health care facility,
because of their housing in the interior of rural or tribal
areas, as well as poor knowledge about child rearing,
illiteracy, and strong cultural beliefs, the question of
having their own family physician does not arise. In the
families, who have their own pediatrician, he can do this
job well. Voluntary agencies and social organizations may
be of help. In our country, foster care, adoption, and
placement in orphanages are of limited options. Improve-
ments in general living conditions, social awareness, and
changes in the attitudes, economic status are important to
control the scourge of CAN. Responding to CAN is a
shared responsibility. The ramifications of CAN are so far
reaching, that it is beyond the scope of any one professional
to tackle it. The medical profession, including general
practioner, specialists, social services, the police, judiciary,
and the community, all have joint as well as specific roles
to play. Awareness towards CAN, its ill-effects on the
affected child, his/her family and the society, should be
generated amongst all above concerned disciplines.
Similarly, involvement of all the related Government
departments, police and legal functionaries is vital.
Pediatrician has the main role to play in terms of correct
240 IAP Textbook of Pediatrics
diagnosis, management, rehabilitation, as well as
prevention not only in the same child, but also in the sibs.
He/She should be helped by the social services, the police
and the judiciaries for a comprehensive approach.
Ironically, till recently the pediatricians have been too busy
tackling infections and malnutrition and lack the needed
awareness to CAN. Even if rarely diagnosed, the
implementary judicial system, the Indian Penal Code does
not recognize child abuse. Child labor cannot be
abolished, as there are no alternative arrangements, for
the jobs for the parents of these working children, or
economic settlement of these families. To educate these
children, there are not enough schools, trained teachers
or the other necessary infra structure. With the drive and
propaganda for the abolition of child labour, without the
necessary provision for the rehabilitation of these working
children, the entire family starves along with the child.
This indirectly leads and encourages to recycling of child
labour in clandestine circumstances. It is depressing to
note that there is no legislation on child abuse and neglect
in India, whereas our neighbours, Sri Lanka and Pakistan,
with more or less similar socioeconomic background and
smaller than India in area as well as population are ahead
of us in legally dealing with child abuse.
PROVISION FOR SAFEGUARD/CHILD PROTECTION
IN INDIA
The Indian Constitution contains provisions for safe-
guarding the interests of children and protecting them
against cruelty and exploitation. Article15[3] empowers
the state to make any special provision in favor of children.
Article 39 [i] of the constitution enjoins the State that it
shall in particular direct its policy to ensure that childhood
is protected against exploitation and against moral and
material abandonment. Article 39[e and f] specify that the
state shall direct its policy in such a manner that the tender
age of the children is not abused and children are given
opportunities and facilities to develop in a healthy manner.
Article 24 prohibits from employment of children below
the age of 14 years in any mine, factory, or other hazardous
job. Article 45 provides for free and compulsory education
for all children upto the age of 14 years. Indian Penal
Code sections 363a, 365, 366, 366a, 366b, 370, 372, 373
and 376, too deplores child exploitation and considers
exposing a child below 12 years to physical risk or
disserting it with the intention of abandoning it, by the
parents or any other person entrusted with the care of the
child, kidnapping or maiming a child for begging and
selling a child for prostitution, etc. as offence. The National
Policy for Children 1974 confers the responsibility of
nature and solicitude of children on the nation and
expresses concern about all forms of neglect, exploitation
of and cruelty to children. The National Policy on
Education, 1986, too, adopts a child centered approach
and explicitly calls for ‘firm exclusion’ of corporal
punishment from education system. The Child Labour
Policy adopted by the nation in1987, seeks to protect the
interest of children at work and to prevent their exploi-
tation by the employers. Subsequently the National
Decadal Plan of Action for Girl Child [1991-2000] for
protection from exploitation, assault, and physical abuse
came in vogue . The National Initiative for Child Protection
[NICP] strives to ensure a childhood to every child in need
of care and protection. These are (a) street children, (b)
child labor (c) children who have been abused (d) child
victim of flesh trade (e) child addicts (f) mentally ill child
(g) children affected by HIV/AIDS (h) children affected by
conflicts and distress (i)child political refugees and (j)
children whose families are in great crisis. The Allied
system have a direct impact on child’s life, they are (1) the
police, (2) the health care system (3) the judicial system (4)
the education system, 5)the transport system, (6) the labour
department, (7) the media, (8) telecommunication
department (9)the corporate sector (10) and all others—
all of us. Every one can be an allied system.
National Charter for Children 2003 was announced
in 2003. This was done in accordance with the pledge in
the National Agenda of Governance, i.e. through National
Policy for Children 1974, wherein we are committed to
providing for adequate services to children, both before
and after birth and throughout the period of growth, to
ensure their full physical, mental and social development;
Underlying this charter is our intent to secure for every
child, its inherent right to be a child and enjoy a healthy
and happy childhood, to address the root causes that
negate the healthy growth and development for children,
and to awaken the conscience of the community in the
wider societal context to protect children from all forms of
abuse, while strengthening the family, society, and the
nation.29 While there is no single legislation to deal
exclusively with the problem of child abuse in India, there
are various acts such as Juvenile Justice Act 1986, Child
Marriage Restraint Act [Amendment], which deal with
one aspect or the other of child exploitation and cruelty. A

number of voluntary organizations are also engaged in
protection and rehabilitation of the abused children While
some of child abuse like child labour and to a lesser extent
female sexual abuse, have engaged the attention of
legislators, social welfare administrators and social
workers, not enough attention has been paid to other forms
of child abuse.
LEGAL ASPECTS
Raising children has been the concern of the parents and
not the government. The law has therefore given parents
the custody of children to give protection and care. The
law has however provided for intervention by society
when parental care is dangerously faulty or insufficient.
Two types of proceedings can result: (1) Criminal
proceeding against one or both parents in adult courts.
(2) Care proceedings for the child in the juvenile court.
Under the criminal proceedings, the case is brought in the
adult court under the children and young person act on
the grounds of cruelty. The prosecution must have
evidence which pine responsibility on one or more
individuals, If found guilty the adult can be imprisoned/
punished. Under the care proceedings the local authority
usually the police brings the case. A parent may be
acquitted in the adult court, but the juvenile court can take
its own action, for the court is primarily concerned with
the child’s actual situation and welfare. Voluntary
arrangement may be made by the parent which can be
approved by the court. Almost a supervision order is
passed . Sometimes the child may be removed to another
place. As per the National Policy for Children of August
1974, which is in accordance with the constitutional
mandate of India, any child born in the territory of India
irrespective of the fact whether the parents or either of the
parents is an Indian Citizen would be an Indian citizen.
The various articles namely 5a, 24, 39f, 41, 45, 46, 47 of
Indian constitution offer a comprehensive care and
protection to any child born in India. Further as per the
International Convention of the Rights of Children, to
which India is a signatory, the child has the priviledge of
fulfillment of all the four sets of rights namely, the right to
survival, protection, development, and participation. The
Convention also said that the children are at a risk in
every country in the world and argued that children
invariably ‘wind up’ at the bottom of almost all national
agenda for political and social actions.
Child Abuse, Neglect and Child Labor 241
A UNIFIED APPROACH TO PROTECTION/
PREVENTION
19 th November is the world day for Prevention Of Child
Abuse, launched in the year 2000, by the Women’s World
Summit Foundation, at Geneva, Switzerland The
principal objective of the World Day is to help, create a
culture of prevention of child abuse – emotional, physical,
and sexual and violence against children. It is organized
in synergy with the anniversary date of the Convention
of Rights of Children (20th November). A coherent policy
can be formulated to combat child abuse in the family
and society via primary prevention. This probably can
be achieved by increasing the awareness of the respon-
sibilities of parents instead of blaming the community,
much less the Government. There is in this traditional
wisdom, but who will help the families who cannot help
themselves? More than making new policies concerning
child care and protection, implementation will be vital.
Facilities will have to be provided of supplying clothing,
food, housing and education, the basic rights of the child.
To what extent the National Policy for Children, The
National Decadal Plan for the Girl Child, The National
Initiative for Child Protection and The National Charter
for Children 2003, and the resolution on children’s funds
and special welfare programs will assist in the
comprehensive welfare of our Indian children, our future
national assets remains an unanswered query! The cause
of children has lacked concern and advocacy, whereas a
number of agencies and organizations have paid up lip
service some have made notable impact. In this scenario,
The Indian Academy of Pediatrics [IAP], has taken up
the cause of children, has opted ‘Comprehensive Child
Care’. The IAP’s status is now recognized by the
government and important national/international
agencies like UNICEF, WHO, World Bank, etc. and its
advice is sought on important matters concerning
children. Hence IAP has constituted ‘Child Abuse,
Neglect and Child Labour [CANCL] Committee to
spearhead its endeavour with the following goals: (1) To
reach out to the neglected, deprived and abused children
for their comprehensive needs including healthcare,
education and development, rehabilitation and protec-
tion. (2) To formulate recommendations to the government.
(3) To create social and community awareness to the
problems of child abuse and neglect in its various forms
and child labor and bring about attitudinal changes. To
242 IAP Textbook of Pediatrics
implement these goals on a wider national scale, it has set
up branches in different states of India. Various strategies
have been formed for the implementation of its activities
and since the inception of this committee, considerable
work has been done, as well as planned for the future. As
one of the goals, the CANCL has submitted a proposal to
the Ministry-Government of India - Panchayati Raj, to
involve village panchayats for education, health and
immunization of rural children, to decentralize such
problems and to encourage village community
participation. Since the last three years, the GOI, has
launched, The National Rural Health Mission- NRHM-
to provide effective health care to rural population
throughout the country, with special focus on 18 states,
which have poor public health indicators and weak
infrastructure, with the emphasis on empowering the local
governments for its management at the village level. With
the success of NRHM, the GOI – Ministry of Health is
planning to launch National Urban Health Mission
[NUHM] for providing basic health care facilities for the
urban population; 22 crore people will be covered,
including 5.5 crore urban slum dwellers under this scheme.
Last year in January 2007, IAP Child Rights Program was
launched under IAP Vision in collaboration with The
Royal College of Pediatrics and Child Health, UK, to focus
on Child Rights and Protection, for children of India.2 The
Tenth Five Year Plan[2002-07], viewed development of
children not only as the most desirable societal
involvement in country’s future, but as the right of every
child to achieve full developmental potential. However
the percentage share of sectoral allocation on children in
union budget 2006-07, was for child development 0.83%,
child health 0.556%, child education 3.487%, and child
protection 0.034% only.12 In the 11th five year plan, the
sum allocated for child protection is a mere 0.7%. We are
far behind our neighbour Bangladesh in spending for
health and education of our children. We need to put
money where it is most needed, and the citizens need to be
alert to prevent misappropriation of funds, the bane of
usual government program. After the report of the
Government of India – Ministry of Women and Child
Development sponsored national study on child abuse
NSCA-revealing alarming facts on child abuse
Smt Renuka Chowdhary—minister MWCD, gave
assurance for the remedial measures. MWCD, was
created in early 2006. This move along with increased
allocations for children in the budget for 2007-08, is a
reflection of the government’s commitment towards
children. She said ‘India’s children are India’s future as
the strength of the nation lies in healthy protected,
educated and well-developed child population that will
grow up, to be productive citizens of the country’. She
dedicated this report to the nation with the hope that it
will help establish and strengthen policies, programs and
legislations on child protection. Further Smt. Deepa Jain
Singh, secretary -MWCD-GOI, has added that GOI is
focusing on issues of child abuse, has taken significant
steps to address child protection by setting up a national
commission for the protection of Child Rights, amending
the Juvenile Justice [CARE and Protection of Children]
Act 2000 and the Child Marriage Restraint Act 1929,
launching the offences against children prevention Bill.2
The Millenium Development Goals in 2000, adopted at
the Millenium summit are about children. Six of the 8
MDGs best met as rights of children to Health, Education,
Protection and Equality are protected. They will only be
sustained as the rights of every child are realized. These
same six match the goals set out in a ‘A World Fit for
Children. If we are to meet these goals; we will only do so
with full participation of children and young people’ Carol
Bellamy, UNICEF-Executive Director. ‘We must do more
than talk about our future, we must start to create it now.’
said Kofi Annan, Secretary General of United Nations.
The Commissions for Protection of Child Rights Bill 2005,
has been passed on December 22, 2005, by both the houses
of the parliament, the Loksabha and the Rajyasabha. This
is a welcome news for the children of our country. We
have to wait and see how it benefits millions of children of
India. As one of the measures towards protection, a 24
hour toll free telephone helpline 1098, of The Ministry of
Social Justice and Empowerment is available for children
in distress and provide crises intervention like medical,
shelter, restoration to native place, protection from physical
or sexual abuse and also to rehabilitate them. This Ministry
of Social Justice and Empowerment, Government of India
is the nodal Ministry, with support from The National
Human Rights Commission, MTNL, UNICEF, Transport
Ministry, etc. as members of the board. This service was
operational in 56 cities and the government is planning to
expand it to cover the entire nation.6 In the recent past a
Home Ministry at the centre approved draft, was
circulated among states. This was in connection to protect
Indian children from child abuse – physical, sexual,
economical. However the draft – Offences against
children, Act 2006, is not comprehensive. No Ministry is
thinking of setting up Child Protection Units [CPUs] and

Child Protection Courts [CPCs], which would deliver these
new laws effectively and speedily. Thus the victimized
child for no fault of his/her will continue to go through
the adult courts. Some statistics which throw light on the
need of the dire requirements of these CPUs and CPCs;
40% of the girls and 25% of our boys are sexually abused,
half the abusers are adults who enjoy the trust of these
children. In 2001, 34.3% of our population was 0 to14
years of age, and 41.6% was 15 to 39 years. That’s sizable
chunk of our population left vulnerable, needing legal
facilitation by the state. It isn’t complex to set up CPUs
and CPSs, several countries have them. Younger specially
trained police persons handle one CPU in each city; they
deal with all the cases where a child is a victim From the
filling of First Information Report [FIR], investigation of
the case, handling of the child where statements are
recorded on video by psychologists, so that the child is
not continuously retraumatized, medical examination on
premises, counseling, follow up visits, and the arrest of
the perpetrators. CPCs have sensitized judges, are child
friendly, case delays are not encountered, cross-
questioning has limits, courts are in camera and victims
shielded from the accused. Indians have every right to
have CPUs and the CPCs. In absence of these our children
have to suffer. International pedophilics who have begun
enjoying India will prey with glee. Especially on boys
caught, they will prefer to be tried here, stay for years in
their cells and finally get away with a simple sentence.
The challenges facing children in the 21st century are
immense and will need to be faced if we are to achieve the
goal of child protection for all. Three specified constraints
are namely, poverty HIV/AIDS infection and war. In many
African and Asian countries the HIV/AIDS orphans and
pandemic has changed the social structure of society, with
AIDS orphans and children infected and affected with
AIDS becoming common. The consequences of post-
traumatic stress resulting from war needs to be stressed
and the development of programmes that place children
in the center of relief programs to foster a culture of
protection in the background of poverty is essential.1,15
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5. Child Abuse and Neglect. The doctor’s response, taken
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2008: Under publication
14. Kellog ND, Merard SN. Violence among family members
of children and adolescents evaluated for sexual abuse.
Child Abuse and Negl 2003;27[12]:1367-76.
15. Lachman P, Poblete X, Ebigb PO, Nyandiya-Bundy S,
Bundy RP, Killian B, Doek J. Challenges facing child
protection. Child Abuse Negl 2002;26[6-7]:587-617.
16. Mehta MN. Physical abuse of Abandoned children in
India. Child Abuse and Negl 1982;6:171-5.
17. Mehta MN. Abuse of Abandoned children in India, ICCW
News Bull 1990;37:3-7.
18. Mehta MN. Child abuse, neglect and child labour. In:
Parthasarthy A [Ed in chief]. IAP Textbook of Pediatrics
3rd ed. Jaypee Brothers Medical Publishers Pvt. Ltd, New
Delhi 2006;953-70.
19. Mehta MN. Child abuse and neglect. In: Udani PM (Ed).
Textbook of Pediatrics. NewDelhi and Jaypee Brothers
Medical Publishers Pvt Ltd, New Delhi 1991;1520-8.
20. Mehta MN. Sociomedical aspects of child abuse. J Appl
Med 1992;257-62.
21. Mehta MN. Child abuse and neglect. In: Gupte S (Ed).
Recent Advances in Pediatrics 4, Jaypee Brothers Medical
Publishers Pvt Ltd, New Delhi, 1994;58-87.
22. Mehta MN. Child abuse and neglect. In Banerjee SR (Ed).
Community and social pediatrics, Jaypee Brothers
Medical Publishers Pvt Ltd, New Delhi 1995;157-74 and
[2nd ed] 2008;326-57.
23. Mehta MN, Lokeshwar MR, Bhatt S, et al. Rape in
244 IAP Textbook of Pediatrics
Children. Child Abuse and Negl 1979;3:673-7.
24. Mehta MN. Sexual abuse in children. Pediatrics Today
2008, Under publication.
25. Mehta MN, Prabhu SV, Mistry HN. Types of physical
health problems in working children. In: Naidu US,
Kapadia K (Eds). Child labour and health. Tata Institute
of Social Sciences, Bombay 1982;138-49 based on National
Seminar on Child Labour and Health organized by Tata
Institute of Social Sciences and WHO, Bombay, 1981.
26. Mehta MN, Prabhu SV, Mistry HN. Child labour in
Bombay. Child abuse and Negl 1985;5:107-11.
27. Mehta MN, Munshi NN, Krishnan P. Adoptions: Follow
up from an Orphanage in Bombay. Child Abuse and Negl
1983;7:78-82.
28. Mehta MN, Damle S, Warde S. Rehabilitation of
Illegitimate Babies, paper presented at the International
Congress on Child Abuse and Neglect, Amsterdam and
published in the book of Abstracts, 1984.
29. Menon Gupta Kasturi. Secretary to the Government of
India, National Charter for Children 2003, from HAQ,
Center for Child Rights, in Every Child in School,
souvenir released on November 14, 2004, New Delhi by
IAP-CANCL Group: 9.
30. National Family Health Survey -3 [NFSH –3]. Hindustan
Times, Feb. 15th, 2007;8.
31. National Study on Child Abuse [NSCA]. Report released
in March 2007. Ministry of Women and Child Develop-
ment—Repots in Hindustan Times 2007 – March 9, 10
April 10, 13- editorial and by Kanth A[ref.13], Aggarwal
K [ref 2] and Mehta M [ref. 24] and CANCL News July
8.2 Child Labor
CHILD LABOR
Child labor is a pervasive problem throughout the world,
specially in developing countries. India has the largest
number of child labor in the world and constituted around
3.6 percent of the total labor force. Majority (75%) of them
work in rural settings and 1/3 are girls. But the alarming
feature of the problem in recent years was the enormous
increase of child workers in urban settings.
In India, a sizable number of children are still far away
from the hopes and expectations expressed in the UN
Convention on the `Rights of the Child’. In the developing
countries like India, it is not uncommon to see a young
child behaving and becoming a premature adult, having
been pushed and burdened to `work’, earn and support
the family. Children work in almost all the countries of
2007;21-2.
32. Pradhan SN. Five decades of Government and Children,
Courtsey Yojana. A development journal of Information
and Broadcasting. CANCL News 2003;1-2.
33. Sangwan S, Menon V. Indian Penal Code does not
recognize child abuse, Hindustan Times 14th Dec, 2000
as quoted in CANCL News 2002;1:16.
34. Seth R. Allocations for Children in Union Budget, CANCL
News, July 2007;26.
35. Sterir DM, Leventhal JM, Berg AT, et al. Are children
born to young mother at increased risk of maltreatment?
Pediatr 1993;91[1]1-3:642-8.
36. The Commissions for Protection of Child Rights Bill 2005;
CANCL News, 2006;6[1]:12.
37. The Millenium Development Goals, CANCL News, July
2005;5:7.
38. UNICEF- State of World’s Children 2008 Report from
Hindustan Times, 25th March 2008.
39. UNDP Human Development Report 2006. “No where
to go”- editorial opinion-The Times of India, Nov 22nd,
2006.
40. Virani P. Child protection and You: Proposed legislation
must be water tight, Editorial Opinion. The Times of India,
Mumbai, April 16th, 2006.
41. Waller P. The Politics of Child abuse, Society 1991;6:13.
42. Walsh C, Macmillan HL, Jamieson E. The relationship
between parental substance abuse and child maltreat-
ment. Findings from ontario health department. Child
Abuse and Negl 2003;27[12]:1409-25.
Meenakshi N Mehta, SR Banerjee
the world. Participation of children in work in different
forms is not unusual amongst various societies and this
is an acceptable phenomenon in the human history. In
the less privileged countries, culturally gradual
involvement in work occurs between the ages of 5 and 15
years.4-8 Although these children often help in their family
vocation, most of the times in the agricultural activities
and are not gainfully employed. An equal number who
have no family business, or income, or are in adverse
situation are forced to take up any activity which will
help to support the family. Whether they like it or not, they
land up working in inhuman stressful situations for petty
income. As economic work opportunities are limited in
the rural areas, children have to migrate to the urban areas
in search of jobs. Thus, the problem of child labor assumes

a grave issue in the cities and the townships of almost
every third world country.
HISTORICAL BACKGROUND
Child labor has a long history. From the ancinet times,
children worked in agriculture and as apprentices to
artisans. In colonial America, children who helped in their
own farms and households were commonly hired out to
perform similar tasks in neighboring farms and
households. Child labor underwent major expansion and
restructuring during 1700’s as a consequence of the need,
created by the industrial revolution for large number of
workers. In that era most mill owners preferred to have
children rather than adults, children as young as eleven
years especially girls, were sent by their families to work
in the mills because the wages they could earn for exceeded
the volume of their parents at home on their rural farms.
Thus in the pre-industrial revolution period, the
phenomenon of child labor was prevalent all over the
world, though having an altogether different nature and
magnitude. In India, child labor was identified as a major
problem as early as 19th century. The first factory was
started about the middle of 19th century and children were
employed in cotton, jute mills and coal mines. As early as
1881, during the British period, legislative measures for
the protection of child worker employed in hazardous job
were adopted. In the 20th century industralized countries
have taken care of many child labor problems and evils.
However, these problems, and evils very much exist in
Africa and Asia.
DEFINITION
According to encyclopedia of Social Sciences (1959) child
labor was defined as: when the business of wage earning
or participation in self and family support conflicts
directly or indirectly with the business of growth and
education, the result is child labor. According to ILO (1986)
the definition of child labor is to include children below
the age of 15 years in work and employment with the aim
of earning a livlihood for themselves or for the families.26
UNICEF has given comprehensive formulation in its
attempt at defining the child labor:
1. Starting fulltime work at too early an age
2. Working too long within or outside the families so
that children are unable to attend school
3. Work resulting in excessive physical and psycholo-
gical strain upon the child
Child Abuse, Neglect and Child Labor 245
4. Work and life on the street in unhealthy and dangerous
conditions
5. Too musch responsibility at too early an age with
inadequate remuneration for working out side the
family
6. Work that inhibits the child’s self-esteem as in bonded
labor and prostitution.
The definitions therefore must be relevant to particular
situation in various countries. Various authors have also
tried to define it in various ways:
Kulshrestha defines it as the employment of children
in gainful occupations which are dangerous to their health
and denying them the opportunities of development.
Khan uses the term “Child Labor” in the sense of
gainful employment secured from the employed for
wages, whereas committee on child labor Govt. of India
defines it as “that segment of populations which parti-
cipates in work either pain or unpaid.” Maheswari et al
it as “any work done by the child in order to economically
benefit their families or themselves, directly or indirectly,
at the cost of their physical, mental, and or social develop-
ment.
CHILD LABOR VERSUS CHILD AT WORK
The term “child at work” indicates unexploitative
employment of children, for example, in the developing
countries, children as they grow, learn to get involved in
the household work or vocation of the family as soon as
they are capable of helping. This helps the child in the
informal preparation and training for adulthood tasks.
Needless to say this is virtually free from any exploitation
or harmful effects and on the contrary may prove
interesting, educational and socially useful. However,
work outside the family environment involves a sharp
change of environment, discipline and lifestyle.
Thus “child labor” indicates employment of child for
economic wage earning work and the child is subjected
to various hazards related to his mental, physical, and
social health. The child looses his “childhood” abruptly
and is prematurely pushed to live an adult life and
shoulder responsibilities (Figs 8.2.1 to 8.2.23).
MAGNITUDE OF THE PROBLEM
The magnitude of such child labor is estimated around
100 to 200 million, which is 4 to 8 percent of the total
world employment (2.4 billion persons) in 1994 and after
a decade it would have increased considerably. Sixteen
nations of Asia9 contained 261.3 million child workers in
246 IAP Textbook of Pediatrics

Figure 8.2.1: School dropout

Figure 8.2.4: Child working in road side restaurant

Figure 8.2.2: Children working on tea stall

Figure 8.2.5: Child working at the canteen

of industrial estate

early 1990s. On an average in developing countries more

than 18 percent of children between 10 and 14 years are
estimated to be working which amounts to 18 million
Figure 8.2.3: Children working in college canteen
children working as per official reports, whereas
 Child Abuse, Neglect and Child Labor 247

Figure 8.2.9: Children working in plastic bottle factory

Figure 8.2.6: Child working in industrial hardware factory

Figure 8.2.10: Child working in

packing waste (dry) material

Figure 8.2.7: Girl working in packing industry

Figure 8.2.8: Children working in packing industry Figure 8.2.11: Child working in plastic packing firm
248 IAP Textbook of Pediatrics

Figure 8.2.15: Boy working in garage (on battery)

Figure 8.2.12: Girls working in hosiery factory

Figure 8.2.16: Brother and sister working

as cobbler—shoe repairer
Figure 8.2.13: Girls working in ready-made
garments factory

Figure 8.2.14: Children working in garage Figure 8.2.17: Child working as cobbler
 Child Abuse, Neglect and Child Labor 249

Figure 8.2.18: Child working as a fish seller

Figure 8.2.20: Child working to clean

road potholes and drains/gutter

Figure 8.2.19: Children working as vegetable vender

unofficial figures are around 100 million child workers,

i.e. 1 in every 16 children is a child labor.21 India has
probably the largest child labor force in the world
amounting to 17.4 million in 1990,2 and has increased to
20 million in 1994. (Indian Labor Ministry). From the
Government of India census 1991, out of total 203.3
million children between 5 and 14 years, 5.9 percent
children were in labor force. There is lack of information
on the vast majority of children engaged in the Figure 8.2.21: Child keeping monkey as pet and worked
unorganized sector and comprising about 92 percent of for entertaining people, doing road side shows
250 IAP Textbook of Pediatrics

Figure 8.2.22: Child lifting heavy stones on neck and

doing shows for entertainment of people

the total labor force. In 1996, UNICEF estimated

178 million children in the age group of 6 and 16, of these,
the International Labor Organization estimated 14.4
percent children between 10 to 14 years as economically
active. The female children constituted 70 percent of child
workers in weaving industry and 90 percent in match
industry.
In India according to 2001 census there were 253.16
million children agent 5-14 years comprising 24.61
percent of the country’s total population. Nearly 75.38
percent of them lived in rural area. Out of 12.7 million
working children, approximately 5.78 million children
were classified as main worker and 6.89 million as
marginal workers. Main workers are those engaged in a
full-time economic activity and marginal workers are those
who are part-time workers as shown in Table 8.2.1. Figure 8.2.23: Child employed in hazardous street play
involving climbing and walking on poles/bamboo
TABLE 8.2.1: Distribution of work force in
million aged 5-14 years wisdom, but what does it really mean? To begin with,
Category Both sexes Male Female
parents have little choice but to sent their children to work,
parents depends on their children. Child labor is a
Main workers socioeconomic problem. It is generally considered that the
Total 5.78 3.60 2.18
Rural 4.82 2.93 1.90
socioeconomic conditions are the roots of child labor.
Urban 0.96 0.67 0.28 However, for ease of understanding they can be grouped
Marginal workers under three major heads, i.e. causes pertaining to:
Total 6.89 3.21 3.68
Rural 6.52 3.00 3.52 Familial poverty, parental illiteracy/ignorance, parental
Urban 0.36 0.21 0.16 unemployment and death, large family especially with
more children, father’s addiction and debt, bonded labor,
Source: Census of India 2001
etc.
Causes of Child Labor Child poor academic scholastic performance and or
The real causes of child labor are deep rooted in repeated failures at examinations, repeated birth of
inequality and poverty. This has become conventional female child in the same family, following the path of

elder sib who is gainfully employed, the sense of economic
independence, and false belief of social respect related to
earning.
Social poor access to educational facilities, poverty,
literary ignorance, lack of land reforms and appropriate
rural development, migration of children from rural to
urban areas in search of livelihood, economical
advantage of the employers by employing cheap labor
instead of employing adults; vulnerability to sexual
exploitation for prostitution. Further no threat of
formation of unions of the child workers (unlike adults)
and the most important the non-enforcement of child labor
laws and poor punitive law provisons.
WORKING CONDITIONS
Clear demarcations between hazardous and non-
hazardous work are essentials to control and protect the
working child from the ill-effects related to the work. Any
occupation which allows the child while working to come
in contact with the harmful substances like chemicals,
dust, raw materials, unfinished products, wastes, effluents
or explosives/inflammable is termed “hazardous”.
Children working in the following industries are listed as
hazardous by the Child Labor Act (prohibition and
regulation) 1996, such as tobacco industry, carpet weaving,
cement manufacturing, stone quarry, wood carving, cloth
printing, silk weaving, zari work, dying and weaving,
match manufacturing, explosive and fireworks, mica
cutting and splitting, shellac manufacturing, tanning and
the construction work. The other industries like glass
manufacture, lock making, gem and diamond polishing,
and sex related activities like child prostitution should be
included. Table 8.2.2 lists the type of occupation and
related health hazards.
Among the non-hazardous industries are the ones,
where the children work in the unorganized sectors
mainly in the urban areas, like commerce and service
sectors, multigrade activities like roadside hotels,
restaurants, tea stalls, street vendors, working in garages,
as cleaners, on the petrol pumps, minor help in
construction work, as rag pickers, as news papers boys,
selling flowers, fruits and vegetables, and selling
miscellaneous items in the trains, stations, bus stops, etc.
At such work situations the risk of health hazards are
minimal. In the area of domestic work the risk of physical
and sexual exploitation is quite high (especially for
females) (Refer Table 8.2.2).
Child Abuse, Neglect and Child Labor 251
Consequences and Health Hazards of Child Labor20,21
Working children belong to critical period of important
physical and psychosocial development. It is the time of
pubertal and adolescent growth spurt and maturation
of personality development. Health hazards can be
divided basically into two groups:
1. Hazards inherent to the working children themselves
and
2. Hazards related to their occupation.
Working for long hours in unhealthy environment
has deleterious effect on child’s health. Besides physical
health hazards children have to bear emotional,
psychological and at times sexual trauma. Children, who
work in industries where they have to carry heavy
weights, grow up shorter and weigh less than normal
children. (ILO 1996).
Children who are forced to work beyond their
physical capacity are prone to occupational injuries
because of fatigue, inattention and poor judgment. This
may be compounded with hunger and thirst for long
hours, inadequate and improper sanitary facilities, and
shortage of rest and sleep. Such children become irritable
or depressed and develop psychological symptoms like
headache, giddiness, inattention; lack of concentration
will further make them prone to otherwise avoidable
injuries. Children who develop serious injuries at work
and remain poorly treated are likely to land up with
permanent handicaps as well as social and emotional
maladjustments. Lack of adequate rest, sleep, food,
emotional deprivation, family support and no access to
entertainment or recreation as well as education may lead
them to take up and participate in antisocial activities
like, stealing, gambling, consumption of drugs and alcohol,
and at times sexual activities. Children entrapped in
brothels or gambling, etc. are at an additional risk of
developing venereal diseases like HIV/AIDS. In adult life
due to inadequate education, they are unable to compete
for better job opportunities and have to struggle for a
comfortable and socially gainful life. Children chronically
deprived of adequate food suffer from irreversible severe
malnutrition, poor immunity, hence are prone to infection
and may die prematurely.
Bonded Child Labor
Bonded labor is prevalent in some developing countries
like India, where the peasant family committed to
providing certain labor services by custom often in return
repayments of debt. One form of bonded labor is where
252 IAP Textbook of Pediatrics

TABLE 8.2.2: Occupational health hazards

Occupation Disease/disabilities/consequences

Baloon factories Pneumonia, bronchopneumonia and breathlessness, heart failure.

Match and fireworks Industries Breathing problems, severe burns, muscle fatigue, mutilation, deformities due to long
hours of work in one position, fire accidents, eye and kidney diseases.
Lock industry Tuberculosis and respiratory tract diseases, asthma, pneumoconiosis, acute headache,
acid burns.
Glass and bangle industries Heat stroke, conjunctivitis, tuberculosis, burns on face hands, eye sight defects, skin
diseases.
Slate industry Silicosis, tuberculosis, asthma.
Stone quarries/Asbestos factories Tuberculosis, respiratory disorders, physical injuries, asbestosis, pneumoconiosis
Brick kiln Tuberculosis, urinary infections, eye problems, headache, shoulder pains, malaria,
injuries.
Gem polishing …….do…….
Diamond polishing ……..do…..
Zari embroidery Eye defects, spondylitis, lung ailments.
Handloom/powerloom Asthma, tuberculosis, bronchitis, posture related eye defects, byssinosis, spinal
and silk products problems.
Cotton hosiery ……..do…….
Printing and dyeing Pigmentation and injuries to nails and fingers, posture related disorder.
Brassware Eye injuries, respiratory disorders, tuberculosis, asthma and lung ailments, loss of limbs,
burns, vomiting, early death.
Carpet weaving Eye defects, lung problems, distorted back, loss of fingers, poisoning from coloring
agents
Mines and pottery Asthma, bronchitis, tuberculosis, eye defects, silicosis
Bidi making Chronic bronchitis, tuberculosis, posture related disorders
Construction workers/ Physical injuries, stunting, sexual abuse, drug addiction, isolation from society females
Domestic labor more vulnerable for sexual abuse as domestic workers
Watch and microcomputer Damage to eyesight, postural problems
industry
Child prostitution Physical injuries, risk of conception and threatened abortion, venereal diseases
including HIV/AIDS, emotional and psychological problems
Agriculture/farming Due to constant wetness skin infections of feet, insect bites, allergic rashes due to
pesticides, risk of poisoning, cuts injuries to hands

Source:
1. Born to work- Neera Burra} In Child Abuse Neglect and Child Labor (CANCL) NEWS Vol. 1, 23-24, Jan 2002.
2. Children in darkness.
3. Press release- Oxford University Press, 1995.

children are pledged to landlords, often as domestic
servants as part of debt for all through out their lives.
In many of these situation, child workers are neglected
and poor nutrition and bad health. In India 8.7-21 percent
bonded laborers are below sixteen years of age. Another
type of bonded child labor which appears to be very recent
but increasing rapidly is constrictive military services.
Here children have been involved directly as solidiers or
paramilitary personnel. There may some benefits as in
regular food, clothing and shelter, medical attention to
these children but these can hardly compensate for the
danger of exposure to work.

LEGISLATION AND GOVERNMENT
POLICY ON CHILD LABOR
The laws governing child labor vary in different countries
and for different jobs undertaken by these children.
In India, the first Factory Act was passed in 1881 by the
British Government, defining the child labor as working
between the ages 7 and 12 years with working hours 9 and
with 1 hour rest. It took 10 years to raise this age limit to 14
years. Subsequent to that various laws were passed
periodically which were related to specific industries.
Regarding the Indian Government enforcement, the central
statutes mainly cover:
• Employment in industries, mining, transport,
railways, ports, oil, and employment run by and
under the government;
whereas the state statutes cover
• Shops and establishments, factories, plantations, etc.
As India is party to the ILO convention and consi-
dering its poor economic conditions, special provisions
are made and lower the standards for implementation.
The Indian law accepts the maximum hours of work
and deals with the following four matter:
1. Minimum age of employment of children
2. Medical examination of children
3. Maximum hours of works
4. Prohibition of night work for children
Unfortunately the Indian laws are not applicable to a
numerable unorganized industries including agriculture
and this is an important deficiency in our law.
To counteract the above shortcoming 1973 the ILO
passed a convention establishing 15 years as the
minimum age for working for most sectors, while
permitting light work from the age 13 years. This is to
safeguard child’s health, morals, safety or prejudice his/
her school attendance. Although 28 countries have till
date actually ratified the convention, most have passed
legislation of their own along similar lines. Further
recommendations have been given by the Child Labor
Committee in 1979.
What Can be Done-Recommendations
The phenomenon of child labor is so complex and deeply
rooted in the society that it may not be wise to rely on
one single approach for its amelioration or elimination.
Although emotionally we might agree that child labor
should be abolished or banned; but whether we like it or
not, in reality and in practical terms we have no choice
Child Abuse, Neglect and Child Labor 253
but to agree with the ILO statement that “suppressing
child labor is unlikely to improve the welfare of many of
the children unless substitute sources of income and
opportunities for personal development are created.”
Protection and not abolition is the need of today. It sounds
good that children cannot and should not work and they
must be in schools, but do we have enough schools or do
the children have easy access to these schools and all
that goes with the primary and secondary education?
Besides, discrepancies exist between rural and urban
educational setups. Amongst the strategies suggested to
alleviate child labor are:
RECOMMENDATIONS
1. National campaign to create public awareness of its
pernicious effects
2. Enlisting trade unions to combat it
3. Create facilities for education formal and informal
4. Increase opportunities for adult employment and
fairer income distribution patterns
5. Measures to control population growth
6. Steps to improve overall socioeconomic development
7. Allowance to poor families whose children are in
schools.
These recommendations are idealistic, are extremely
difficult to be implemented. Till such time child labor
will thrive and continue, if not diminish. There is thus
urgent need for practicable and workable suggestions:
The NCLPS being the main initiative of the
Government of India constitute the backbone for
elimination of child labor activity in the country.
Specific measures which can be implemented are:
1. The employers with whom the children are
employed should be taken into confidence, and
could be motivated to have a more gentle and
humane attitude towards the children. Once
convinced, gradually they could be requested to
provide minimum facilities lacking in their work
place. 21,25 This should be done by the locally
influential political or religious leader or any
popular citizen, a social activist, a film star, etc, but
never a police or a lawyer as the latter may have
adverse effect. The employers who are already
motivated could then be looked upon as role models
and thus set examples to the other employers of that
area.
2. Work place and environment can be improved.
254 IAP Textbook of Pediatrics
3. Adequate facilities for separate area for food/eating,
safe and clean drinking water, toilets- separate for
males/females, and washing area and sanitation.
4. Provision for health check up and treatment for
medical problems at the work place, arrangement for
investigations, referrals for specialized diagnosis and
appropriate care, all these free if possible.
5. Some arrangement for rest, recreation, games,
playgrounds/open areas for outdoor games, access
to gymnasiums at nominal cost, access to entertain-
ment, television, radio, music, etc.
6. Motivation for taking formal/nonformal education
free of cost during free time or leisure hours,
attendance at night schools, street classes and
incentives to those who perform better academically17
7. Training in socially useful tasks like post, banking,
budgeting simple accounts and savings
8. Refrain from vices and addictions like smoking,
consumption of addictive drugs and substance abuse,
alcohol and sex education for prevention from
venereal diseases, AIDS and sexual abuse
9. To teach morals and how to lead a productive life
with tolerance to all the religions and social
adjustments
10. These measures are not only possible but have been
implemented successfully in various child labor
projects.21, 22
GOVERNMENT OF INDIA AND NATIONAL CHILD
LABOR POLICY AND PROJECTS (NCLP)
The concern for children and elimination of child labor
continues to be an area of great concern for the Government
of India. With a view to addressing the problem of child
labor, a National Child Labor Policy was announced in
1987 which is the genesis of the National Child Labor
Projects. A major activity undertaken by the NCLP is the
establishment of special schools of rehabilitation centers
to provide nonformal/formal education, etc. for children
withdrawn from employment in various hazardous
occupations and processes. In pursuance of this objective,
so far 100 NCLPS have been sanctioned which are being
implemented in various districts of 13 states across the
country for the rehabilitation of 2 to 11 lakh working
children. The NCLP is implemented by a district level
project society headed by the District Collector as its
chairman. He plays a key role in right from policy
formation, implementation and its eventful evaluation.
He has to play the pivotal function of holistic approach of
meaningful convergence of resources and staff at all levels
at center top officers to district and field middle level to
the lowest level functionaries, i.e. the people actually
performing the program. Thus, he has to interact and
coordinate with all the departments particularly
education, rural development, health, social welfare,
women and child development, nutrition, etc.
The NCLPS being the main initiative of the
Government of India constitute the backbone for
elimination of child labor activity in the country.
Children are the most precious resources, are the key
to the future of our planet. Every effort should be made
to protect their childhood, the time to grow, play and
learn. The first right of the child is the childhood, if that
is missed then the child misses all that goes with it. We
as the pediatricians, parents, guardians, teachers, social
workers, and caretakers—the advocates of children owe
a duty to our children and if determined we can do it.
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9. Batalvii IH. Childhood denied. The situation of children
in Pakistan. International Children’s right Monitor;
1990;1/2:14-6.
10. Banerjee SR. Child labor. In: Banerjee SR (Ed).
Community and social pediatrics, (2nd ed), JP Medical
Publishers, New Delhi 2008;375-6.
11. Burra N. Child labor in the urban industries of India.
World employment programme research, working
paper no. 25, ILO Publication, Geneva, International Labor
Office, 1988;30-3.

12. CANCL News. Child labor in major industries in India.
2002;1:23-4.
13. Falkner F. Editorial. International Child Health USA,
1994;2.
14. Ghosh S. Girl child in the SAARC countries. Indian Pediatr.
1990;57:16-9.
15. Gupte S. Child labor. Indian Pediatr 1987;24:177-80.
16. Khatu KK et al. Working children in India. Baroda. Baroda
Operation Research Group, 1983;69-70.
17. Kulshrestha JC. In: Kulshreshtha JC (Ed): Child labor in
India. New Delhi, Ashish Publishing House 1978 ;1-19.
18. Maheshwari RK, Karuanakaran M, Gupta BD, Bhandari
SR. Child labor. Indian Pediatr 1986;23:701-04.
19. Mehta Meenakshi N, Prabhu SV, Mistry HN. Child labor
in Bombay. International Jr Child Abuse and Neglect
1985;9:107-11.
20. Mehta Meenakshi N. Child abuse and neglect. In: Udani
PM (Ed): Textbook of Pediatrics, Jaypee Brothers Medical
Publishers (1st ed), New Delhi 1991;1520-28.
21. Mehta Meenakshi N. Child labor. In: Gupta BD,
Maheshwari RK (Eds): Recent trends in pediatrics,
Churchill Livingstone, New Delhi 1983;135-50.
22. Mehta Meenakshi N, Prabhu SV, Mistry HN. Types of
physical health problems in working children. In: Usha
Child Abuse, Neglect and Child Labor 255
Naidu, Kamini Kapadia (Eds): Child labor and health.
Tata Institute of Social Sciences, Bombay, 1984;135-50.
23. Satyanarayanan K, Naidu AN, Narasing Rao BS.
Nutritional deprivation in childhood and the body size,
activity and physical work capacity of young boys. Am J
Clin Nutr 1979;32:1769-75.
24. Sawant ST. Legal aspects of child labor in India, CANCL
News, 2004;27-30.
25. Shah PM. Child labor. A threat to health and develop-
ment [2nd revised edn]. Geneva, Switzerland, Defence
for Children International 1985;79-98.
26. Yajurvedi VP. Convergence and elimination of child
labor, Ministry of Labor, Government of India, CANCL
News 2003;2:16-7.
27. Mehta Meenakshi N, Banerjee SR. Child labour. In:
Parthasarthy A et al (Eds): IAP textbook of pediatrics.
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28. Pinto GJ. Child labor, New Delhi: UNICEF 1987;1-3.
ACKNOWLEDGEMENT
All photographs pertaining to this chapter are from
the collection of Prof Meenakshi N Mehta, with due
acknowledgement.
 9.1 The Principles and Practice of Immunization: T Jacob John ............................................................................................................. 258
9.2 Vaccines and Vaccine Preventable Diseases: Today and Tomorrow: AB Desai ............................................................................. 262
9.3 Newer Vaccines: AK Dutta, Anju Aggarwal ............................................................................................................................................ 265
9.4 Vaccine Storage and Handling: RK Agarwal, Digant D Shastri ........................................................................................................... 271
9.5 Management of Adverse Effects Following Immunization (AEFI): M Indra Shekhar Rao, Tanmay Amladi .................................... 277
9.6 Approach to Management of Fever in Newborns, Children and Adolescents in Office Practice: Digant D Shastri .................... 285
9.7 Fever and Fever of Unknown Origin: PP Maiya ................................................................................................................................... 295
9.8 An Approach to a Child with Fever and Skin Rash: Jayakar Thomas ............................................................................................... 302
9.9 Tuberculosis in Children: Vimlesh Seth ............................................................................................................................................... 315
9.10 Abdominal Tuberculosis: Saroj Mehta, Vimlesh Seth .......................................................................................................................... 332
9.11 Neurotuberculosis: Vimlesh Seth .......................................................................................................................................................... 336
9.11.1 Revised National Tuberculosis Control Program (RNTCP) including Directly Observed Treatment: Vimlesh Seth ...................... 342
9.12 Poliomyelitis: Ashok Gupta .................................................................................................................................................................... 350
9.12.1 Differential Diagnosis of Acute Flaccid Paralysis: AD Tewari ............................................................................................... 354
9.12.2 National Immunization Days (NIDs) as a Vital Component of
Polio Eradication Strategy: Vipin M Vashishtha, Naveen Thacker .......................................................................................... 359
9.13 Diphtheria: AP Dubey, Jaydeep Choudhury ........................................................................................................................................... 362
9.14 Pertussis (Whooping Cough): YK Amdekar ......................................................................................................................................... 364
9.15 Tetanus: AP Dubey, Jaydeep Choudhury ............................................................................................................................................... 366
9.16 Measles: AP Dubey, Jaydeep Choudhury ............................................................................................................................................... 368
9.17 Mumps: Epidemic Parotitis: Ashok K Gupta ......................................................................................................................................... 370
9.18 Rubella: AP Dubey, Jaydeep Choudhury ............................................................................................................................................... 372
9.19 Staphylococcal Infections: AK Dutta, Anju Aggarwal ........................................................................................................................... 374
9.20 Pneumococcal Disease and its Prevention: Rohit C Agrawal ............................................................................................................ 376
9.21 Hemophilus Influenzae b Disease: RK Agarwal, Anju Aggarwal ......................................................................................................... 383
9.22 Typhoid Fever: YK Amdekar ................................................................................................................................................................... 383
9.23 Leprosy: Rajeshwar Dayal ...................................................................................................................................................................... 387
9.24 Leptospirosis in Children: S Ramesh ................................................................................................................................................... 392
9.25 Chickenpox (Varicella): AP Dubey, Jaydeep Choudhury ...................................................................................................................... 394
9.26 Dengue Illnesses: Ashok S Kapse ......................................................................................................................................................... 396
9.27 Infectious Mononucleosis: S Ramesh .................................................................................................................................................. 404
9.28 Respiratory Syncytial Virus Infection: A Balachandran, SO Shivbalan .............................................................................................. 405
9.29 Rotavirus Disease: Raju C Shah ............................................................................................................................................................ 408
9.30 Rabies: Tapan Kumar Ghosh, A Parthasarathy ...................................................................................................................................... 409
9.31 Pediatric HIV Disease: Meena Malkani .................................................................................................................................................. 414
9.32 Chikungunya Fever: Utpal Kant Singh, Rajniti Prasad .......................................................................................................................... 419
9.33 Malaria in Children: Ashok S Kapse ...................................................................................................................................................... 423
9.34 Kala-azar (Visceral Leishmaniasis): Yogesh Jain, Rakesh Lodha ....................................................................................................... 440
258 IAP Textbook of Pediatrics
9.1 The Principles and
Practice of Immunization
ACTIVE IMMUNIZATION
The induction of immune response by the deliberate
inoculation of appropriate immunogen(s) in the form of
a vaccine is termed as active immunization or simply
immunization or vaccination. In practice, this term app-
lies to the inoculation of vaccine, regardless of the success
or failure of inducing the desired immune response.
PASSIVE IMMUNIZATION
The injection of pre-formed antibodies to a specific
antigen, in the form of “antiserum” or “immune
globulin” is termed passive immunization. The term
“gammaglobulin” is used to denote that the product is
not “hyperimmune” to any specific antigen, but contains
antibodies to all common antigens encountered by adults
from whom plasma had been collected for its extraction.
The physiological transfer of immunoglobulins across the
placenta to the fetus from the mother, provides natural
but passive immunity to the infant.
ANTISERA AND IMMUNE GLOBULINS
Antisera prepared in horses against tetanus toxin,
diphtheria toxin, rabies virus and snake venom are
widely used in India. Horse serum may cause hyper-
sensitivity reactions including anaphylaxis and serum
sickness. The active principle is immunoglobulins; hence
unwanted components such as albumin may be removed
and more concentrated “hyperimmune” equine
immunoglobulins may be prepared. Even with such
preparations hypersensitivity remains a problem. The Fc
part of immunoglobulins are responsible for such
responses and removing Fc portion while preserving the
antigen-binding Fab portion has become the standard
prarctice in presenting equine hyperimmune immuno-
globulins against rabies and hepatitis B antigens.
Homologous products prepared from pooled human
plasma are safer and more potent, but also more
expensive. Human immune globulins against tetanus,
rabies and HBV are available in India; elsewhere other
preparations are available, for example, Varicella-Zoster
T Jacob John
immune globulin. Apart from these antigen-specific
products, human gammaglobulin preparations are
available for intramuscular and intravenous injection
either as replacement in hypogammaglobulinemia or for
therapeutic purposes in certain specific autoimmune
disorders.
IMMUNE SYSTEM AND RESPONSES
A network of cells with the functions of detection of any
specific immune response to introduced immunogens
constitute the immune system. The cells of the immune
system include antigen-presenting cells which detect and
ingest the microbes or their subunits in the vaccine, and
process and present the immunogenic epitopes to the T
and B lymphocytes which are thus stimulated to respond.
The CD4 positive T helper (Th) cells of Th-1 type respond
and regulate cell-mediated immunity (CMI) through
various subsets of cytotoxic lymphocytes, which are
mainly CD8 positive. Humoral immunity, mediated
through the different classes of antigen-specific
immunoglobulins, called antibodies, is induced by B-
cells, but regulated by Th-2 cells. When stimulated, the
B-cells transform into plasma cells and secrete antibodies.
After adequate stimulation of the regulatory (T-cells) and
effector cells (T-and B-cells), memory cells (T- and B-cells)
survive for very long periods, ready to respond to the
same immunogens without delay, when introduced by
infection or immunization. Most protein antigens induce
complete immune responses, namely IgM and IgG
antibodies, CMI and memory. On the other hand,
polysaccharide antigens are T-cell-independent, meaning
thereby that they can only directly stimulate B-cells; the
consequent responses do not go through the class switch
from IgM to IgG and no memory cells are produced. B-
cells become mature to respond to T-independent stimu-
lation, only after the child is about two years old.
Mucosal immunization (with live attenuated viruses or
bacteria) induces mucosal (secretory) and serum IgA
responses also in addition to systemic immunity as described
above. However, mucosal protection from infection is
mediated through several factors and IgA is one of them.

The desired effect of immune responses to a vaccine
is protection from infection when exposed or at least from
disease even when infection occurs. However, most
immune responses to a variety of microbial antigens are
not protective. Live attenuated and killed viral and
bacterial vaccines elicit immune responses to a number
of antigens of the microbes. For subunit vaccines, the
“protective” antigens must be identified and included
for the vaccine to become successful.
Vaccines in Current Use
The vaccines licensed in India include live attenuated
bacteria (BCG; S. typhi Ty 21a), live attenuated viruses
(OPV, trivalent and monovalent types 1 and 3; measles,
mumps, rubella, varicella, Japanese encephalitis,
rotavirus and hepatitis A), killed bacteria (B. pertussis),
polysaccharides (pneumococcal capsular antigens with
23 serotypes; S. typhi Vi; meningococcal capsular
antigens), protein-conjugated polysaccharides (H.
influenzae b antigens conjugated with different proteis;
pneumococcal conjugated antigens of 7 serotypes), killed
viruses (rabies, polioviruses, hepatitis A, Japanese
encephalitis, influenza and Kyasanur forest disease),
structural subunits (hepatitis B, B. pertussis, papilloma
virus).
Several combination vaccines are widely used–such
as DPT, MMR, DPT-HBV, DPT-Hib, DPT-HBV-Hib.
Schedules of Immunization
The Global Expanded Program of Immunization (EPI)
designed and popularized by the WHO recommends the
use of BCG, DPT, OPV, measles, HBV and Hib vaccines
for all infants. Booster doses of DPT, DT and TT and a
second opportunity for measles vaccine are recom-
mended during later childhood and adolescence. The
National Immunization Program in India (Universal
Immunization Program, UIP) is sponsored and suppor-
ted by the union government and implemented by state
governments. UIP gives BCG, DPT, OPV and measles
vaccines and has accepted in policy the inclusion of HBV
and Hib vaccines nationally.
The recommended age schedule of the primary and
booster doses of UIP vaccines is given in Table 9.1.1.
The Indian Academy of Pediatrics recommends the
supplementation of the UIP schedule with additional
doses of some of the vaccines and adding others not in
UIP. While the UIP vaccines will be given free of charge
Immunization and Infectious Diseases 259
TABLE 9.1.1: UIP schedule (1985)
Universal Immunization Program,
Childhood Immunization Schedule
Govt of India
• BCG : Birth or 6 weeks
• OPV : Birth, 6,10, 14 weeks
16-18 months
• DPT : 6,10,14 weeks
16-18 months
• Measles : 9 months plus
• DT : 5 years
• TT** : 10 and 16 years
**if given for the first time at this age, give 2 doses at 4 weeks interval.
**
for pregnant mothers 2 doses of TT at 4 weeks interval
(if supplied by UIP) the families will have to purchase
non UIP vaccines. The IAP Immunization Time Tables
is given in Table 9.1.2.
The Logistics of Immunization
The Supply of Vaccines
Vaccines are allowed to be marketed in India, only after
licensing by the drugs controller. Every batch of vaccine
manufactured in India or imported, is checked for quality
assurance by the Central Research Institute (CRI) of the
Directorate General of Health Services at Kasauli. All UIP
vaccines are centrally purchased by the Department of
Family Welfare and distributed to the governments of
all states and union territories. Pediatricians are allowed
to collect all UIP vaccines from the local area health
authority without any charge, to be given to children
according to the national schedule. Vaccine utilization
must be accounted for by returning the list of bene-
ficiaries.
Vaccines outside the UIP list, such as measles-
mumps-rubella vaccine (MMR), hepatitis B vaccine
(HBV), H. influenzae b vaccine (Hib), typhoid fever
vaccines, Hepatitis A and Vericella vaccines which are
available for purchase from various vaccine distributors
have since been licensed in India.
The Cold Chain
All vaccines are susceptible to loss of potency, when
exposed to warm temperatures, but are very stable at 2
260 IAP Textbook of Pediatrics

TABLE 9.1.2: Revised IAP immunization time-table (2008) to 8°C. Lyophilized vaccines (BCG, Measles, MMR) and
Age Age recommended
unadjuvanted liquid vaccines (OPV) are also stable when
frozen. Adjuvanted vaccines (DPT, HBV) lose potency
Birth BCG
when frozen. If they accidentally freeze, they should be
OPV0
HepB 1 rejected. When these norms are followed, vaccines should
be used within their date of expiry.
6 weeks DTWP1/DTaP1
The system of transporting, distributing and storing
OPV1*/OPV1 + IPV1
Hib1 vaccines from the manufacturer right up to the point of
HepB2 use under refrigeration using any convenient methods,
10 weeks DTWP2/DTaP2
is referred to as the cold chain. In clinics, vaccines must
OPV2/OPV2 + IPV2 be stored in a refrigerator which maintains the inside
Hib2 temperature between 4 and 8 degrees. If temperature falls
14 weeks DTWP3/DTaP3 below 3, there is a chance for some vaccines to freeze
OPV3/OPV3 + IPV3 solid. Where vaccines are maintained in the cold chain
Hib 3 in clinics, multidose vials can be used to reduce cost.
HepB3** Partially used vials must be maintained under cold
9 months Measles conditions for subsequent use. However, care should be
15-18 months DTWP B1/DTaP B1
taken to disinfect the top, before puncturing the vial.
OPV4/OPV4 + IPVB1 Reconstituted lyophilized vaccines (BCG, measles,
Hib B1 MMR, varicella and Hib) should be used immediately
MMR1 after reconstitution. Multidose BCG or measles vaccine
2 years Typhoid# may be used over some time, but they must be used up
within 6 hours; during the interim they should not be
5 years DTWP B2/DTaP B2
OPV5 frozen, but kept cold and not exposed to bright light.
MMR2$ Any left-over contents must be discarded after 6 hours.
10 years Tdap
HPV^ Techniques of Vaccination
* OPV alone if IPV cannot be given Every pediatrician must familiarize oneself with the
** The third dose of hepatitis B can be given at 6 months
# Revaccination every 3 years
descriptive leaflet supplied by the vaccine manufacturer
$ The second dose of MMR vaccine can be given at any time 8 and also with the techniques of inoculation, side effects
weeks after the first dose and contraindications, if any.
^ Only females, three doses at 0, 1-2 and 6 months When OPV is given, the nose of the infant should not
be pinched in order to make the infant to open the mouth.
Vaccines to be given after one to discussion with parents
Instead, a slight pressure may be applied on both cheeks,
Age Vaccine between the upper and lower jaws, using the thumb and
> 6 weeks Rotavirus vaccine* a finger. There is no need to withhold breastfeeding for
PCV 7# long periods before or after giving OPV; in practice a
> 15 months Varicella$
gap of 10 to 15 minutes is usually observed to breastfeed
> 18 months Hepatitis A^
after OPV.
*Rotavirus vaccine [2/3 doses (depending on brand) at 4-8 weeks BCG must be given intradermally; the preferred site
interval]
is the lateral aspect of the convex region of the left
# PCV 7 (three doses at 6, 10 and 14 weeks and 1 booster at
15-18 months) shoulder. In infancy, intramuscular (IM) are given in the
$ Varicella (< 13 years single dose, > 13 years two doses at 4-8 anterolateral aspect of the high and subcutaneous
weeks interval) injections (SC) by pinching the posterior skin fold of
^ Hepatitis A (2 doses at 6 months interval)
triceps muscle. HBV should not be given in the gluteus.

In older children, the deltoid muscle is often chosen for
IM injections and the triceps region for SC injections.
There is no need to warm the vaccine vial in the hands
before it is drawn in the syringe, or given in the mouth.
Frozen OPV needs to be just thawed before giving.
Adverse Reactions and Contraindications
All licenced vaccines except the brain tissue rabies
vaccine (not used now a days) and OPV are virtually/
completely safe products. However, all vaccines do cause
some adverse reactions, most of which are temporary,
self-limited and inconsequential. Specific contraindica-
tions are also very few. Minor illnesses are not a
contraindication to giving any vaccine. However, if the
nature of illness is not clear, caution must be exercised
in order to avoid the vaccine from being blamed for the
worsening of an illness. Immunization is better
postponed when there is any illness that requires
treatment, unless access to the infant is difficult later or
there is an outbreak of illness, e.g. measles. Every clinic
or hospital visit or admission must be used as an
opportunity to assess the immunization needs of the child
and to offer any pending doses.
No gastrointestinal or systemic reactions occur after
giving OPV and oral typhoid fever vaccines. On rare
occasions OPV-associated paralytic illness has been
documented in western countries, either in the vaccinee
or in adults in close contact with the vaccine. Its frequency
in India is unknown but it appears to be more common
than previously recognized; adults are not at risk in India,
since virtually all adults are immune due to prior
asymptomatic infections. Since hypogamma-
globulinemia has been noted as a risk factor for vaccine-
virus-induced paralysis, the recommendation is to give
the non-infectious killed polio vaccine to immuno-
deficient children. Indian experience is scanty and the
risk is not considered to be a factor in our policies. Infants
born to HIV-infected mothers, whether or not themselves
HIV-infected, are usually given OPV without problems.
DPT vaccine causes local inflammation and fever in
a proportion of vaccines. Paracetamol is advised to
prevent or reduce symptoms. If any neurological
reactions other than febrile convulsions are observed
within days after DPT, the infant must be carefully
assessed for any pre-existing disease process. There is
no evidence that DPT per se causes any neurological
illness; in specific instances of difficulty, expert opinion
must be obtained and discussed with the family before
continuing or discontinuing further doses of DPT.
Immunization and Infectious Diseases 261
The immunization clinic staff must be trained to
recognize vasovagal syncopal reactions and anaphylaxis
in vaccinated infants/children. While it is true that rural
health workers vaccinate at convenient places in the
villages where there are no facilities for resuscitation, and
in spite of no liability on the part of the doctor for a
genuine adverse reaction following vaccination, the clinic
must be equipped to handle such events. Any serious
event, not recognized as the usual side reaction of the
vaccine, must be reported to the local area health
authority.
Pulse Immunization
Herd Effect and Herd Immunity
Immunization against a specific disease mimics infec-
tion by the causative microbe in the inoculated
individual, inducing immunity without the risk of
disease. Only the immunized children are benefitted; the
unimmunized peers remain fully susceptible to infection
and disease, when exposed. However, as increasing
proportions of children in a community are immunized
against a specific disease, the transmission/circulation
of the infectious agent may be retarded; hence, the
incidence of disease may decline even in the unimmuni-
zed segment of the childhood population. This pheno-
menon is called the “herd effect” of the immunization
activity.
The term “herd immunity” refers to the proportion
of individuals in the population that are not susceptible
to the disease due either to natural infection or to
immunization or both. As immunization coverage
increases, herd immunity increases and herd effect may
become manifest. “Herd effect” can be recognized, only
if the incidence of disease is measured before and
during/after the immunization activities.
The Method and Purpose of Pulse Immunization
An epidemic of an infectious disease reaches a peak and
declines rapidly because of the very high herd immunity
consequent upon the epidemic spread of the agent. The
transmission may be interrupted soon after an epidemic.
Only when sufficient numbers of susceptible children
accumulate overtime, will the agent re-establish itself in
the community. This principle is applied in pulse
immunization. When a large proportion of susceptible
children are vaccinated in a short period of time, an
262 IAP Textbook of Pediatrics
epidemic is simulated. The consequent “herd effect”
usually results in break of transmission of the agent. For
epidemic-prone diseases with more than one year of
inter-epidemic intervals, such as poliomyelitis and
measles, the pulsing of the vaccine may be conveniently
given at annual intervals. The term pulse immunization
is given to denote the repetitive campaigns at annual
intervals.
The herd effect of the total doses of vaccine given by
pulse would be much higher than when given routinely
throughout the year. In other words, better “herd effect”
for the same “herd immunity” is achieved with annual
pulse immunization. In developing countries where the
transmission of polio viruses is not interrupted in spite
of high coverage with the routine use of OPV, pulse
9.2 Vaccines and Vaccine Preventable Diseases:
Today and Tomorrow
Experiences of the past lead us to a better future, hence,
it is important to know the events of the past. Infectious
diseases are as old as mankind. People knew how to deal
with some of the infections using herbs and many a times
they succumbed to infections. With increasing civiliza-
tion and documentation, India, China, Egypt had their
own manuscripts. Increasing European influence made
the literature in various European languages especially
English more popular.
The practice of variolation was known since 1000 BC
in India and China, but the first documentation was by
Jenner in 1798 AD. He demonstrated use of variolization
in the prophylaxis of smallpox. Almost a century later,
Louis Pasteur the pioneer of immunology, from France
observed the process of “attenuation” and its use in
prophylaxis against infections. He suggested that terms
“vaccine” and “vaccination” should be used for all
substances and procedures useful for prevention of
infectious diseases.
Pasteur Institute established in Paris mainly for
research on rabies, soon became a seat for studies on
method can be applied to interrupt it. Since measles virus
is very contagious, it will be virtually impossible to
interrupt its transmission without resorting to pulsing
of vaccine at intervals, that are shorter than the regional
inter-epidemic intervals.
BIBLIOGRAPHY
1. John TJ. Quovadis, Expanded Programme on Immuni-
zation? Indian J Med Res 2007;125: 13-6.
2. John TJ, Sammel R. Herd immunity and herd effect: New
insights and definitions. Euro J Epidemiol 2000;16:
601-6.
3. Writing Committee Singhal T, Amdekar YK, Thacker N.
Policy Update. IAP Committee on Immunization. Indian
Pediatr 2007; 44:390-2.
4. Writing Committee Singhal T, Amdekar YK, Agarwal
RK, Policy update. IAP committee on immunization.
Indian Pediatr 2008;45:645-6.
AB Desai
various vaccines. The antiserum therapy for prevention
and treatment of diphtheria and tetanus was soon found
out by Von Behring and later on led to the discovery of
“toxoid”, the detoxified toxin.
Twentieth century has been most memorable. The
important events of the century are:
i. Isolation of bacteria and viruses.
ii. Growing them in tissue cultures.
iii. Production of various vaccines both against
bacteria and viruses.
vi. Production of tissue culture vaccines against virus.
v. Advances in cell biology, genetic engineering and
in-depth understanding of immune mechanism
leading to development of “recombinant DNA
vaccines”.
vi. Eradication of smallpox by universal immuni-
zation.
vii. Pledge to eradicate poliomyelitis by 2000 AD.
viii. Pledge to eliminate neonatal tetanus and reduce
the mortality due to measles.
 Immunization and Infectious Diseases 263

TABLE 9.2.1: Microbial vaccines* TABLE 9.2.3: Polysaccharide vaccines*

Years Events Years Events

1892 Cholera vaccine by Haffkine 1968 Meningococcus C vaccine (Gotschlich)
1896 Typhoid vaccine by Wright 1971 Meningococcus A vaccine (Gotschlich)
1913 Diphtheria immunization, toxin-toxoid by Behring 1978 Vaccine against pneumococcal infection
1921 Tuberculosis vaccine by Calmette and Guérin (BCG) 1980 Vaccine against Haemophilus influenzae type b
1984 Vi Polysaccharide typhoid vaccine
1923 Diphtheria toxoid by Roman and Glenny
*Adapted
1923 Pertussis vaccine by Madsen from “Vaccination”—Nizar Ajjan (3rd edn)
1927 Tetanus toxoid by Roman and Zoller
1972 Acellular pertussis vaccine
*Adapted TABLE 9.2.4: Vaccines under study
from “Vaccination”—Nizar Ajjan-(3rd edn)
Cytomegalovirus vaccine
ix. Many old vaccines like typhoid, rabies, yellow Gonococcal vaccine
fever, influenza, etc., are totally modified and new Vaccines against parasites—malaria, toxoplasmosis
“safe”, effective and economic vaccines are made Synthetic vaccines
available. Vaccines using genetic engineering
x. Some old vaccines like cholera vaccine are dis- Idiotypic vaccines
carded and attempts are on to prepare better and Vaccine against dental caries
safer vaccines. Leprosy vaccine
There are about 200 infectious diseases caused by Vaccine against AIDS
bacteria, viruses, parasites and fungi. Some 21 vaccines *Adapted from “Vaccination”—Nizar Ajjan (3rd edn)

TABLE 9.2.2: Viral vaccines

Years Events are available to fight against 25 diseases and many more
are on the way (Tables 9.2.1 to 9.2.4).
Viral Vaccines discovered before the development of tissue
culture techniques* “What will happen to various diseases in 21st
1932 Yellow fever vaccine by Sellard and Laigret century” and “how many vaccines will be available” are
1937 Yellow fever 17D vaccine by Theiler—the first vaccine the questions to be considered. The vaccination schedule
prepared on embryonic chicken egg as proposed by Plotkin is shown in Table 9.2.5. It must
1937 First inactivated influenza vaccine by Salk
1949 Mumps vaccine by Smorodintsev (live-attenuated be re-emphasized that vaccination or immunization is a
vaccine) lifelong need and does not end with the end of
Viral vaccines discovered since the development of childhood.
tissue culture technique This is well-supported by the recent development of
1949 Tissue culture of the poliomyelitis virus (Enders,
Robbin, Weller) a vaccine to prevent cervical cancer in women. It is
1954 Inactivated poliomyelitis vaccine by Salk known that 99 percent of cervical cancer is caused by
1957 Live attenuated oral poliomyelitis vaccine by Sabin human papilloma virus or HPV. HPV16 is the strain
1960 Measles vaccine first the Edmonston B (Enders) then linked to 50 percent of cervical cancers. The vaccine is
the Schwarz
1962 Rubella vaccine (Weller, Neva and Parkmann) developed including HPV16 and has been tested in
1966 Mumps vaccine (Weibel, Buynach, Hillemann, then sexually active women. None of them got infected with
Takahashi) HPV16 in a follow-up up to 18 months. Of course, more
1967 Rabies vaccine cultivated on human diploid cells trials and longer follow-ups will reveal the future and
(Wiktor)
1973 Chickenpox vaccine (Takahashi) we hope to prevent cervical cancer in large number of
1976 First administration of the vaccine against hepatitis women. A vaccine containing HPV16 and HPV18
B (Maupas, then Hillemann) together is expected to prevent 70 percent of cervical
1984 Hepatitis A vaccine cancer.
Rotavirus vaccine
Human papiloma virus (HPV) vaccine By 2008 the Human Papilloma Virus vaccine is
available for use in sexually active women (for details
*Adapted from “Vaccination”—Nizar Ajjan-(3rd edn)
read the section on newer vaccines).
264 IAP Textbook of Pediatrics

TABLE 9.2.5: Predicted vaccine schedule for During the World Summit in 1990 at Washington,
2025 (Plotkin) USA, the thought of good-high quality vaccine, accessi-
Age Vaccine ble to all the world’s children, protecting them against
all major infectious diseases, administered in one or two
0-1 year BCG, HBV, DPT, OPV, Hib, measles, hepatitis A, oral doses was conceived. CVI is a coalition of inter-
RSV (resp. syncytial virus) parainfluenza, national agencies, national governments, nongovern-
rotavirus, adenovirus, malaria, dengue, hepatitis
mental organizations, public and private sector com-
E, enterotoxigenic E.coli, cholera, Shigella,
Campylobacter, Pneumococcus and panies. It was established in 1991 to promote, coordinate,
Meningococcus V. and accelerate the development and introduction of
1-2 years MMR, Booster, DPT, OPV, and Hib; Lyme improved and new vaccines and thereby enhance the
disease, dental caries, typhoid, schistosomiasis, protection of the world’s children against infectious
rabies, varicella. diseases.
4-6 years Boosters DPT, typhoid, HBV Efforts of CVI and GPV (Global Program on
11-12 years Cytomegalovirus, Epstein-Barr, parvovirus, HIV, Vaccines and Immunization) of WHO (immunization)
herpes, human papilloma.
Adults Pneumococcus, influenza
TABLE 9.2.6: Vaccines for Asian children in
the 21st century (Lolekha S, 1997)
Regards the various vaccines under study listed in
Table 9.2.4. Rotavirus vaccine another revised vaccine is Vaccines usually used routinely
• Oral polio vaccine (OPV), injectable polio vaccine (IPV)
now available. Vaccines against leprosy, aids, malaria
occasionally
are not yet available for use. The trials have not been • BCG
successful at various stages. • Diphtheria-pertussis-tetanus
Many new vaccines have been recently tried like the • Hepatitis B
vaccine against dengue fever. Earlier respiratory • MMR—measles, mumps, rubella
syncytial virus vaccine had failed. Now fresh attempts • Typhoid Vi—strongly recommended
are taken up. Various types like live attenuated vaccine Traveler’s vaccine while traveling to endemic areas
and subunit vaccines are under trial. It is learnt that live Viral vaccines
virus attenuated virus vaccine is not very efficacious. • Hepatitis A,C,D
Various old vaccines are modified like BCG can be • Rotavirus
• Respiratory syncytial virus (RSV)
inhaled instead of being administered intradermally and
• Dengue
another advantage is that it does not require refrigeration. • Herpes simplex
Animal trials are successful. • Japanese encephalitis
Vaccine is defined as a substance which prevents • Varicella
infectious diseases. There is a report that a vaccine is
Bacterial
developed for cure of hypertension. Whether it could be • Leprosy
called a vaccine? Or will there be a need to redefine • Cholera
vaccine? This is a new field where substances are • Meningococcus polysaccharide
developed to neutralize harmfully activated hormones, • Pneumococcus
to cure conditions like hypertension. • Hib (Haemophilus influenzae B)
• Shigella
• Streptococcus
CHILD VACCINE INITIATIVE
Parasitic
WHO with the help of the research scientists is in the • Malaria
search of an ideal universal vaccine. The process is • Kala azar
termed child vaccine initiative (CVI). The goal is to have
Through pregnant mother immunization
a vaccine which could be orally administered in one or
• Tetanus toxoid
more doses after birth which can prevent many infectious • Group B streptococcal vaccine
diseases.

will help world’s children to fight against various
infectious diseases in the current century. The Global
Alliance on Vaccines and Immunization (GAVI) initiated
in 1999 is one step forward and aims at immunization of
all children against all diseases. There is already a shift
to the right in the age groups affected by some vaccine
preventable diseases, e.g. measles is affecting older
children, the whooping cough is more in adults. The
changes may make the vaccination program a lifelong
and even growing one. The world in 21st century will
not even see occasional faces with pox marks, will not
see any new cases of poliomyelitis, no neonatal tetanus
and no deaths due to measles. The rotavirus vaccine will
possibly prevent 4,79,000 deaths annually, 3,50,000 of
them from low income countries alone (Table 9.2.6 ).
GAVI has also launched a priority project on safety
of immunization practices in 1999. Discoveries in
molecular biology, immunology and genomics have
added to safety and efficacy in the development of potent
vaccines.
Safe vaccine administration is equally important. The
needle pricks besides being painful can also lead to various
9.3 Newer Vaccines
The ultimate goal of any immunization program
is to eradicate the disease. However, the immediate goal
is to reduce mortality and morbidity of individuals and
groups. In the Universal Immunization Program (UIP),
only six vaccine preventable diseases are included taking
into consideration, the epidemiology, cost effectiveness
and availability of the vaccine in the country. In the last
decade, several new vaccines have been developed and
are available in the country. Physician should be able to
counsel the parents regarding the efficacy and impor-
tance of these vaccines in the present health situation.
This chapter includes a brief description of these
vaccines.
Typhoid Vaccine
Typhoid vaccine was included in the National Immu-
nization Schedule till 1987 but then discontinued because
vaccine had lot of side effects and it was believed that
typhoid had low mortality. Now typhoid is occurring in
younger age groups and there is emergence of multiple
Immunization and Infectious Diseases 265
other complications including infections, bacterial or viral.
Therefore, various methods of vaccine administration are
considered which can avoid pricks or make it less painful,
e.g. intranasal administration. During the mass immuni-
zation programs and also for individuals shot guns have
been used which avoids the needle prick. The syrings and
needles used have also been changed. To avoid intro-
duction of viral infections by reusing the syring and
needles, autodisabled syringe are used which give the
precise dosage and cannot be reused. Use of devices are
also on the way wherein there is no needle prick.
Safe, effective, potent vaccines well-preserved by
various methods and safe, needle free administration will
make the immunization programmes effective and
widely acceptable and tear free as majority of recipients
are children.
A new antihypertension vaccine containing the action
of angiotensin in adults has been successfully tried with
3 doses in a 0, 4, 12 weeks schedule is promising in adults.
Large scale trials are however needed. Similarly a new
inhaled and anti TB spray dried vaccine has produced
promising recuts in abnormal model.
AK Dutta, Anju Aggarwal
drug resistance typhoid. Hence, the need for typhoid
vaccines. There are three types of typhoid vaccines
available.
Parenteral Killed Whole Cell Typhoid Vaccine
The vaccine contains 1000 million heat killed phenol
preserved or acetone inactivated bacteria per ml. The
former is a liquid vaccine and the acetone killed is freeze
dried. This vaccine is now not available in India.
Efficacy The efficacy was 55-65 percent.
Dose and schedule: Dose for six months to ten years is
0.25 ml and more than 10 years is 0.5 ml subcutaneously
over the deltoid area and the second dose is repeated
after four weeks.
The booster dose of the same volume of vaccine is
recommended every three years.
Storage: The vaccine is stored in dark at 2º to 8ºC. The
liquid vaccine should not be frozen.
266 IAP Textbook of Pediatrics
Adverse reactions: Local pain, swelling, redness, fever
and severe headache. Very rarely, severe reactions like
anaphylaxis, chest pain, liver damage, neurological
problems and reactive arthropathy could occur.
Precautions and contraindications: The vaccine is con-
traindicated in persons with a history of allergic or severe
reactions following previous dose and in pregnancy.
Live Oral Typhoid Vaccine
Ty21a live attenuated oral typhoid vaccine was available
as enteric coated capsule form. Ty21a is a mutant strain
developed by genetic manipulations and is devoid of “O”
antigen. This vaccine is not available in India.
Dose and schedule: The vaccine is administered as oral
capsule in three doses on alternate days (0,3 and 5th day)
and a booster dose every three years. This vaccine can
be given only after 5 to 6 years of age, as children below
this age group cannot swallow the capsule. Moreover,
the efficacy of the vaccine below five years of age group
has not been studied. The vaccine is stored at 4° to 8° C.
Efficacy: The efficacy of the vaccine in Egyptian study
was found to be as high as 96 percent. In subsequent
trials, the efficacy of the vaccine varied from 52 to 69
percent.
Adverse reactions: Fever, vomiting and abdominal pain
occurs rarely (< 1%). There are no contraindications.
Vi Polysaccharide Typhoid Vaccine
The Vi antigen of S. typhi is a capsular antigen with
known virulence property of the organism and is
available as injectable vaccine containing 25 microgram
purified Vi capsular polysaccharide per dose.
Dose and schedule: Since, this is a capsular poly-
saccharide vaccine, it is effective after the age of two
years. The dose is 0.5 ml single injection intramuscularly
in the deltoid region above the age of two years with
one booster dose every three years. The vaccine is stored
at 4° to 8° C.
Efficacy: The efficacy of the vaccine varies from 64 to 72
percent in various studies.
Adverse reactions: Pain, erythema and induration at the
local site and rarely fever. All the reactions are of mild
nature and self-limiting.
Inactivated Polio Vaccine (IPV)
This vaccine is prepared from the virus of the original
salk strain grown in monkey's kidney, human diploid or
vero cell line and is inactivated by formalin. Presently, it
is available as enhanced potency vaccine containing 40,
8 and 32 D antigen units against types I, II and III polio
viruses in 0.5 ml of the vaccine. The vaccine is also
available as quadruple vaccine along with DPT.
Dose and schedule: Three doses of 0.5 ml intramuscularly
along with DPT vaccine, can be given according to the
DPT schedule (6, 10, 14 weeks or 2, 3, 4 months or 2, 4, 6
months) of the country. The booster dose is recommen-
ded along with DPT at 18 months and five years of age.
After 6 months 2 doses are required.
Efficacy: The efficacy of the enhanced potency IPV is over
95 percent in various studies.
Adverse reactions: Local minor adverse reaction, e.g.
pain, swelling and erythema which is self-limiting.
Advantages over OPV: IPV is more thermostable than
OPV. It is recommended to be stored at 4° to
8° C.
It is more immunogenic and can be combined along
with DPT. It is the vaccine of choice for immuno-
compromised children.
Limitations of IPV: Apart from being costly, this vaccine
is not suitable for preventing circulation of wild polio
virus in the community which is the ultimate goal of polio
eradication.
Acellular Pertussis Vaccine
The whole cell pertussis vaccine in DTwP occasionally
causes major side effects. Hence, further modification of
the pertussis component has been made, by removing
the toxic fraction, i.e. lymphocyte promoting factor (LPF).
Acellular pertussis vaccine may be 2 component, 3
component or 5 component depending on presence of
toxin, pertactin, filamentom hemagglutinin, etc. This
vaccine has been in use in Japan since 1981.
Dose and schedule: The vaccine is a part of DTaP and
comes in liquid form. The dose is 0.5 ml administered
deep intramuscularly and is given at 6, 10 and 14 weeks
and the booster doses at 16 to 18 months and at five years
of age. The vaccine is stored at 4° to 8° C and should not
be frozen.

Adverse reaction: Local and systemic adverse reactions
like swelling, erythema, tenderness, fever and crying
episode are very mild and self-limiting.
Hepatitis B Vaccine
Hepatitis B vaccine has been included as seventh EPI
vaccine by WHO since 1992. It is included in immu-
nization schedule of Delhi and strategies are being
developed to include in the National Immunization
Schedule. Now only recombinant vaccines are used and
plasma derived vaccine is no more available.
Recombinant Vaccine
HbsAg DNA sequence from hepatitis B virus has been
isolated and integrated in the genome of common baker’s
yeast, to produce recombinant vaccine. This vaccine is
highly immunogenic and is free from transmission of
blood-borne diseases.
Dose and Schedule
Vaccine is to be given in a dose of 10 μg (0.5 ml) till 19
years and 20μg (1ml) after that.
The recommended schedules are:
1. Birth, 6 and 14 weeks
2. 6, 10 and 14 weeks (combined DTPwc/hepatitis B can
be preferred).
3. For older children, adolescents and adults the
recommended schedule is first dose, after 1 month
and after 6 months.
Efficacy
Vaccine efficacy is more than 94 percent after recom-
mended doses.
Adverse Reactions
Minimal local reactions at the injection site which are
self-limiting could occur.
At present booster dose of vaccine is not required.
Younger the age of infection more the chronicity of the
disease. To prevent mother to child transmission the
vaccine should be given soon afterbirth preferably within
12-48 hours. Till the vaccine is included in the National
Immunization schedule it is recommended in high-risk
groups, e.g. babies born to HBsAg positive mothers,
patients on hemodialysis, intravenous drug addicts,
homosexuals, medical and paramedical personnels,
Immunization and Infectious Diseases 267
thalassemics and hemophilics requiring repeated blood
transfusions.
Hepatitis A Vaccine
Most widely available hepatitis A vaccine contains
formaldehyde inactivated hepatitis A virus adsorbed
onto aluminium hydroxide.
Dose and schedule 2 doses of 0.5 ml I.M. containing
720 ELU in children 1 to 18 years of age. After 18 years
vaccine containing 1440 ELU in 1.0 ml is used at 0 and 6
months, 0 being the elected date and a booster after 6
months.
Storage Vaccine should be stored at +2 to +8°C and ot
to be frozen.
Adverse reaction Minimal, self-limiting local reactions
at injection site.
It is used in high-risk groups like food handlers,
travellers, persons working in nurseries and day care
centers. It can be given with other vaccines but at a
separate site. It can be given after 18 months in children.
It can be used as a routine vaccine because with
increasing sanitation and safe water supply incidence of
subclinical natural infection is low.
Other Hepatitis A Vaccines
Live attenuated hepatitis A vaccine has been manu-
factured from the H 2 strain in China. Dose is 1 ml
subcutaneous in children more than 2 years of age single
dose has been recommended by the manufacturers
longterm efficacy studies are awaited
Virosomal based hepatitis A vaccine has been
introduced. This vaccine is given in a dose of 0.5 ml
intramuscularly. It has faster induction of antibodies and
lesser side effects.
Hemophilus Influenzae b Vaccine
At present, only conjugated polyribosyl ribitol
phosphate (PRP) vaccine is used. There are four types of
conjugate PRP Hemophilus influenzae vaccines available.
They are PRP-D, PRP-CRM, PRP-OMP and PRP-T.
PRP-D
In this vaccine conjugation of PRP antigen with diph-
theria toxoid is used. This vaccine has not been found to
be effective in infants, but is effective in children after
268 IAP Textbook of Pediatrics
the age of one year. Hence, it is not recommended for
primary immunization in infants.
PRP-CRM (PRP-HBOC)
In this combination, CRM197 protein from non-toxic
mutant diphtheria toxin is used. This vaccine is highly
immunogenic. The efficacy is more than 97 percent after
three primary doses, given at 2, 3, 4 months or 2, 4, 6
months or at 6, 10, 14 weeks along with DPT schedule.
The fourth dose is recommended at the age of 12 to 15
months. The vaccine is administered intramuscularly. If
the vaccine is missed before 6 months, then 2 doses at 1
to 2 months of interval is allocated up to 12 months
followed by one booster dose at 12 to 15 months of age.
After 12 months till 15 months primary immunization
consists of 1 dose followed by another dose after 15
months. After 15 months till 5 years of age only one dose
is recommended.
PRP-OMP
Conjugation of PRP with outer membrane protein of
meningococcus is done to produce this vaccine. The
advantage of this vaccine is that only two doses at two
months interval for primary vaccination with a booster
at 12 to 15 months of age, produces more than 97 percent
protective efficacy.
PRP-T
Tetanus toxoid is used in this vaccine for conjugation.
This vaccine is highly efficacious with almost 100 percent
seroconversion. The dosage schedule is same as in PRP-
CRM vaccine with very minimal self-limiting adverse
reactions.
Pneumococcal Vaccine
A 23 valent capsular polysaccharide vaccine is available.
The vaccine covers most of the prevalent strains of
Pneumococcus causing disease. It is given as a single dose
of 0.5 ml subcutaneously or intramuscularly in children,
more than two years of age. The vaccine being a capsular
polysaccharide, is not immunogenic in children of less
than two years of age. At present, the vaccine is
recommended in children with sickle cell disease,
functional and anatomic asplenia, nephrotic syndrome,
patients with cerebrospinal fluid leak and children with
malignancies.
Polysaccharide vaccine fails to elicit a protective
immune response in children less than 2 years, though
80 percent of the preumoccocal disease occur in children
less than 2 years of age.
7 Valent Conjugate Vaccine (PCV7)
Vaccine contains 7 purified capsular polysaccharide of
S. pneumoniae coupled with a non logic variant of
diphtheria to CRM 197. It has serographs 4, 9v, 14, 19f,
23f, 18c, 16 b responsible for 85 percent of invasive disease
and 65 percent of otitis media in western countries. It
covers nearly 50 percent of the prevalant stains in India.
Dose is 0.5 ml IM. Schedule is same as DPT 6, 10, 14 weeks
with a booster at 15-18 months. After 6 months 2 doses
are required, single dose is required after 2 years.
Now 10 valent and 13 valent conjugate vaccines are
undergoing.
Meningococcal Vaccine
A capsular polysaccharide meningococcal vaccine is now
available. Available vaccines are monovalent group A
or C, bivalent A and C and a tetravalent vaccine
containing group A, C, Y and W-135. Each dose contains
0.5 ml containing 50 micrograms of each polysaccharide
available as lyophilized powder.
Dose and schedule: The vaccine is given as 0.5 ml single
dose after the age of two years subcutaneously. The
vaccine is not recommended for routine use and is to be
given in epidemic situation and in children with
functional asplenia and complement deficiencies.
Efficacy: Following single dose the vaccine efficacy in
children has been found to be 90 percent and in children
older than two years 75 percent. The vaccine is effective
for at least three years. The vaccine has no efficacy on
carrier state.
Mumps Vaccine
This is a live attenuated vaccine produced from either
Jeryl Lynn strain, Leningrad-3 or Urabe 3 strain. The
vaccine is available as combined vaccine with measles
and rubella (MMR) vaccine.
Dose and schedule: A single injection of 0.5 ml of vaccine
containing 5000 TCID either alone or in combination with
measles and rubella has been found to give an immunity
against mumps. The efficacy varies from 93 to 97 percent.
No booster dose is recommended. The vaccine is
recommended at 15 to 18 months of age.

Adverse reactions: It is a very safe vaccine. Minor allergic
reactions, febrile seizure, rash, pruritus and encephalo-
pathy (very rare) have been reported.
Contraindications: In patients with immunodeficiency
diseases and lymphoreticular malignancies, mumps
vaccine should not be administered.
Rubella Vaccine
It is a live attenuated vaccine containing RA 27/3 strain
grown in human diploid cell line and is available for use,
either as monovalent rubella vaccine or in combination
with measles and mumps, as MMR vaccine.
Dose and schedule: The vaccine is usually given as single
IM or S/C injection along with mumps at the age of 15
to 18 months. However, the vaccine can be administered
at any age. It is contraindicated in pregnancy and in
immunocompromised and in malignant conditions.
Rabies Vaccine
For prophylaxis against rabies, several vaccines have
been made available.
Nerve Tissue Vaccine
The vaccine (Sample vaccine) contains, 5 percent weight
by volume rabies virus infected sheep brain. The dose
depends on the age and on the class of exposure and
varies from 2 ml to 5 ml and 7 to 14 doses are given
subcutaneously in the abdomen. The efficacy of the
vaccine is less than optimal. This vaccine is nowadays
not used because of severe adverse neuroparalytic
reactions, e.g. postvaccination myelitis and ascending
paralysis including death. The vaccine is occasionally
used in places where the other vaccines are not available.
This vaccine is used in postexposure prophylaxis.
Tissue Culture Vaccine
Following tissue culture vaccines are for both pre- and
post-exposure prophylaxis.
Human Diploid Cell Vaccine
It is produced from fixed rabies virus grown in W-1-38
or MRC-5 human kidney cell culture line. Side effects
are mild local reactions like pain, erythema, itching,
headache, nausea and abdominal pain. Efficacy is almost
100 percent. The vaccine is costly.
Immunization and Infectious Diseases 269
Purified Chick Embryo Vaccine
This vaccine is propagated in primary chick fibroblast
cell. This vaccine is also very highly immunogenic. The
adverse reactions are very mild local reactions and
lymphadenopathy, headache, lethargy and allergic skin
reactions.
Verocell Vaccine
The vaccine is produced by using continuous cell line,
e.g. baby hamster kidney fibroblasts. The efficacy is
excellent, i.e. 100 percent and very mild local and
systemic reactions.
Dose and schedule: Post-exposure prophylaxis—All
tissue culture vaccines are given in 5 doses on 0, 3, 7, 14
and 30 days. The vaccine is given intramuscularly in the
deltoid region or in anterolateral aspect of thigh in
infants. The vaccine is not given in gluteal region. The
dose is same irrespective of age viz 2.5 IU per dose in 1
ml or 0.5 ml as recommended by the manufacturer.
Preexposure prophylaxis: This is indicated in persons at
high-risk of exposure, e.g. laboratory staff working with
rabies virus, veterinarians, animal handlers and wildlife
officers. Three doses on 0, 7, 28 days are recommended
with reinforcing doses given 1 to 3 years, if the antirabies
antibody titer falls below 0.5 IU/ml.
If persons who have received full course of post-
exposure (re-exposure) prophylaxis get an animal bite
i.e, suspected rabies within 5 years of the last completed
dose, two doses on day 0 and 3 and after 5 years full
course of day 0,3,7,14 and 30 days of 5 doses are
recommended.
Varicella Vaccine
A live attenuated varicella (LAV) vaccine containing
OKA and DKA/Merck strain is now available. Since
1986, it has been given to all children in Japan as a routine
and is a part of routine immunization in USA.
Dose is 0.5 ml subcutaneously and as single dose in
children one year or older till 13 years. Two doses at an
interval of 1 month is recommended after 13 years of
age. It has an efficacy of 95 to 100 percent and common
side effect is varicella like rash and fever 1 week after
vaccination. It is indicated in immunocompromised
children and group of high-risk children like children
suffering from leukemia and malignant tumors, AIDS,
chronic kidney disease, nephrotic syndrome and children
270 IAP Textbook of Pediatrics
on long-term steroids. Vaccine is also recommended for
all adults and adolescents above age of 15 years, who
have not been exposed to chickenpox.
Influenza Vaccine
Influenza vaccine is available as whole cell or split virus
vaccine. Strains of influenza virus used in the vacine have
to be changed every year according to the prevailing
strains in the geographical area. In children less than 13
years, two doses of split virus vaccine in dose of 0.5 ml
intramuscularly at one month interval is recommended
for first time. Thereafter single dose should be given
every year. It is recommended in high-risk groups, e.g.
immunocompromised children and children with
cardiopulmonary diseases as well as elderly people over
65 years of age. Now protein of influenza A virus which
is common to all strains of influenza A.
Japanese B Encephalitis Vaccine
Inactivated vaccine: An inactivated vaccine derived from
infected mouse brain is recommended for travellers to
endemic areas as well as in endemic areas. Vaccine is
given in a dose of 1 ml subcutaneously on day 0, 7 and
30 in travellers planning to spend more than 30 days in
endemic area at least 10 days before travel. It is also
recommended in persons residing in areas where
Japanese B encephalitis is endemic or epidemic. Dose in
children of 1-3 years of age is 0.5 ml. In India JE vaccine
manufactured at Kasauli is recommended in a dose of
0.5 ml, 2 doses at 10–14 days interval with a booster at
1 year. This vaccine is 80–88 percent efficacious.
Cell Cultured Live SA 14-14-2 Vaccine
This vaccine contains neuro-attenuated strains of JE virus
(SA 14-14-2). Dose is 0.5 ml subcutaneously single dose
at 1 year of age with a booster after 1 year and a second
booster after 2 years. Vaccine is about 85 percent effica-
cious. It is recommended in endemic areas and in
travellers.
HPV Vaccine
Human papilloma virus serotypes 16 and 18 are
implicated in 70 percent of cervical cancers globally.
Types 6 and 11 are known to cause 90 percent of
anogenital warts.
Quadrivalent Vaccine
L1 protein of HPV serotypes 16, 18, 6, 11 are made into
moninfectious virus like particles using recombinant
DNA technology. Dose is 0.5 ml at 0, 2, 6 months.
Recommended age of starting the schedule is 10-12 years.
Bivalent Vaccine
This contains HPV serotype 16 and 18. Dose is 0.5 ml at
0, 1, 6 months. Recommened age of starting is 10-12 years.
Rotavirus Vaccines
Currently two live oral vaccines are available.
A monovalent attenuated human rotavirus vaccine
derived from human rotavirus strain 18-12 that contains
GIPIAC strain. It is available as a lyophilised vaccine to
be reconstituted with a diluent. First dose can be given
at 6 weeks (not later than 12 weeks). Second dose is given
4 weeks later. 2-dose schedule should be completed by
16 weeks and not later than 24 weeks.
A pentavalent human bovine reassortant vaccine and
consists five reassortants between the bovine WC 23
strain and human G1, G2, G3, G4 and P1A (8) rota virus
strain. Recommended schedule is 3 oral doses at 2, 4, 6
months starting at 6-12 weeks with a interval of 4-8
weeks. Vaccination should not be started after 12 weeks.
All 3 doses should be given before 32 weeks. It is available
as a liquid vaccine.
Vaccines are 85-98 percent efficacious against
rotavirus gastroenteritis and 42-59 percent efficacious
against hospitalization from diarrhea of any cause.
Tdap Vaccine
Immunity followting primary/booster DTP/DTaP
vaccination waves over 5-10 years. Standard strength
DTP and DTaP vaccines cannot be used in children above
7 years due to increased reactogenicity. Tdap vaccine
lower doses of diphtheria and acellular pertusis compo-
nents, hance can be used in children above 7 years.
Systemic side effects are rarely seen. A dose of this
vaccine can be given at 10 years.
Combination Vaccines
Combination vaccines are defined as multiple antigens
to prevent diseases or to protect against multiple strains
of infectious agents causing same disease. With the

increasing number of vaccines a child receives up to 13
pricks in the first year of life. Combination vaccines will
reduce the number of pricks, number of visits, increase
compliance and decrease the cost of vaccination as well.
Currently combinations available are hepatitis A +
hepatitis B, DPT + Hib, DPT + hepatitis B, DPT + killed
polio and DPT + killed polio + Haemophilus influenzae B
(Pentavalen). Efforts are on to combine as many vaccines
as possible, e.g. hepatitis A, hepatitis B, DPT, pneumo-
coccal and Hib vaccines.
BIBLIOGRAPHY
1. Committee of Infectious Diseases Amterican Academy
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Red Book, 27th Ed. 2006.
2. Dhah RC, Shah NK, Kukerja S. IAP Guide Book on
Immunization (4th edn). Committee on Immunization,
Indian Academy of Pediatrics. 2005-2006.
9.4 Vaccine Storage and Handling
The ‘cold-chain’ is the system of transporting and
storing vaccines within the temperature range of 2°C to
8°C from the place of manufacture to the point of
administration. This temperature range is recommended
because outside this range vaccines may (very quickly)
lose their potency. Immunization service providers
should maintain their vaccine refrigerators as close as
possible to 5°C, as this gives a safety margin of + 3°C
The cold chain has three main components:
1. Transport and storage equipment,
2. Trained personnel, and
3. Efficient management procedures.
All three elements must combine to ensure safe
vaccine transport and storage. World Health Organi-
zation’s Expanded Program on Immunization (EPI)
developed detailed guidelines on the maintenance of an
effective cold-chain. Maintenance of the cold-chain
system requires that processes are in place to ensure that
a potent vaccine reaches recipients. Apart from invention
of new heat stable vaccines, the improvisation in cold
chain and the understanding of the ideal methods of vaccine
storage and transport by officials, doctors and field staff are
the factors for the reduction of mortality and morbidity due to
vaccine preventable diseases.
Immunization and Infectious Diseases 271
3. Immunogenicity and safety of a pediatric dose of a
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2007;26:705-10.
4. Mittal DK, Dutta AK, Agarwal V; Immunization update
CBS Publishers and Distributors, New Delhi, 1994.
5. Murphy TV, Slade BA, Broder KR, et al. Prevention of
pertusis, tetanus and diphtheria among pregnant and
postpartum women and their infants recommendation
of advisory committee on Immunization practices (ACIP)
MMWR Recomm Rep 2008,57:1-51.
6. Parashar VD, Alescander JP, Glass Rl, et al. Prevention
of rotavirus gastroenteritis among infants and children
recommendation of ACIP, MMWR Recomm Rep.
2006,55:1-13.
7. Pneumococcal conjugate vaccine for childhood immuni-
zation - WHO position paper. Wkly Epidemiol Rec
2007;82:93-104.
RK Agarwal, Digant D Shastri
The vaccines which are not stored in the recommen-
ded temperature range get degraded (Fig. 9.4.1).
Contrary to the common belief that exposure of vaccine
to the higher temperature only can be damaged, freezing
of vaccines also can causes degradation and consequently
total or partial loss of potency. Commonly the
degradation rate of a vaccine is determined by the storage
temperature: The higher the temperature, the more rapid
and extensive is the degradation. There are considerable
differences between degradation rates for different
vaccines. In spite of knowing all these facts, still at many
places vaccines are not stored and transported properly.
This leads stocks of vaccines exposed for varying periods
to elevated temperatures/ freezing.
Cold Chain Equipment Supplied under
the Immunization Program
Cold chain equipment is used for storing vaccines and/
or transporting them in an appropriate desired tempe-
rature to maintain its potency. There are equipment of
different capacity for storage of vaccines at different
levels as described below.
1. Walk-In-Freezers (WIF)
272 IAP Textbook of Pediatrics

Primary Intermediate Primary health Health post/Session

(National) center site
Regional District

6 months 3 months 1 month 1 month Daily Use

OPV –15°C to –25°C
BCG WHO no longer recommends that
Measles freeze-dried vaccines be stored at
MMR –20°C. Storing them at –20°C is
MR not harmful but is unnecessary.
Instead, these vaccines should be
Yellow fever
kept in refrigeration and
+2°C to +8°C.
Hib freeze transported at +2°C to +8°C.
dried
HepB
DPT
DPT + Hep B
DPT + Hieb
Hib liquid
DT
Td
TT

Diluent vials must NEVER be frozen. If the manufacturer supplies a freeze-dried vaccine packed with its diluent, ALWAYS store the
product at between +2°C and +8°C. If space permits, diluents supplied separately from vaccine may safely be stored in the cold chain
between +2°C and +8°C.

Figure 9.4.1: WHO recommended vaccine storage conditions

(Source: WHO-UNICEF Joint Statement on Effective Vaccine Store Management WHO/IVB/04.17)

2. Walk-In-Coolers (WIC) Domestic refrigerators that have a separate freezer

3. Deep Freezers compartment are recommended for vaccine storage. Safe
4. Ice Lined Refrigerator (ILR) (Fig. 9.4.2) vaccine storage is possible in most refrigerators if the
5. Automatic Voltage Stabilizer following procedures or modifications are carried out
6. Cold Boxes (Coolers) and standards are maintained:
7. Vaccine Carriers • Vaccine should be stored in a dedicated refrigerator:
8. Ice Packs never store food or drink in vaccine refrigerators.
• The refrigerator should maintain internal tempe-
ratures in the recommended range without fluctua-
ting into the danger zones (<+2°C, >+8°C). The
refrigerator compartment should maintain tempera-
tures between 2° and 8°C. The freezer compartment
should maintain temperatures at or below 5° F
( –15°C).
• The refrigerator has not required repairing for last 2
years.
• The refrigerator is free of any water or coolant leaks.
• The door seals are in good condition and are sealing
tightly.
• The door closes properly automatically on leaving it
free.
• The refrigerator compressor does not make sound.
• The size of refrigerator is adequate to meet individual
Figure 9.4.2: Ice lined refrigerator (ILR) storage needs.
 Immunization and Infectious Diseases 273

Tips for Better Vaccine Storage in G. Store that Vaccines

Domestic Refrigerators
A. Placement of Refrigerator
• Refrigerator should be placed out of direct sunlight
and away from heat source.
B. Recognize Individual Vaccine Refrigerator
Before starting storing the vaccines in the refrigerator
identify which are the cold and warm areas in the
refrigerator. Also note the temperature variations from
top to bottom and from back to front.
C. Stabilize the Temperature of the Refrigerator
before Stocking
D. Monitoring Temperatures Inside the Refrigerators
Ensure that each domestic refrigerator storing vaccine
has a Celsius digital minimum - maximum thermometer.
The thermometer should be placed in a central location
within the storage compartment:
E. The Power Source
in Enclosed Plastic
Containers/Labeled
Baskets
This will allow easy
identification of
vaccines and minimize
the time spent with the Storing of vaccines in “labeled
door opened searching plastic containers”
for vaccines. Do not
crowd the vaccines by overfilling the shelves. Allow
space between containers for air circulation. Vaccines or
its diluents must never be stored in the door of the
refrigerator. Freeze-tolerant vaccines (Measles, Mumps,
Rubella, OPV and BCG) should be placed in the shelves
identified as being the coldest and the freeze-sensitive
vaccines (DTP containing vaccines; Hib, Pneumococcal,
Influenza, Hepatitis, IPV and some varicella vaccines)
on shelves identified as having more stable temperatures
(e.g. no ‘cold spots’). Vaccine stock should be rotated with
“1st to in 1st to out”—policy and vaccines with the
shortest expiry date are used first.

Avoid accidental disconnection

from the power source and to
ensure this mark the power
source clearly. This will prevent
the refrigerator from being
accidentally unplugged or
turned off. Arrange for alter-
native power-supply which will
very well back up load of at least
one refrigerator.
H. Keep the Door Closed as
Much as Possible
Minimizing the door opening
helps to keep internal
temperatures stable. The
vaccine refrigerators should Sticker on the refrigerator
door
have a sticker to remind staff
Safeguard the power
supply of same.

I. Alarm Systems
F. In the Freezer, Place Water
Bottles or Install a security/alarm system which will give a warning
Ice Packs/Gel Packs and Fill if:
Lower Drawers and Door with • The temperatures rise or fall outside normal ranges.
Water Filled Plastic Containers • There is power failure.
It will help to stabilize the • The door is left open.
temperature by increasing the Gel packs and ice
J. Training and Assigning Staff
‘cold mass’. This will assist in packs in freezer
stabilizing the temperature in Good vaccine storage and handling depends on
refrigerator. This is particularly useful if there is a power knowledge and habits of the staff. Ensure that one person
cut or other cause of refrigerator failure. is responsible for adjusting refrigerator controls.
274 IAP Textbook of Pediatrics

K. To Develop Own Documented Protocols and is ready for use again. If the refrigerator coils are exposed
Procedures for Vaccine Storage on the back, keep them clean and dust free. This will
improve operating efficiency.
L. Immediate Identification of Breach in Cold Chain and
its Management PURPOSE-BUILT VACCINE REFRIGERATORS
In order to ensure that effective vaccine is administered Purpose-built vaccine refrigerators are the preferred
it is important to promptly identify and manage cold refrigerators for vaccine storage. It is recommended that
chain breaches. Establish and document protocols for if possible purpose-built refrigerators are used by larger
response to cold chain breaches. vaccination services, including hospitals, pharmacies,
larger community health centres and larger general
M. Periodic Self-audit of vaccine storage practices. It is also recommended that they be used in
remote settings. They are considerably more expensive
N. Ordering Vaccine than domestic refrigerators. The purpose built
refrigerators have following advantages over the
Keep vaccine stock to a minimum by regularly ordering
domestic refrigerator:
only the quantity of vaccine required for the period until
• Do not require to be modified for vaccine storage.
the next delivery.
• They are programmed to maintain an internal
temperature between 2°C to 8°C.
Maintenance of the Vaccine Refrigerator and
• Cabinet temperature is not affected by ambient
Defrosting (Table 9.4.1)
temperature and is stable and uniform.
The door seals should be in good condition so that the
door closes securely. Refrigerator seals should be checked
regularly to ensure that a good seal is maintained. If the
seals are damaged or there is leakage of cold air from
the refrigerator, it should be replaced soon. As ice-build-
up can reduce the efficiency and performance of a
refrigerator the refrigerators that are not ‘frost free’
should be defrosted regularly to prevent ice build up.
During defrosting or cleaning of the refrigerator, move
the vaccines to a second refrigerator. This temporary
storage refrigerator must also be monitored to ensure the
correct temperature is maintained. Alternatively, the
vaccines can be stored in a precooled insulated container
with ice packs or ice until the normal vaccine refrigerator

TABLE 9.4.1: Checklist for Preventive Maintenance

External Internal Technical

1. The exterior is clean
2. It is firm on the floor
3. It is properly leveled
4. Its sides are at least 10 cm
away from walls
5. It is away from direct sunlight
6. Room is well ventilated
7. It is opened only when necessary
1. Doors seals properly without gap
2. The door seal is clean
3. Ice packs are in proper position
4. Vaccines are neatly placed with
space for air circulation
5. DPT, TT, HepB and DT are not
touching the cooling surface
6. Thermometer has been kept amongst
the vaccine
7. Temperature is recorded twice a day
1. Temperature is within prescribed limit
(if not, set the thermostat)
2. Voltage stabilizer is working properly
and equipment are connected through it
3. Plug of the voltage stabilizer is fitted
properly to the power line
4. There is no abnormal noise
5. Compressor mounting bolts are tight
 Immunization and Infectious Diseases 275

• Defrost cycle allowing defrosting without rise in Minimum/maximum: Tells the highest and lowest
cabinet temperature temperatures reached, but will be difficult to read.
• They automatically defrost
Digital: These are the most accurate constant monitors
• They have an external temperature reading display
and also offer continuous alarm capability to safeguard
and a maximum/minimum temperature continuous
against damage from refrigerator malfunction. But the
display, and an alarm for deviations outside the
temperature probe must be placed in the proper location
programmed temperature range.
inside the unit in order to get an accurate reading.
• Less demanding maintenance than domestic refri-
gerator. Continuous reading: Will record the temperature inside
• Good temperature recovery, when the fridge is open the unit at all times, 24 hours a day, on a sheet of paper,
to access the vaccines. but the paper must be changed when it is running low.
• Nearly all internal space can be used to store the Using this thermometer is the most effective method of
vaccines, so the size of the purpose built refrigerator tracking the refrigerator/freezer temperature over time.
may be smaller than the previously used domestic The minimum/maximum thermometer must be reset
refrigerator. regularly (i.e. at least daily, on work days) for meaningful
temperature recording. Ensure you choose a thermo-
Maintaining and Monitoring meter that reads Celsius. Different models of minimum/
Refrigerator Temperatures maximum thermometers may vary in accuracy. They also
require annual checks to ensure accurate measurement,
To measure the tempe-
as flat batteries or a damaged probe or cable can affect
rature during storage of
readings.
vaccines, different types
of thermometers are used.
Temperature Indicators
Minimum/maximum
thermometer is essential Vaccine Vial Monitor (VVM)
requirement for tempera- A vaccine vial monitor (VVM)
ture monitoring during is a label placed on a vaccine
vaccine storage and trans- vial, which contains a heat
Digital thermometer
port. The minimum/ sensitive material. It registers
maximum thermometer should be placed on a middle cumulative heat exposure over
shelf and temperatures should be checked and recorded time. A VVM enables user to
daily. The most effective minimum/maximum know whether vaccine has
thermometer is a digital type been damaged by exposure to
with a probe. If using a digital heat or not. The inner square
thermometer with a probe, of the VVM is made of heat
place the probe directly in sensitive material that is light
contact with a vaccine vial or at the starting point. The combined effect of time and
package. The refrigerator temperature causes the inner square of the VVM to
temperature should be read darken, graudally. The color change is irreversible. There
around the same time each is a direct relationship between rate of color change and
day, preferably prior to each temperature. Lower the temperature, slower the color
working session. Minimum/ change and higher the temperature, faster the color
change.
maximum thermometer must
Continuous temperature be reset regularly, the
Thus VVM gives information about the main factor
recorder that affects vaccine potency (heat exposure over a period
thermometer battery must be of time). It does not give any information about the other
checked and replaced time to factors responsible for vaccine degradation, e.g. sunlight
time and one should choose a thermometer which and age. VVMs are not substitutes for expiry dates. Vaccines
records temperature in Celsius. must never be used after their expiry dates.
276 IAP Textbook of Pediatrics
Vaccine vial monitor
Different types of VVM: Depending upon the heat stability
four different types are designed.
Apart from proper storage of the vaccines in the
refrigerator, it is equally important to safeguard the
vaccines during immunization sessions also to serve its
purpose of extending protection to recipients.
Reconstitution of Vaccine
• Diluents for every vaccine are specifically designed
for the needs of individual vaccine, and therefore,
interchanging of it is not recommended.
• As the diluents which are warmer than the vaccine
can affect the potency of live vaccines, it is recommen-
ded that diluents should be of the same temperature
as the vaccine at the time of reconstitution.
• Use the entire volume of the cooled diluent supplied
when reconstituting the vaccine.
• Reconstituted vaccines should be used within one
hour (30 minutes for varicella), provided they have
been kept between +2°C to +8°C and protected from
sunlight and fluorescent light.
• Reconstituted MMR can be stored in the plastic
syringe in a dark place between +2°C to +8°C without
loss of potency for up to four hours.
MANAGEMENT OF COLD CHAIN PROBLEMS
Out of Range Temperature
If any temperature reading is outside the recommended
range, immediate action is required. Action may include
readjustment, repair or replacement of the unit and
removal of the vaccine to a functional unit till repair or
replacement is possible.
Power Failure
• If the power failure is of 4 hours or less the vaccines
should be kept in the refrigerator and the door should
be kept closed.
• If there is no back-up generator facility, another
storage unit in near by site should be identified and
assure that it is working properly.
• Before moving vaccine, call the alternative storage
site to ensure that the back-up generator is working.
• In situations where a location with a back-up
generator cannot be identified within a reasonable
distance, preparations should be made to have coolers
and gel packs ready to temporarily and safely store
vaccine.
• If a refrigerator with a backup generator has not been
located or is not working, and for power failures more
than 4 hours store vaccines in a cooler with condi-
tioned ice packs/gel packs.
• Continue to monitor the temperature of the vaccines
by placing the thermometer probe inside a vaccine
box inside the cooler.
Do’s
• Mark power source to prevent accidental unplugging
or turn off.
• Place water bottles or ice pack/gel packs in your
freezer.
• Fill the lower drawers and the door with plastic water
containers.
• ‘Know your vaccine refrigerator’ by monitoring and
recording the temperatures throughout the refri-
gerator
• Modify and stabilize refrigerator before stocking with
vaccine.
• Store vaccines in original packaging in labeled plastic
containers.
• Place freeze sensitive vaccines on temperature stable
shelves.
• Place freeze-tolerant vaccines on coldest shelves.
• A Celsius digital minimum/maximum thermometer
and a temperature recording chart is a must.
• Check accuracy and change battery of thermometer
every 12 months.

• Put thermometer probe in container of freeze-
sensitive vaccines.
• Check and record temperatures daily before the
vaccine is used.
• Only 1 staff should be responsible for adjusting the
controls.
• Establish written protocols for cold chain breaches.
• Do vaccine storage audit at least every 12 months.
• Rotate stocks to use near expiry vaccines first.
• Keep an alternative means of vaccine storage
available.
Don’ts
• Don’t place refrigerator in direct sun light.
• Don’t store any vaccine in door of refrigerator.
• Don’t over stock your refrigerator with vaccines.
• Don’t open refrigerator door frequently.
• Don’t expose light sensitive vaccines to bright light
(most vaccines are sensitive to any form of UV light,
including fluorescent light).
• Don’t store diluents separately.
• Don’t use unconditioned the ice/gel packs. It can
easily cause vaccines to freeze.
9.5 Management of Adverse Effects
Following Immunization (AEFI)
INTRODUCTION
Immunization is a major contributor to the success story
of child health in the last century, which has enhanced
and improved the child survival all over the world.
Vaccines used in National Immunization Programs are
extremely safe and effective. Several scientific ethical, and
statutory obligations are fulfilled by the manufacturers;
elaborate field trials regarding safety and protection
offered by individual vaccines are established before they
are recommended for routine use. However no vaccine is
perfectly safe and adverse events can occur following
immunization. In addition to the vaccines themselves,
Immunization and Infectious Diseases 277
• Don’t allow temperature to reach 0oC. Most vaccines
are to be considered to be damaged at 0oC.
• Don’t use un-chilled cooler.
Bibliography
1. Galazka A, Milstien J, Zaffran M. “Thermostability of
Vaccines”. WHO (Global Programme for Vaccines and
Immunziation), 1998.
2. Indian Academy of Pediatrics, Surat. Target-5, Guide to
vaccine storage and handling.
3. Department of Health and Human Services, CDC.
Atlanta. Vaccine Management, Recommendations for
handling and storage of selected biologicals.
4. Utah VFC program. Vaccine Management, Handling and
storage details for vaccines.
5. Weir E, Hatch K. Preventing cold chain failure: vaccine
storage and handling, 2004;JAMC 2004;171(9):1050.
6. Immunization in Practice: A practical guide for health
workers. WHO 2004.
7. Strive for 5, National Vaccine Storage Guidelines.
Australian Government Department of Health and
Aging.
8. Safety of vaccines affected by a power outage. Quick
Clinical Notes, Disaster management and response,
2004;2:62-3 CDC.
9. UK Guidance on Best Practice in Vaccine Administration.
The Vaccine Administration Task Force, Shire Hall
Communications, London.
M Indra Shekhar Rao, Tanmay Amladi
being products of biological nature, the process of
immunization is also a potential source for adverse events.
An adverse event following immunization (AEFI) is
one that is believed to be caused by immunization.
Reported adverse event can be true adverse event or an
event coincidental to the immunization. For the purpose
of these guidelines—AEFIs are classified into five
categories.
Immunization can cause adverse events from the
inherent properties of vaccine (Vaccine reaction) or some
error in Immunization process (Program error). The event
may be unrelated to the immunization but have temporal
association (Coincidental event). Anxiety-related
278 IAP Textbook of Pediatrics

TABLE 9.5.1: Classification of adverse events following
immunization (AEFIs)
Vaccine Event caused or precipitated by the vaccine
reactions when given correctly, caused by the inherent
properties of the vaccine.
Program error Event caused by an error in vaccine preparation,
handling, or administration.
Coincidental Event that happens after immunization but not
caused by the vaccine – a chance association.
Injection Event from anxiety about, or pain from the injection
reaction itself rather than the vaccine.
Unknown Event’s cause cannot be determined.
Source: Immunization Safety Surveillance – WHO 1999, p 9(2).
reactions can arise from fear or pain of the injection rather
than the vaccine itself. In some cases, the cause of AEFI
remains unknown (See Table 9.5.1).
The adverse event following the immunization may
be minor and anticipated, the one which is expected and
not severe enough to cause discomfort for a long duration
of time, e.g. pain or fever after STP vaccination; whereas
a severe or a rare event following the vaccine may be in
the form of unexpected anaphylactic shock or induction
of active disease following measles or OPV vaccine
respectively. Hypothetical type of reaction may be related
to vaccine scar, which has causal relationship relating to
the issues, which are themselves of controversial nature
occurring in vaccinated children.
The common vaccine reactions are due to the immune
response of the host and sometimes due to vaccine
components (e.g. aluminum adjuvant, and preserva-
TABLE 9.5.2: Adverse events following immunization
Anticipated reaction Pain, fever following DTP vaccination
Minor reaction
Severe reaction Disseminated BCG infection, anaphy-
laxis
Vaccine controversies MMR vaccination and autistic syndrome
and casual relationship
tives). A successful vaccine reduces these reactions to a
minimum while inducing the best possible immunity.
These anticipated reactions occur within a day or two of
immunization and they are listed in Table 9.5.3.
The vaccines scar-related adverse events have a very
casual link and are most often hypothetical as listed in
Table 9.5.4.
Another notable component of adverse events
following immunization is due to program errors that
would result from errors that would result from error
and accidents in vaccine preparation, handling or
administration (Table 9.5.5).
The identification and correction of these errors are
of great importance, which would otherwise lead to a
cluster of other events associated with immunization. The
most common program error is iatrogenic infection as a
result of non-sterile injection, e.g. sterile abscess, which
may have a systemic effect or blood-borne infection (e.g.
HIV, hepatitis B).
Each vaccine administered in the immunization
program has specific complications most of which are
anticipated and mild. Some of them are serious adverse
reactions, which always have to be expected, and

TABLE 9.5.3: Common, minor vaccine reactions and treatment

Vaccine Local reaction Fever >38oC Irritability, malaise and

(pain, Swelling, redness) systemic symptoms
BCG 90-95 percent — —
Hib 5-15 percent 2-10 percent —
Hepatitis B Adults-15 percent 1-6 percent —
Children-5 percent
Measles/MMR/MR 10 percent 5-15 percent 5 percent (Rash)
Oral polio vaccine (OPV) — < 1 percent < 1 percent
Tetanus/DT/dT 10 percent 10 percent 25 percent
Pertussis (DTwP) Up to 50 percent Up to 50 percent Up to 50 percent
Treatment • Cold sponging at • Given extra fluids • Give extra fluids
injection site. • Wear cool clothing • Oral paracetamol
• Oral paracetamol • Tepid sponge or bath
• Oral paracetamol

Source: Immunization Safety Surveillance – WHO 1999, p 10(2)

 Immunization and Infectious Diseases 279

TABLE 9.5.4: Vaccination scars

Hepatitis B Multiple sclerosis, lupus, diabetes

Whole cell pertussis
Diphtheria, tetanus and pertussis
Inactivated polio vaccine
Influenza
Haemophilus influenzae type b
Measles, mumps and rubella
Encephalopathy, epilepsy, learning disorders
Cot death/ sudden infant death syndrome (SIDS) HIV infection
Diabetes mellitus
Diabetes mellitus
Autistic spectrum disorder, inflammatory bowel disease, childhood arthropathy.

Rubella
Thiomerosal-containing vaccines
Aluminum-containing vaccines
Various vaccines
Ethical concerns because grown in cells from an aborted fetus, neuro-
developmental disorder, autism, muscular fibrosclerosis.
Diseases of unknown or only partially understood etiology, e.g. asthma, autism,
inflammatory bowel disease, cot death, chronic fatigue syndrome, immune deficiency,
leukemia, autoimmune diseases, learning disorders, increase in violent crime, etc.,

Source: Vaccines- Children and Practice Vol-5, No. 2, 2003 (3)

TABLE 9.5.5: Program errors leading to adverse events

Nonsterile injections Infection:

• Reuse of disposable syringe or needles [e.g. Local suppuration at injection site, abscess, cellulitis,
• Improperly sterilized syringe or needles systemic infection, sepsis, toxic shock syndrome, transmission
• Contaminated vaccine or diluents of blood-borne virus (HIV, hepatitis B or hepatitis C) ]
• Reuse of reconstituted vaccine at subsequent session

Vaccine prepared incorrectly

• Vaccine reconstituted with incorrect diluent Local reaction or abscess from inadequate shaking effect of
• Drugs substituted for vaccine or diluent drug (e.g. muscle relaxant, insulin)

Immunization injected in wrong site

• Subcutaneous instead of intradermal for BCG
• Too superficial for toxoid vaccine (DTP, DT, TT)
• Buttocks
Vaccine transported/stored incorrectly
Contraindications ignored
Local reaction or injection site abscess
Sciatic nerve damage (+ ineffective vaccine-hepatitis B and
rabies)
Increased local reaction from frozen vaccine (and ineffective
vaccine)
Avoidable severe vaccine reaction.

Source: Immunization Safety Surveillance – WHO 1999, p 30 (2)

immediate remedial measures have to be given as b. Regional axillary adenitis:

described below. • Below 2 cm no treatment
• Fluctuant, more than 2 cm, treatment INH
VACCINATION COMPLICATIONS AND (3-6 months)/excision.
THEIR MANAGEMENT c. BCG complex: Local lymphadenitis + Positive
Mantoux reaction + para-tracheal lymph node.
BCG
Treat with RHZ (2 months) + RH (4 months).
Anticipated reactions: Nodule formation at the site of 2. Systemic: Disseminated infection, TB osteomyelitis,
vaccination (3-6 weeks) which liquefies, ulcerates and scrofuloderma – treat like tuberculosis.
heals by tiny scar (10-12 weeks).

Adverse Reactions DTP

1. Local: Anticipated reaction: Pain, discomfort, fever, induration
a. Persistent discharging sinus at the site of vacci- (treatment analgesics + antipyretics) paracetamol 15 mg/
nation. kg/dose.
280 IAP Textbook of Pediatrics
Adverse Reactions
• Incessant cry (more than 3 hours)
• Febrile convulsions
• Hyperpyrexia
• Hypotonic hyporesponsive episode
(shock-like state)
• Acute encephalopathy
• Anaphylactic shock.
DTaP
Adverse events like pain or swelling are minimal with
above vaccine.
These reactions must be distinguished from syncope,
breath-holding spells, and anxiety, which are common
benign reactions, which only require symptomatic
treatment.
Clinical features of anaphylaxis: Involve multiple body
systems (skin, respiration, circulation).
a. Itchy urticarial rash, facial flushing.
b. Progressive edema involving face, mouth and body
parts.
c. Respiratory symptoms: Sneezing, coughing/
wheezing, airway obstruction.
d. Hypotension. Shock.
Treatment: Place the patient in recumbent position and
elevate the feet.
a. Clear the airway, establish breathing (O2 supplemen-
tation and bag mask application) and maintain
circulation.
b. Injection adrenaline (1:1000) 0.01 ml/kg SC/IM
(severe cases). Repeat dose at 20-min intervals till
response.
c. Volume expanders (20 ml/kg normal saline or RL
over 20 minutes) repeat till response.
d. Dopamine (5-10 microgram/kg/min and
dobutamine (5-40 microgram/kg/min)
e. Monitor vital signs.
f. Other measures: To reduce the absorption of vaccine
from injection site:
• Placing a tourniquet above vaccination site.
• Local adrenaline to reduce vaccine absorption
(only in vaccines given through SC route).
OPV
• AEFI almost none
• Very rarely vaccine associated paralytic poliomyelitis
(VAPP).
IPV
Local reaction: Erythema, induration. Patients sensitive
to streptomycin/neomycin might develop hypersensi-
tive reactions as IPV contains these as preservatives.
Transient Arthralgia, rarely agitation, somnolence and
convulsions.
Measles
Anticipated reactions: Mild fever, rash, coryza (upto
4-7 days following vaccination).
Treatment: Paracetamol.
Adverse Reactions
a. Toxic shock syndrome (TSS) due to contamination of
measles vaccine by Staph aureus
b. Exaggeration of tuberculosis
c. Encephalitis.
Toxic shock syndrome: It occurs due to contamination
of measles vaccine with Staph aureus due to usage of
unsterile syringes, needles/and using a vaccine vial
beyond 4 hours after reconstitution.
C/F: Can occur after 30 minutes to few hours after
vaccination presenting with fever, vomiting, diarrhea,
shock.
Treatment : Should be treated as medical emergency.
a. ORS, paracetamol (home treatment )
b. IV fluids, (RL and normal saline), antibiotics
(cloxacillin 100-200 mg/kg/day in divided doses),
steroids, antipyretics, supportive therapy.
MMR
Anticipated reactions: Mild fever, rash, febrile seizures.
Mumps
Adverse reactions: Fever rarely, encephalopathy, seizures,
GBS, parotid swelling, hemolytic-uremic syndrome,
aseptic meningitis.
Rubella
Adverse Reaction
• Arthralgia, lymphadenopathy, fever, sore throat.
• Rarely thrombocytopenia and peripheral neuro-
pathy.

Hepatitis B Vaccine
Local reactions: Soreness at the site of injection.
Systemic reactions: Mild fever, myalgia, arthralgia, rarely
anaphylaxis.
Typhoid Vaccine
1. AKD Vaccine (Acetone Killed)
Local reactions: Pain, swelling, tenderness.
Systemic reactions Headache, nausea, fever and relapse
of chronic diseases like rheumatoid arthritis and
compensated cardiac conditions.
2. Vi Antigen Vaccine
Local reaction: Mild pain, swelling for 1 day.
3. Ty21 A (Oral Vaccine)
Local reactions: Diarrhea , vomiting.
Systemic reactions: Transitory exanthema.
Tetanus Toxoid (TT)
Repeated TT injections after trivial injuries can lead to
reduced immunogenicity, hypersensitivity, hemolytic
anemia, and amyloidosis. Also increased risk of
hemorrhagic disease of newborn.
Hib Vaccine
Local reactions: Mild redness, pain and swelling.
Varicella Vaccine
Local reactions: Papular vesicular eruption in less than 4
percent of vaccinees.
Systemic reactions: Mild fever, headache, pneumonitis,
arthropathy, breakthrough varicella.
Rabies Vaccine
1. Nervous Tissue Vaccine (Not used nowadays)
Local reactions: Pain, redness, itching, abscess formation.
Systemic reactions: Fever, headache, giddiness,
palpitation, chock, generalized urticaria.
Neuro-paralytic complications (1:5,500):
a. Cranial nerve paralysis
b. Paralysis of limbs
Immunization and Infectious Diseases 281
c. Ascending paralysis
d. Encephalopathy.
Treatment of complications: Discontinue the vaccine,
bedrest, steroids, further vaccination if required by tissue
culture vaccine.
2. Tissue Culture Vaccine
Local reactions: Soreness
Systemic reactions: Headache, fever, anaphylaxis, rarely
transient neuroparalytic illness (Gullian-Barre type).
Meningococcal Vaccine
Local reactions: Inflammation
Systemic reactions: Anaphylaxis rarely.
Pneumococcal Vaccine
Local reactions: Swelling , redness, pain.
Systemic reactions: GBS, anaphylaxis, relapse of ITP.
Wheezing, lymphadenopathy
Japanese Encephalitis Vaccine
Local reactions: Redness, swelling, pain.
Systemic reactions: Fever, headache.
Influenza Vaccine
Local reactions: Pain, swelling.
Systemic reactions: Rarely GBS (1 in 1,00,000). Transient
lymphadenopathy.
Rotavirus Vaccine
The mild undesirable side effect like fever, vomiting,
irritability and rash may occur. The risk of intussuscep-
tions with rotavirus is not increased as with placebo
group.
VACCINES AND CONTRAINDICATIONS
Vaccines might cause adverse reactions. It is often
difficult to prove definite cause-effect relationship
between the act of vaccination and subsequent complica-
tion. However, following guidelines will help in deciding
vaccine administration as shown in Table 9.5.6.
Guidelines for Safe Vaccination
Always ensure safe injection practices for safe health by
using disposable syringes.
282 IAP Textbook of Pediatrics
TABLE 9.5.6: Vaccines and contraindications
1. Avoid: Live vaccine
Avoid: DTP (1st dose)
Avoid: Rubella vaccine during pregnancy
Avoid: Antibiotics effective against S. typhi: 1 week prior / after Ty21a vaccination
Avoid: If person is sensitive to egg protein measles vaccine should not be given
2. Delay: Live vaccine
3. Discontinue
4. Do not stop vaccination in:
Source: Bhatia Rajesh, Ichhpujani RL. Immunization against infectious diseases 1996; p 20-60
1. Select proper vaccine. Follow manufacturer’s
instructions (dose/route/administrations).
2. Maintain cold chain.
3. Inform the mother regarding vaccine benefits and
their anticipated reactions.
4. Obtain written or atleast oral consent before
vaccination.
5. Keep the child under observation for 30 minutes
after vaccination. Be equipped and geared up to treat
any untoward reactions.
6. Have always resuscitation kit ready.
7. Use desired injection procedure, i.e. load the vaccine
into appropriate syringe size. Discard the needle
used for drawing and use a fresh needle for injection
(1 syringe and 2 needles for each vaccination).
8. Do not mix vaccines in single syringe unless
approved for such use. Use different syringes for
different vaccines. Use different sites for injection.
9. Always use anterolateral aspect of thigh in young
children and deltoid area for older children for
injections. Never use gluteal region in children.
10. Avoid fomentation/vigorous rubbing after vaccina-
tion. Firm pressure for a few minutes is sufficient.
11. Document every vaccination procedure in the
immunization card and keep a copy of it.
12. Complete the vaccination schedule as per immuni-
zation calendar. Remind the mother regarding next
date.
a. Immunodeficient individuals
b. Immunosuppressant therapy
c. Chronic debilitating illness (till recovery)
a. Progressive neurological disease
b. Uncontrolled seizure disorder (postpone till control)
a. Measles /MMR for 6 weeks following immunoglobulin therapy.
b. Severe febrile illness
DTP in case of severe postvaccinal reactions
a. Malnutrition
b. Moderate fever
c. Respiratory infections
d. Mild diarrhea
e. Any benign ailment
13. There is no need to restart immunization within a
year of administering the first dose of multi-dose
vaccine, e.g. Hib, DTP, etc. if the child is not brought
for immunization on suggested date. Instead just
continue and complete the schedule.
The best way to minimize the adverse events
following the immunization is to anticipate the expected
type of reaction for a specific vaccine and to identify the
events vaccination.
PREVENTION AND TREATEMENT OF
VACCINE REACTION
It is mandatory for the person administering the vaccine
to have sufficient knowledge regarding vaccines and
expected side effects and to inform parents thoroughly
regarding such adverse effects, which may however
occur very rarely. It is also essential to be prepared and
to always have a ‘kit’ with life saving drugs and
equipment at each place of vaccination.1
Advice on managing the common reactions should
be given to parents as well as the instructions to return
to the clinic if there are more serious symptoms. This
will help to reassure parents about immunization and
prepare them for common reactions. Program errors are
easily preventable. Identification and correction of these
errors are of great importance. WHO guidelines to avoid
program errors are as follows:

• Vaccines must only be reconstituted with the diluent
supplied by the manufacturer.
• Reconstituted vaccines must be discarded at the end
of each immunization session and never retained.
• No other drugs or substances should be stored in the
refrigerator of the immunization center.
• Immunization workers must be adequately trained
and closely supervised to ensure that proper
procedures are being followed.
• Careful epidemiological investigation of an AFEI is
needed to pinpoint the cause and to correct immuni-
zation practices.
Reporting AEFIs
The reportable EAFI must include any death or serious
event believed by the public or health worker to be caused
by immunization (Table 9.5.7).
The minor common reactions such as local reactions,
fever, and self-limiting systemic symptoms need not be
reported. It is important for the persons administering
the vaccine to advise the parent/patient at the time of
immunization that these reactions are expected and
advise them how to manage these common reactions
(e.g. paracetamol to treat fever). For more serious
problems, the patient should be advised to return or to
seek medical attention and to allow detection of AEFI.
More importantly, they should be advised not to delay
TABLE 9.5.7: List of reportable AEFIs2
Occurring within 24 hours of immunization
Occurring within 5 days of immunization
Occurring within 15 days of immunization
Occurring within 3 months of immunization
Occurring within 1 and 12 months after
BCG immunization
No time limit
Source: Immunization Safety Surveillance – WHO 1999, p 23 (2)
Immunization and Infectious Diseases 283
treatment of a coincidental illness falsely attributed as
vaccine reaction. Severe local reactions, especially if
occurring in clusters, should be reported, as they can be
markers for program errors or for problems with specific
vaccine lots.
When to report ? Who should report ?
Reporting should be done as quickly as possible so than
an immediate decision on the need for action and
investigation can be made.
Private physicians and hospitals should also report
events that come to the notice. In the community,
peripheral health worker or supervisor should report to
the district office.
The report should contain at a minimum:
• Description of the event
• Timing of the event in relation to immunization
• Vaccines given
• Patients identifying details.
The routine vaccination program should continue
while awaiting the completion of the reporting and
investigation.
Responding to AEFIs
Private physicians and the health workers need to know
how to recognize, treat and report AEFI immediately as
• Anaphylactoid reaction (acute hypersensitivity reaction)
• Anaphylaxis
• Persistent (more than 3 hours) inconsolable screaming and crying.
• Hypotonic hyporesponsive episode (HHE)
• Toxic shock syndrome (TSS)
• Severe local reaction
• Sepsis
• Injection site abscess (bacterial/sterile)
• Seizures, including febrile seizures (6-12 days for measles.
MMR; 0-2 days for DTP)
• Encephalopathy (6-12 days for measles/MMR; 0-2 days for DTP)
• Acute flaccid paralysis (4-30 days for OPV recipient; 4-75 days for
contact)
• Brachial neuritis (2-28 days after tetanus containing vaccine)
• Thrombocytopenia (15-35 days after measles/MMR)
• Lymphadenitis
• Disseminated BCG infection
• Osteitis/osteomyelitis
• Any death, hospitalization, or other severe and unusual events that
are thought by health workers or the public to be related to immunization
284 IAP Textbook of Pediatrics
per the guidelines discussed earlier. It is always wiser to
keep the community informed, investigate fully and
avoid making the premature statement about the cause
of the event. Always safeguard the public during
investigation.
Communicating with the Media
The media plays an important role in public perception.
The media are more interested in stories that will attract
attention, hence there is tendency to dramatize and
personalize the event. It is easy for the media to create
sense of panic and outrage about the events, which are
unrelated to immunization (coincidental). The guiding
principle dealing with media must be one should show
empathy and caring, honesty and openness, dedication
and commitment, whenever possible positive terms like
immunization safety or vaccine safety should be used.
Key messages have to be prepared before media contact
and they should include some of these facts:
• That benefit of immunization in preventing disease
is well proven.
• It is very risky not to immunize (risk of disease and
complications).
• Vaccine-preventable diseases caused millions of
death and/or disability before the introduction of
vaccines, and that situation would return without
continued use of vaccines.
• Vaccines do cause reactions, but these are rarely
serious and hardly ever cause long-term problems.
• Immunization safety is of paramount importance,
and any suspicion of a problem is investigated
(advantage of well established immunization safety
surveillance).
• The AEFI is currently being investigated but is likely
to be coincidental/due to a local problem (depending
on type of event), and the immunization program
must continue to keep the population safe from
disease.
Immunization Safety and Safe Injection Practices
The issues concerning the practices and policies dealing
with various aspects of correct administration of vaccines
focus on minimizing the risk of transmission of disease,
and maximizing the effectiveness of the vaccine. The term
encompasses the spectrum of events from proper
manufacture to correct administration, which includes
both injection safety and vaccine safety.
The immunization safety project includes the WHO,
UNICEF, UNAIDS, World Bank, PATH, Bill and
Melinda Gates Children Vaccine Program, Industry,
USAID, CDC who are the main partners and financial
supporters.
The project has main areas of focus:
1. Vaccine safety.
2. Research and development of safe thermostable
vaccines.
3. Access to safe vaccine delivery and safe disposal.
4. Identification and management of risks related to
immunization, develop resource material, train all
EPI managers in the surveillance and management
of adverse events following immunization.
5. Strengthening of monitoring system for vaccine
adverse event reporting system (VAERS).
The immunization focus, as established by the WHO,
has objective “ to eliminate sickness and death caused
by vaccine preventable diseases through the
development of strong, sustainable National
Immunization Programs, capable of delivering high
quality vaccines in a safe and effective way to all
children.”
Safe and efficient immunization practices with
thorough knowledge of the vaccines, well-maintained
cold chain, proper parent education and efficient
resuscitation equipment are vital components essential
to make immunization most cost-effective public health
tool in child survival programs.
BIBLIOGRAPHY
1. Adverse events following immunization. In:
Parthasarathy A, Lokeshwar Mr, Shah NK (Eds):
Immunization Digest. (1st edn). New Delhi: Jaypee
Brothers 2004;59-62.
2. Bhatia R, Ichhpujani RL. Immunization against infectious
disease 1996;20-60.
3. Immunization Safety Surveillance. Guidelines for
managers of immunization Programmes on reporting
and investigation adverse events following Immuni-
zation. Manila: WHO; 1999.
4. Rao M Indra Shekhar. Immunisation in clinical practice.
Jaypee Brothers 2005;37-46.
5. Rao I. Vaccination complications, their management and
contraindications. Paediatric Clinics of India 2001;36:
30-35.
6. Vaccines – Children and Practice, 2003;vol.5(2).

9.6 Approach to Management of
Fever in Newborns, Children and
Adolescents in Office Practice
Fever is one of the most common symptoms in children
in routine office practice. Feverish illness is also one of
the most common reasons for children to be seen in
hospital emergency departments and it is a leading cause
of admission to children’s wards. Many children
suffering from fever may be only mildly unwell and have
a focus of infection identified on clinical examination.
Fever in young children usually indicates an underlying
infection of some kind and, as such, the condition is a
cause of concern for parents and carers. The condition is
also a diagnostic challenge for healthcare professional
because it is often difficult to identify the cause. Infectious
diseases remain a major cause of childhood mortality and
morbidity. Often the illness is due to a self-limiting virus
infection and the child will recover quickly without
intervention. However, fever may also be the presenting
feature of serious bacterial illnesses such as meningitis,
septicemia, urinary tract infections and pneumonia. The
children with fever without apparent source (FWS) are
a particular concern to healthcare professionals because
it is especially difficult to distinguish between simple
viral illnesses and life-threatening bacterial infections in
this group. In general, FWS tends to be a problem in
young children. The younger the child, the more difficult
it is to establish a diagnosis and assess the severity of
illness. As a result, there is a perceived need to improve
the recognition, evaluation and immediate treatment of
fever in children.
RATIONALE FOR CLINICAL APPROACH—AGE
Nenates and Young Infants
• May not have the characteristic signs of serious
infection (temperature can be high or low).
• Localising features may be absent.
• Can deteriorate rapidly.
Young infants with fever, especially those under three
months of age, need rapid assessment and investigation,
and admission to hospital.
Immunization and Infectious Diseases 285
Digant D Shastri
Older Infants/Toddlers
• Localise infection better than neonates, but may still
be pre-verbal.
• Risk group for occult bacteremia (i.e. circulating
pathogens with no clear focus).
• Frequently exposed to infectious diseases in group
childcare.
• Get viral infections as well as the ‘typical’ childhood
organisms of pneumococcus H. Influenza b and
meningococcus.
Older Children
• Usually verbalize and localize symptoms well.
• More tolerant to fluid loss-less likely to need IV
rehydration.
• Can get ‘typical’ childhood organisms plus others
such as Mycoplasma and infectious mononucleosis.
Causes of Elevated Temperature
Fever is the body’s response to a variety of external and
endogenous stimuli such as infection, inflammation or
toxins and is generally medicated by the production of
pyrogens. It can also occur when body metabolic heat
production or environmental head load exceeds heat
losing capacity or when there is impaired heat loss.
Thus fever can be either due to:
1. Pyrogen production: Infection, inflammation,
toxin, cell destruction, immune mediated.
2. Metabolic: Infection, Malignancy, Hormonal.
3. Impaired thermal regulation: Central.
• Infectious etiologies are the commonest cause of fever
particularly in children less then 5 years and serious
bacterial infection is the concern in the evaluation of
the child with fever. Following are some of the
common infectious cause of fever in children.
– Meningitis, or encephalitis.
– Upper respiratory tract infection (URI).
286 IAP Textbook of Pediatrics

–
Bacterial or viral pneumonia. – Recent exercise
–
Otitis media. – Malignancy
–
Malaria – Rheumatoid diseases
–
Local skin infections, such as cellulites. • Complications of routine administration of childhood
–
Oral infections, including pharyngitis due to vaccinations carry the risk of temperature elevation
Streptococcus pyogenes (group A Streptococcus as a common adverse effect.
species). – Administration of the diphtheria, tetanus, and
– Urinary tract infection (UTI). pertussis (DTP) vaccine may cause fever within a
– Generalized viral illness.
few hours after administration and may persist
• Amongst non-infectious causes, fever associated with
up to 48 hours.
malignancy and that of rheumatoid origin are many
– Administration of live virus vaccinations, such as
times overlooked. Rheumatic conditions leading to
fever are more common in grown up children – the measles, mumps, and rubella (MMR) vaccine,
particularly adolescents. Fever of non-infectious may result in temperature elevations up to
causes include following: 7-10 days after its administration.
– High external temperature (especially in the
Clinical Assessment of Risk in a Child with Fever
warmer weather months)
– Over bundling of children in colder weather The majority of children presenting with fever will have
months either a self-limiting viral condition or an obvious cause

Traffic light system for identification of serious illness

Green-low risk Amber-intermediate risk Red-high risk

• Normal colour of skin, • Pallor reported by parent carer • Pale/mottele/ashen/blue

lips and tounge

Activity • Responds to social cues • Not responding normally to • Not responding to social cues
• Stay awake social cues • Appears ill to health care professional
• Strong normal cry/no cry • Wakes only on strong stimuli • Does not waken, or if roused does not
• Content/smile • Decreased activity stay awake
• No smile • Weak high-pitched or continuous city

Respiratory • Nasal flaring • Grunting

• RR >50/min in 6-12 months • RR > 60/min
> 40/min in > 12 years • Moderate to sever indrawing
• SpO2 : < 95% in air
• Crackles

Hydration • Normal skin and eye • Dry musus membrane • Reduced skin turgor
• Moist mucus membrane • Poor feeding
• CRT >3 sec
• Reduced urine output

Others • None of amber or red sign • Fever > 5 days
or symptom
• Swelling of limb/joint
• Non weight bearing
• A new lump > 2 cm
• Children < than 3 months with a temp.
> 38°C
• Children aged 3-6 months with a temp.
> 39°C
• Nonblanching rash
• Bulgine fontanelle
• Neck stiffness
• Status epilepticus
• Focal neurological signs
• Focal seizures
• Billestained vomiting

CRT = capillary refill time; RR = respiratory rate.


for their fever for which specific treatment can be given.
Although most children with a fever will have a self-
limiting illness, a minority will have a serious or even
life threatening illness. The priorities for healthcare
professionals should be to:
1. Identify any immediately life threatening features
2. Assess the child’s likelihood of having a serious illness
of self-limiting illness, without necessarily diagnosing
any one particular condition
3. Determine a source of the illness to direct specific
treatment
4. Make appropriate management decisions based upon
the results of the assessment.
First, one should identify any immediately life-
threatening features, including compromise of the
airway, breathing or circulation, and decreased level of
consciousness. Children with fever should be assessed
for the presence or absence of symptoms and signs that
can be used to predict the risk of serious illness.
Traffic light system for identifying risk of serious
illness. Children with fever and any of the symptoms or
signs in the ‘red’ column should be recognized as being
at high risk.
Children whose symptoms or combination of symp-
toms suggest an immediately life-threatening illness
should be referred immediately for emergency medical
care. Children with any ‘red’ features but who are not
considered to have an immediately life-threatening
illness should be urgently assessed. Children with ‘green’
features and none of the ‘amber’ or ‘red’ features can be
managed at home with appropriate advice for parents
and carers including advice on when to seek further
attention form the healthcare services.
History
One should realize that there is no alternative to proper
history taking in routine office practice. Relevant history
and through physical examination form the base of
probable diagnosis. Obtaining an accurate history from
the parent or caregiver is important; the history obtained
should include the following information:
Age
Fever in infants less then 3 months of age is considered
evidence of serious bacterial infection until proved
Immunization and Infectious Diseases 287
otherwise and hence warrants immediate and close
attention.
Fever History
• Ask what was child’s temperature prior to presen-
tation and how was temperature measured? Ask also
about the degree and duration of fever. The reason
for these questions is that it is often assumed that these
variables can be used to help differentiate serious
bacterial illnesses from less serious self-limiting viral
infections. Regarding the height of recorded fever, it
is often thought that there is a higher risk of serious
illness with increasing body temperature. High grade
fever (>41°C) often indicates failure of distal
thermoregulation mechanism (heat stroke, malignant
hyperthermia, etc) occurring alone or in combination
with infection. Regarding duration of fever, many
times it is thought that an SBI is more likely with
increasing duration of fever. Fever lasting more then
4-7 day is very rarely likely due to viral illnesses as
usually viral fevers resolve spontaneously over a
shorter period of time. Always remember that normal
or low temperature does not preclude serious, even
life-threatening, infectious disease.
Ask about periodicity (pattern) of fever
• Remitten Fever: Daily elevated temperature (>38°C
or 100.4°F), fever returns to baseline but not to normal
(98.6° C). The daily fluctuation of temperature is more
than 2°C.
• Intermitten Fever (Periodic Fever): Intermittently
elevated temperature (>35°C, 100.4°F), temperature
returns to baseline and to normal.
• Hectic Fever: Daily elevated temperature (>38°C or
100.4°F), fever can have either a remittent or
intermittent pattern, the temperature excursion is
>1.4°C (2.5°F) e.g. intermittent bacteremia (dental
abscess, UTI), Familial Mediterranean Fever, Still’s
disease, etc.
• Sustained or Continuous Fever: Daily elevated
temperature (>38°C or 100.4°F) Fluctuation of
elevated temperature never >than 1°C (1.5°F), e.g.
Enteric fever, Drug fever.
Ask about progress of Fever: Fever due to viral infection
usually peaks over a day or two and gradually decline
over 3-4 days. Bacterial infection presents with fever,
288 IAP Textbook of Pediatrics
which if untreated either persists or even gets worst over
the time. Sudden rise and decline of fever suggests the
likelihood of malaria infection
Chills and rigors: Rigors are common accompaniment with
infections like malaria, UTI bacterial endocarditic,
tonsillitis, pneumonia and deep seated abscess.
Inter febrile state: Evaluation of the clinical state of the
patient in between two fever parozysms is very useful
guide for predicting probable cause of fever. Carefully
assess the level of activity of lethargy, eating and drinking
pattern, sensorium, threshold of responsiveness, quality
of cry, etc. A child who continues to appear toxic,
lethargic, and apathetic even when the temperature
reaches normal is more likely to have a serious infection,
usually bacterial. Such a child should be observed
carefully. Against that the child whose inter febrile
clinical state depicts general well-being and who appears
non toxic in between fever spikes is more likely to have
viral fever.
Fever at presentation: If one finds that the infant has been
excessively bundled, and if a repeat temperature taken
15-30 minutes after unbundling is normal, the infant
should be considered afebrile.
Medical History
• Urinary output: Inquire as to the number of wet
diapers.
• Immunization history: What is the patient’s immuni-
zation status? Which vaccines have been given
recently?
• Drug History: Ask about recent long term use of
antibiotic or recent high dose usages of drugs like
atropine, which cause poisoning, which many times
can cause drug fever.
• Has there been recent antibiotic use?
• Has there been exposure to illness through baby-
sitters, day care contacts, or other caregivers? Are
other at home sick?
• Ask about absence of perspiration: children with
Anhidrotic ectodermal dysplasia will have history of
absent/impaired sweating and history of high grade
fever particularly in summer months. Such children
have dry skin and spars hair with or without dental
abnormalities.
• For the neonate, the history is explored for possible
evidence of poor feeding, vomiting, poor social
interaction, changes in the quality of crying, and
possible apneic episodes.
– Any of these finding are reasons to suspect serious
bacterial infection and may warrant laboratory
evaluation.
– The birth history is explored to ascertain risk
factors for underlying pathology, such as
prematurity, premature rupture of membrane,
maternal infections.
• When assessing a child with feverish illness, one
should enquire about recent travel abroad and should
consider the possibility of imported infections
according to the region visited.
Physical Examination
The physical examination of the febrile child is directed
at locating a source of the temperature elevation, with
specific attention to potential serious bacterial illnesses.
Hypothermia is a common presenting vital-sign
abnormality in septic neonates. While performing a
complete physical examination, pay particular attention
to assessing hydration status and identifying the source
of infection. Physical examination of every febrile child
should include the following:
I. Record vital signs
• Temperature: Rectal temperature is the standard.
Temperature obtained via tympanic, axillary, or oral
methods may not truly reflect the patient’s
temperature.
• Core skin temperature mismatch: Measurement of
temperature difference between core and skin
temperature is particularly important in patient with
shock or sepsis. Such children show significant core
skin temperature mismatch beyond normal range.
• Dissociation between temperature and pulse rate is
seen in older children in typhoid, brucellosis,
Legionnaire’s disease. Factious fever is also accom-
panied with inappropriately low pulse. Fever with
low pulse rate likely to be due to viral myocarditis,
fever with low pulse rate with high blood pressure
could be due to increased intracranial tension with
CNS infection
• Respiratory rate: Presence of dyspnoea, tachypnea,
grunting, flaring, and retractions should be noted.
• Blood pressure
• One should record capillary refill time as part of the
routine assessment of a child with fever. A capillary
refill time of 3 seconds or longer should be recognized
as an intermediate-risk group marker for serious
illness.
 Immunization and Infectious Diseases 289

Height of body temperature alone should not be used Symptoms and signs suggestive of specific diseases
to identify children with serious illness. However,
Diagnosis to be Symptoms and signs in conjunction with
children in the following categories should be recognized
considered fever
as being in a high-risk group for serious illness:
• Children younger than 3 months with a temperature Meningococcal Nonblanching rash, particularly with one
disease of more of the following:
of 38°C or higher
• an ill-looking child
• Children aged 3–6 months with a temperature of 39° • lesions larger than 2 mm in diameter
C or higher. (purpura)
• Children with temperatures form 39-39.5°C (102.2- • capillary refill time of > 3 seconds
103°F) have an approximate 2-4% risk of having occult • neck stiffness
bacteremia. Those with temperatures higher than Meningits Neck stiffness
Bulging fontanels
39.5°C (103°F) have an approximate 5-10% chance of
Decreased level of consciousness
having occult bacteremia. Convulsive status epilepticus
II. Observation of the infant or child’s interactions with Herpes simplex Focal neurological signs
the parent or caregiver is easily done while the history encephalitis Focal seizures
is obtained. Decreased level of consciousness
– What is the quality of the cry? Is it abnormal, high Pneumonia Tachypnoea (RR>60 breaths/minute,
age 0-5 months; RR > 50 breaths/minute,
pitched, or weak in effort?
age 6–12 months; RR>40 breaths/minute,
– Does the child appear afraid of the examiner? age >12 months)
Beyond infancy, healthy young children should Crackles in the chest
fear strangers. In this situation, the child who lies Nasal flaring
on the examination table without much inter- Chest indrawing
action or who is not disturbed by an ear Cyanosis
Oxygen saturations < 95%
examination is more likely to have a more serious
Urinary tract Vomiting
illness. infection Poor feeding
– What is the skin color? Are there areas of cyanosis Lethargy
or jaundice? Are there any rashes present? Irritability
– What is the response to social overtures? Does the Abdominal pain or tenderness
baby smile at the examiner? Does the baby smile Urinary Frequency or dysuria
Offensive urine or haematuria
or appear interested in a small toy or other shiny
Septic arthritis Swelling of a limb or joint
object? Social smile remains one of the best Not using an extremity
predictors of well babies Non-weight bearing
III. Record an accurate weight as all pharmacologic and Kawasaki disease Fever for more than 5 days and at least
procedural treatments are based on the weight in four of the following:
kilograms. • bilateral conjuctival injection
• change in mucous membranes
IV. Concentrate on identifying source of fever: One
• change in the extremities
should also look for a source of fever and check for • polymorphous rash
the presence of symptoms and signs that are cervical lymphadenopathy
associated with diseases.
Physical examination finding suggestive of serious when crying, and/or a lack of urine output (by
illness (e.g. serious bacterial infection) include the history).
following: • Persistent irritability despite feeding or inability of
• Presence of dysponea, techypnea, grunting, flaring, parents to console the child is concerning. True
and retractions should be noted. These finding are irritability and lethargy are physical signs tradi-
abnormal and require further exploration (e.g. pulse tionally associated with an ill-child.
oximetry, chest radiography). • The presence or absence of meningeal signs should
• Hydration status should be documented. Specific be documented in older children.
signs of dehydration might include dry mucous • Caution: In some infants and younger children
membrane, sunken fontanelle, absence of tears (perhaps less than 12-15 months), who develop
290 IAP Textbook of Pediatrics
meningitis, specific meningeal signs, such as the
Kernig or Brudzinski sign, may not be present.
• A hemorrhagic rash is classically described as
resulting from overwhelming systemic bacterial
infection due to meningococcemia but may be due to
other (usually serious) infections like malaria/
dangue. The presence of petechiae or purpura in
febrile children indicates the need for prompt
evaluation and therapy.
Management of Fever in Children
less than 3 months old
Although fever in the young infant is relatively
uncommon, when it occurs there ia higher risk of serious
bacterial infection than in later life. Approximately 10
percent of well-appearing young infants with a
temperature higher than 38°C (100.4°F) harbour a
serious bacterial infection or meningitis. The neonate
is at risk of rapidly developing infection because of a
relatively poorly developed immune system. Babies
born preterm or with low birth weight are particularly
vulnerable. The infections may be those acquired from
the mother at the time of delivery (e.g. group B
streptococcus), or hospital-or community-acquired
infections. SBI, particularly meningitis and UTI, are
more common in the first 3 months than later in
childhood. Because of the greater probability of serious
bacterial infection, a more aggressive approach to the
evaluation and management of fever is warranted in
young infants. Specific criteria, commonly termed the
“Rochester Criteria,” have been proposed to identify
febrile young infants at low risk for serious bacterial
infection.
ROCHESTER CRITERIA FOR IDENTIFYING
FEBRILE INFANTS AT LOW RISK FOR
SERIOUS BACTERIAL INFECTION
1. Infant appears generally well
2. Infant has been previously healthy:
• Born at term (>=37 weeks of gestation)
• No perinatal antimicrobial therapy
• No treatment for unexplained hyperbilibrubi-
nemia
• No previous antimicrobial therapy
• No previous hospitalization
• No chronic or underlying illness
• Not hospitalized longer than mother
3. Infant has no evidence of skin, soft tissue, bone, joint
or ear infection
4. Infant has these laboratory values:
• White blood cell count of 5,000 to 15,000 per mm3
(5 to 15 ×109 per L)
• Absolute band cell count of ¾ 1,500 per mm3 (¾1.5
× 109 per L)
• Ten or fewer white blood cells per high-power
field on microscopic examination of urine
• Five or fewer white blood cells per high-power
field on microscopic examination of stool in infant
with diarrhea
Infants younger than 3 months with fever should have the
following investigations performed:
• Complete blood count
• Blood culture
• C-reactive protein
• Urine testing for urinary tract infection
• Chest X-ray only if respiratory signs are present
• Stool culture, if diarrhea is present.
Lumbar puncture should be performed on the following children
(unless contraindicated):
• Febrile neonate
• Neonate with symptoms suggestive of sepsis
• Neonate with suspected sepsis prior to starting
antibiotic
• Infants aged 1-3 months with white blood cell count
(wbc) less than 5×109/litre or greater than 15 × 109/
litre.
When indicated, a lumbar puncture should be
performed without delay and, whenever possible, before
the administration of antibiotics. Parenteral antibiotics
should be given to:
• Infants younger than 1 month
• All infants aged 1–3 months who appear unwell
• Infants aged 1–3 months with a WBC count less than
5 × 109/litre or greater than 15 × 109/ litre.
Children with fever without apparent source
presenting with one or more ‘red’ features should have
the following investigations performed:
• Full blood count
• Blood culture
• C-reactive protein
• Urine testing for urinary tract infection.
 Immunization and Infectious Diseases 291

Following investigations should also be considered Flow chart 9.6.1: Child <3 months old with fever
in children with ‘red’ features, as guided by the clinical (>38°C Axillary)
assessment:
• Lumber puncture in children of all ages (if not
contraindicated)
• Chest X-ray irrespective of body temperature and
white blood cell count.
• Serum electrolytes and blood gas.
Children with fever without apparent source who
have one or more ‘amber’ features should have the
following investigations performed:
• Urine should be collected and tested for urinary tract
infection
• Blood tests: Full blood count, c-reactive protein and
blood cultures
• Lumber puncture should be considered for children
younger than 1 year
• Chest X-ray in a child with a fever greater 39°C and
white blood cell count (wbc) greater than 20 ×109/
litre.
Children who have been referred with fever without
apparent source and who have no features of serious
illness (that is, the ‘green’ group), should have urine
tested for urinary tract infection and be assessed for
symptoms and signs of pneumonia. Routine blood tests
and chest X-rays should not be performed on children clear streptococcal bacteriemia without antibiotic
with fever who have no features of serious illness. therapy, Approximately 10% of infants and young
children with fever and S.pneumoniae bacteriemia
Management of Fever in Children progress to a serious bacterial infection, and from 3 to
more than 3 months Old 6% progress to meningitis (i.e., approximately one case
per 1,000 to 2,500 of these febrile children). The risk of
For all patients aged 3-36 months, management decisions
pneumococcal bacteriemia varies based on the patient’s
are mostly based on the degree of toxicity and the height
age, temperature and white blood cell count.
of temperature. The Yale observation scale is a reliable
method for determining degree of illness. It consists of In children aged 3 months or older with fever without
6 variables: quality of cry, reaction to parent stimulation, apparent source, a period of observation in hospital (with
state variation, color, hydration, and response. A score or without investigations) should be considered as part
of 10 or less has a 2.7% risk of serious bacterial infection. of an assessment to help differentiate nonserious from
A score of 16 or greater has a 92% risk of serious bacterial serious illness.
infection.
Most fevers in this age group are viral and the risk of Medical Care
occult bacteriemia and SBI decreases with advancing age.
The risk of occult bacteriemia and SBI is higher in those For children who appear ill, conduct a complete
with temperature >39°C. With widespread immuni– evaluation to identify occult sources of infection. Follow
zation against Hemophilus influenzae infection, Streptococcus the evaluation with empiric antibiotic treatment and
pneumoniae has become the predominant cause of serious admit the patient to a hospital for further monitoring
bacterial infection in infants and young children. and treatment pending culture results. Children aged
Streptococcal bacteriemia affects fewer than 2% of well- 3-36 months may not require admission if they meet the
appearing older infants and young children with a following criteria:
temperature above 39°C. Most children in this age group • Child was healthy prior to onset of fever.
292 IAP Textbook of Pediatrics

Yale Observation Scale

Observation Items 1(Normal) 3 (Moderate Impairment) 5 (Severe Impairment)

Quality of cry Strong with normal tone or Whimpering or sobbing Weak cry, moaning, or
contentment without crying high-pitched cry

Reaction to parent Brief crying that stops or Intermittent crying Continual crying or limited
stimulation contentment without crying response

Color Pink Acrocyanotic or pale extremities Pale or cyanotic or

mottled or ashen

State variation If awake, stays awake; if asleep, Eyes closed briefly while awake Falls asleep or will not
wakes up quickly upon stimulation or awake with prolonged arouse
stimulation

Hydration Skin normal, eyes normal, and Skin and eyes normal and Skin doughy or tented, dry
mucous membranes moist mouth slightly dry mucous membranes, and/
or sunken eyes

Response (e.g., talk, Smiling or alert(< 2 mo) Briefly smiling or alert briefly Unsmiling anxious face or
smile) to social overtures (<2 mo) dull, expressionless, or not
alert (<2 mo)

• Child has no significant risk factors.
• Child appears non toxic and otherwise healthy.
• Child’s laboratory results are within reference ranges
defined as low risk.
• Child’s parents (or caregivers) appear reliable and
have access to transportation if the child’s symptoms
should worsen.
Treatment recommendations for children with fever
without a focus are based on the child’s appearance, age
and temperature.
• For children who do not appear toxic, temperature is
less then 39°C treatment recommendations are as
follows: Observe for 48 hours and instruct parents to
return with the child sooner if the condition worsens.
If at 48 hours fever persist get investigations– CBC,
MP, urine study and blood culture to rule out
infection.
• For children who do not appear toxic and tempe-
rature is more than 39°C treatment recommendations
are as follows:
– Get investigations: CBC, MP, urine study to rule
out infection.
– Consider no antibiotics; however, if absolute
neutrophil count is greater than 15,000/μL,
consider ceftriaxone (50 mg/kg/dose).
– Hospital admission is indicated for children
whose condition worsens or whose evaluation
findings suggest a serious infection.
• For children who appear toxic, treatment recom-
mendations are as follows:
– Admit child, investigate for infection and admi-
nister parenteral antibiotics for further treatment;
pending culture results.
Observation in Hospital
Children with fever are often observed in hospital for a
period of time to help differentiate those with serious
illness from those with nonserious illness. This obser-
vation usually involves the repeated measurement of
‘vital signs’ as well as repeated assessments of the child
to look for the development of any clinical features that
would give cause for concern.
Antipyretic Interventions
Fever is a normal physiological response to infection and
a number of other conditions. Although it is a normal
response, majority of people, including many doctors,
nurses and parents, believe that fever should be treated
to reduce temperature. If it is thought necessary to reduce
fever, there are number of interventions that are or have
been used, either alone or in combination. Pharmaco-
logical treatments differ fundamentally from physical
treatments, as they aim to lower the hypothalamic set-
point rather than simply cool the body. Paracetamol and

nonsteroidal anti-inflammatory agents such as Ibuprofen
inhibit the action of the cyclooxygenase enzyme involved
in the production of the prostaglandin and other and this
is the basis of their antipyretic activity. There are a
number of physical interventions that can be used to
reduce body temperature, including undressing, fanning
and sponging with cool or cold water. These have
advantage of heat loss through convection and evapo-
ration but do not treat the underlying causes of the fever.
Physical treatments do not reduce the levels of pros-
taglandins and so the temperature of the whole body is
not reduced. Furthermore, because the hypothalamus is
still set a higher temperature level, physical treatments
may cause shivering and other adverse effects as the body
aims to meet the hypothalamic set-point temperature,
which continues to be raised.
Paracetamol and Ibuprofen, the drugs most
commonly used to treat, fever, either in combination or
alternately. Paracetamol and Ibuprofen both are equally
effective and equally safe antipyretics. Combination
treatment offers no advantage over single drug therapy
and would not lead to clinically significant further
reduction of body temperature. Paracetamol is the most
widely used antipyretic medicine and has long term
record of excellent safety. It is antipyretic of choice in
the management of fever in any age group. The usual
dose and frequency of administration are 15 mg/kg every
4-6 hours with a maximum total dose of 90 mg/kg/day.
Oral paracetamol is usually well-tolerated, effective and
hence for management of fever parenteral antipyretics
not indicated. For children with intractable vomiting, or
post-operative state, a rectal suppository will be more
useful. Ibuprofen is an antipyretic of second choice and
it is also having good safety. The usual dose and
frequency of administration are 8-10 mg/kg/8 hourly.
In adults it is commonly associated with GI side effects,
but that is very uncommon in children. Since it can cause
upper GI side effects including GI ulcer it is contra-
indicated in dengue infections. Aspirin is not safe for
lowering fever because it can cause Reye’s syndrome in
febrile children with viral infections.
Recommendations on Antibiotics
Antibiotics are used for suspected bacteriemia or
bacteriuria. Empiric antimicrobial therapy must be
comprehensive and should cover all likely pathogens in
Immunization and Infectious Diseases 293
the context of the clinical setting. Whenever feasible,
antibiotic selection should be guided by blood culture
and sensitivity studies. Children with fever presenting
to specialist pediatric care or an emergency department
should be given immediate parenteral antibiotics if they
are:
• Shocked
• Unrousable
• Showing signs of meningococcal disease.
In children with fever and reduced levels of
consciousness, symptoms and signs of meningitis and
herpes simplex encephalitis should be sought. When
parenteral antibiotics are indicated, a third-generation
cephalosporin (for example, cefotaxime or ceftriaxone)
should be given, until culture result are available. For
children younger than 3 months, an antibiotic active
against listeria (for example ampicillin or amoxicillin)
should also be given.
Amplicillin inhibits the biosynthesis of cell wall
mucopeptides. It acts against gram-positive organisms
(excluding beta-lactamase-positive S aureus), enterococci,
gram-negative organisms (e.g. Escherichia coli, and
Proteus, Klebsiella, and Salmonella species), and beta-
lactamase–negative H influenzae. The standard pediatric
dose is 50-100 mg/kg/d IV divided q6h for mild-to-
moderate infections. For severe infections, the dose is
200-400 mg/kg/d IV divided q6h. Adverse effects
include glossitis, stomatitis, nausea, vomiting, black
“hairy” tongue, enterocolitis, pseudomembranous colitis,
diarrhea, hypersensitivity reactions, increasing serum
glutamic-oxaloacetic transaminase, anemia, thrombo-
cytopenia, thrombocytopenic purpura, leukopenia, and
agranulocytosis.
Ceftriaxone is a third-generation cephalosporin that
inhibits cell wall synthesis. It acts against gram-positive
organisms, including beta-lactamase-producing orga-
nisms, but not enterococci, methicillin-resistant
S aureus, and Listeria species. It is active against gram-
negative species (e.g., E coli, H influenzae, Moraxella
catarrhlis and Proteus, Klebsiella, Enterobacter, Citrobacter,
and Pseudomonas species) but not Acinetobacter species.
It is variable in its activity against Bacteroides fragilis
and Pseudomonas species. The pediatric dose is 50-100
mg/kg/d IV divided q12-24h. Adverse effects include
hypersensitivity, colitis, transient elevations of blood urea
nitrogen and serum creatinine, prolonged prothrombin
time (PT), and gallbladder disease.
Cefotaxime is also a third-generation cephalosporin
that shares similar activities with ceftriaxone. It also
294 IAP Textbook of Pediatrics
Flow chart 9.6.2: Child < 3 years old with fever (>38°C Axillary)
inhibits cell wall synthesis. Dosage is 100-150 mg/kg/d
IV divided q6-8h, and the meningitic dose is 200 mg/
kg/d IV divided q6-8h. Adverse effects include hyper-
sensitivity, GI discomfort (e.g., nausea, vomiting,
diarrhea, colitis), neutropenia, increased liver enzymes,
and transient elevations of blood urea nitrogen and
creatinine.
Gentamicin is an aminoglycoside that inhibits
normal protein synthesis in suspeceptible organisms.
It is active against gram-positive organisms (except
methicillin-resistant S aureus and Streptococcus faecium),
gram-negative organisms (but not Xanthomonas
maltophilia, Pseudomonas cepacia, or Flavobacterium
species), and anaerobes. Dosing for the pediatric
population with normal renal function is 6-7.5 mg/kg/
d IV divided q8h for children, 7.5 mg/kg/d IV divided
q8h for infants and neonates, and 5 mg/kg/dIV divided
q12h for premature neonates and full-term neonates
aged 1 wk or younger.
BIBLIOGRAPHY
1. ACEP. Clinical policy for children younger than three
years presenting to the emergency department with
fever. ACEP Clinical Policies Committee; ACEP Clinical
Policies Subcommittee on Pediatric Fever. Ann Emerg
Med 2003;42(4):530-45.
2. Alpern ER, Alessandrini EA, Bell LM. Occult bacteremia
from a pediatric emergency department: current preva-
lence, time to detection, and outcome. Pediatrics 2000;106;
(3):505-11.
3. Baker MD, Bell LM, Avner JR. The efficacy of routine
outpatient management without antibiotics of fever in
selected infants. Pediatrics 1999;103(3):627-31.
4. Baraff LJ, Bass JW, Fleisher GR, et al. Practice guideline
for the management of infants and children 0 to 36
months of age with fever without source. Agency for
Health Care Policy and Research. Ann Emerg Med
1993;22(7):1198-210.
5. Baraff LJ. Management of fever without source in infants
and children. Ann Emerg Med 2000;36(6):602-14.
6. Bauchner H, Pelton SI. Management of the young febrile
child: A continuing controversy. Pediatrics 1997;
100(1):137-8.

7. Bonadio WA. The history and physical assessments of
the febrile infant. Pediatr Clin North Am 1998; 45(1):
65-77.
8. Brook I. Unexplained fever in young children: How to
manage severe bacterial infection. BMJ 2003;327(7423):
1094-7.
9. Crain EF, Gershel JC. Urinary tract infections in febrile
infants younger than 8 weeks of age. Pediatrics
1990;86(3):363-7.
10. Grover G, Berkowitz CD, Lewis RJ, et al. The effects of
bundling on infant temperature. Pediatrics 1994;94(5):
669-73.
11. Ishimine P. Fever without source in children 0 to 36
months of age. Pediatr Clin North Am 2006;53(2):167-
94.
12. Ishimine P. The evolving approach to the young child
who has fever and no obvious source. Emerg Med Clin
North Am 2007;25(4):1087-115, vii.
13. Lee GM, Harper MB. Risk of bacteremia for febrile young
children in the post- haemophilus influenzae type b era.
Arch Pediatr Adolesc Med 1998;152(7):624-8.
14. Luszczak M. Evaluation and management of infants and
young children with fever. Am Fam Physician 2001;64(7):
1219-26.
9.7 Fever and Fever of Unknown Origin
“ Humanity has but three great enemies:
Fever, war and famine. Of these by far
the greatest, by far the most terrible is fever”
— Sir William Oscar
Fever in children is one of the most common manifes-
tations of an illness, which makes the parents seek medical
attention early. Fever occurs when various infectious and
non-infectious processes interact with the host’s defense
mechanism. It is important that all children with fever
are carefully assessed to find the cause. Nevertheless cause
remains undetermined in a significant percentage of cases,
leading to the designation of FWF (Fever with out focus)
and FUO (Fever of unknown origin). But even with the
etiology being determined, fever remains the overriding
source of anxiety.
Definition
The narrow body temperature is maintained between a
range of 36.8 ± 0.4° C (98.2 + 0.7° F) with a circadian
Immunization and Infectious Diseases 295
15. McCarthy CA, Powell KR. Screening for serious bacterial
infections in young febrile infants. Arch Pediatr Adolesc
Med 2000;154(3):315-6.
16. Nozicka CA. Evaluation of the febrile infant younger than
3 months of age with no source of infection. Am J Emerg
Med 1995;13(2):215-8.
17. Perrott DA, Piira T, Goodenough B, Champion GD.
Efficacy and safety of acetaminophen vs ibuprofen for
treating children’s pain or fever: A meta-analysis. Arch
Pediatr Adolesc Med 2004;158(6):521-6.
18. Schriger DL. Management of the young febrile child.
Clinical guidelines in the setting of incomplete evidence.
Pediatrics 1997;100(1):136.
19. Wahba H. The antipyretic effect of ibuprofen and
acetaminophen in children. Pharmacotherapy 2004;24(2):
280-4.
20. Wasserman GM, White CB. Evaluation of the necessity
for hospitalization of the febrile infant less than three
months of age. Pediatr Infect Dis J 1990;9(3):163-9.
21. Yamamoto LG. Revising the decision analysis for febrile
children at risk for occult bacteremia in a future era of
widespread pneumococcal immunization. Clin Pediatr
(Phila) 2001;40(11):583-94.
PP Maiya
rhythm of lowest temp at 6:00 A.M (37.2 °C or 98.9° F)
and highest temperature of 37.7 °C or 99.9°F at 4:00 P.M.
In general Fever is considered to be present if rectal
temperature is above 38.3° C, oral temp is above 37.8 C
or axillary temperature is above 37° C.
Mechanism of Fever
The fever reaction is a series of cellular events that begin
peripherally and ends centrally with a resetting of body’s
temperature set point. Unlike Hyperthermia fever
doesn’t represent a failure of temperature control, but
rather an upward shift of the regulated temperature, as
a result of body’s exposure to infecting micro-organisms,
immune complexes, other sources of inflammation.
Various mediators like Cytokines, TNF, IL-1 and IL-6
stimulate PGE2 production in the anterior hypothalamus,
which then brings about rise in the temperature set point
by a variety of physiological mechanisms including
activation of cAMP. When this happens signals are sent
to various efferent nerves innervating peripheral blood
296 IAP Textbook of Pediatrics
Figure 9.7.1: Pathogenesis of fever
vessels to conserve heat. The vasoconstriction causes the
feeling of chills which may lead to rigors with sudden
elevation of body temperature. Also the thermoregula-
tory center sends signal to cerebral cortex to initiate
behavioral changes like seeking warm environment,
extra clothing and flexed posture. All these mechanisms
act to elevate the core body temperature, so that the blood
bathing neurons in the anterior hypothalamus is warm
and matches with the new temperature set point.
Classification of Fever Syndromes
Fever with Focus
The majority of febrile episodes in children are associated
with infections. The diagnosis is made by identifying the
focus, e.g. Otitis media, respiratory infection, septic
arthritis, etc.
Fever without Focus (Table 9.7.1)
This term refers to fever of acute onset and short duration
(< 1 week) without any localizing symptoms or any
clinical signs on physical examination.
TABLE 9.7.1: Causes of fever without focus
• Acute viral fever
• Septicemia or Bacteremia
• Vaccine associated fever
• Urinary tract infection
• Sinusitis
• Hyperthermia
• Occult Bacteremia
• Prodrome of condition’s like Infectious Mononucleosis,
Kawasaki’s disease, etc.
TABLE 9.7.2: Investigations in patients with FWF
• Complete blood counts, CRP, ESR
• Urine routine, Urine C/S
• Blood C/S
• Lumbar puncture( If indicated)
Occult Bacteremia
• 30% of the febrile children between 3-36 months have
no localizing signs of infections.
• Occult bacteremia occurs due to H. Influenza, N.
meningitides, and salmonella in 4% of well appearing
children.
• Risk factors: Total counts of > 15,000,Raised ESR, CRP
and ANC.
• Increased incidence of occult bacteremia may be due
to maturational immune deficiency in the production
of opsonic IgG (Table 9.7.2).
Treatment Options
1. Obtain blood culture and start empirical anti-
microbial therapy.OR
2. Obtain CBC, If counts are > 15,000 do a blood culture
and start antibiotics.OR
3. Observe selected cases as outpatients after blood for
C/S has been obtained and ask parents to bring back
the child if fever persists or condition deteriorates.
Fever with Nonspecific Signs
When the duration of fever is yet less than two weeks at
presentation and child manifests with hepatomegaly,
splenomegaly, rash, jaundice or lymphadenopathy
specific investigations for anicteric or icteric hepatitis,
enteric fever, malaria, infectious mononucleosis may
provide clues to diagnosis. Assess the epidemiological
details suggestive of Dengue fever, Leptospirosis, etc.

Recurrent Fever
This term refers to children presenting with episodes of
documented fever separated by days or weeks of normal
temperature.
For example, recurrent respiratory tract infections,
relapsing fever, dengue fever, lymphomas.
Fever Complicating Chronic Illness
A child who has fever persisting for over 2 weeks may
have a chronic disease to be investigated for lymphomas
or leukemia. Childhood tuberculosis may present in a
similar way.
TREATMENT OF FEVER
• Whether or not to treat elevated temperature is a
common question. To determine an answer one must
first identify the cause of fever, degree of fever and
then establish goals of therapy.
• In patients with fever of < 40 degree C there is no
benefit of antipyretic therapy.
• The use of antipyretics will alter the pattern of fever,
which may mask the diagnosis.
• Goal of the treatment is to correct fluid deficit and
ensure that the child’s fluid intake is adequate.
The knowledge that fever is an important immuno-
logical defence mechanism has always been used to
support the arguments against treating fever. There is
enough evidence to support this view that uncomplicated
fever is relatively harmless.
Advantages of Fever
• Increases immune response by increased production
of interferon’s, B cell proliferation Increased
bactericidal effect of PMN’S.
• Improves nutrition of cells with protective influence
on their activity.
• Growth and virulence of several organisms like
Malaria, Syphilis is impaired.
• Augments hepatic synthesis of acute phase reactants.
There are situations where fever can be harmful in
young children if not treated, e.g. debilitated or children
with systemic infections.
It is common experience that Fever often makes child
uncomfortable, Increases metabolic rate, increase O2
consumption and CO2 production, Increased demands
Immunization and Infectious Diseases 297
on Cardiopulmonary system, precipitates febrile
convulsions. Thence administration of antipyretics
becomes necessary.
Indications of Antipyretic Therapy
1. Fever > 101°F
2. Febrile convulsions
3. Child is shivering
4. Child with heart disease.
SUPPORTIVE THERAPY
Physical therapy is often used to promote loss of heat in
high grades fever.
• Remove excess clothing or blankets and keep the child
in well-ventilated room.
• Encourage to take extra fluid to compensate for
increase insensible fluid loss and to maintain blood
flow necessary for heat dissipation.
• Discourage vigorous activities.
• Tepid sponging: It is cheap, easy and safe physical
measure to reduce body temperature. Studies have
found that tepid sponging is effective in the first 30
minutes.
Effect of sponging with water at different temperatures
Tap water 20 min 0.2 degree C
Luke warm 15 min 0.8 degree C
Cold water 20 min 0.1 degree C
• Rapid cooling methods such as ice baths, alcohol rub
down and cool water enemas should be avoided.
WHO recommends fanning, tepid sponging and
cooling blankets for treatment of fever in children with
Malaria.
DRUG THERAPY
Most of the drugs used in antipyresis reduce levels of
PG synthesis in brain and thus sets the thermostate back
to normal. The pharmacological therapy includes
different classes of drugs with antipyretic-analgesic,
antipyretic or analgesic effects only. Aspirin once a
preferred drug is no longer used as it has potential to
cause Reyes syndrome. Acetaminophen, Ibuprofen and
Nimesulide are currently three preferred drugs in
treatment of fever (Table 9.7.3).
298 IAP Textbook of Pediatrics
Paracetamol (Acetaminophen); (PCM)
It’s the drug of choice in young children. Its analgesic
effect is equal to that of Aspirin but in clinical doses has
no anti-inflammatory effect. It is well absorbed orally and
is 50% protein bound. It is conjugated in liver to form
sulphate and glucuronide derivatives with a small
amount metabolized to toxic aryl intermediates which
is hepatotoxic when present in quantities greater than
the capacity of liver to conjugate with glutathione. It
exhibits linear dose relationship, higher doses has been
shown to be more effective than lower doses.
Neonates and infants handle PCM less efficiently and
are capable of forming reactive intermediates that causes
hepatocellular damage after multiple dosing.
It has been used alone or in combination with tepid
sponging with equal or better results. It has been used as
suppository in children with nausea or vomiting or
unconscious state with equal efficacy.
The dose is 10-15 mg/kg given at 4 hours interval
.The analgesic dose is 65 mg/kg/dose in divided doses.
Acute PCM toxicity occurs due to accidental exposure
with clinical features of anorexia, vomiting, abdominal
pain, jaundice, hematuria, and metabolic acidosis.
Diagnosis is based on history, clinical findings and raised
LFT. Treatment is with N acetyl cysteine.
Ibuprofen
It is a propionic acid derivative with a comparable
antipyretic efficacy with PCM or aspirin. (Ibuprofen in a
dose of 6 mg/kg has equal efficacy with 8-12 mg/kg of
PCM).
Dose 5-10 mg/kg /dose.
It can lead to gastric ulceration, hemorrhage,
Perforation.
Mefenamic Acid
It is a potent inhibitor of cyclo-oxygenase with both
central and peripheral action. It has been reported to have
longer duration of action and therefore more effective
than Ibuprofen.It has high rate of fecal excretion and
therefore causes diarrhea and other GI effects and
nephrotoxicity if used more than a week.
Nimesulide
It is relatively new drug with selective COX inhibitory
action. It achieves peak conc. in 1-4 hours after oral dose.
It can be used orally or rectally.
Dose is 1.5-2.5 mg/kg/dose. It has a faster and long
antipyretic effect as compared to PCM.
Mechanism of action: It inhibits Cyclo-oxygenase and
thus PGE2, free radical scavenger, anti-histaminic,
activity on myeloperoxidase.
Side effects: Excess perspiration, heartburn, and
flushing and skin rash.
Aspirin
It is an effective antipyretic-analgesic NSAID. It acts buy
inhibiting Cyclo-oxygenase and thus PGE2 in Hypo-
thalamus. Biological half-life is only 15 minutes: t½ of
salicyclic acid is 2-3 hours.
Overdose leads to salicylism characterized by
hyperventilation, depressed level of consciousness and
severe metabolic acidosis.
Unequivocal evidence linked aspirin use in viral
infections like Influenza, chickenpox to Reyes’ syndrome.
Its use as antipyretic is gone into disrepture except in
specific conditions like rheumatic fever and other
collagen vascular disease.
Paracetamol is the drug of choice because it has
minimal side effects and doesn’t affect the beneficial
effects of fever. Also it is safe to use in febrile children
with bronchial asthma, ITP or GI illness.
Most failures with antipyretic therapy are related to
underdosing .PCM can be increased to 15 mg/kg/dose
in resistant fever.
If no response then use Ibuprofen as second line. It’s
the only antipyretic recommended by WHO as an
alternative. It can be used as a combination with PCM
under supervision.
Mefenamic acid or nimesulide are reserved only for
rare difficult cases. Avoid corticosteroids.
FEVER OF UNKNOWN ORIGIN
Fever of unknown origin (FUO) is defined as a single
illness that has lasted for 3 or more weeks, with
temperature greater than 38.3°C on most days and with
uncertain diagnosis after 1 week of intense evaluation
which include hospitalization and CT of the abdomen.
FUO can be further categorised into four types depending on
the causes
1. Classic FUO: The child should have temperature
> 38.3°C for a duration of > 3 weeks and should have
been evaluated on atleast 3 OPD visits or 3 days of
inpatient stay, e.g. Infection, malignancy, inflamma-
tory diseases, etc.
 Immunization and Infectious Diseases 299

TABLE 9.7.3: Comparing different Antipyretics

Drug Pharmacokinetics Dose Drug interactions Dose schedule

Peak T½ Metabolism

Aspirin 2 hrs 15 min Hepatic 10-15 mg/kg/dose Can displace protein Currently not
bound drug favored
Paracetamol ½-1 hr 1-4 hrs Hepatic 10-15 mg/kg/dose Not significant 4-6 hourly
Ibuprofen 1-2 hrs 1.8-2 hrs Hepatic 5-10 mg/kg/dose Can displace protein 4-6 hourly
bound drug
Mefenamic acid 2-4 hrs 2.5-3 hrs Hepatic 4-12 mg/kg/dose Can displace protein 6-8 hourly
bound drug
Nimesulide ½-1 hr 2 hrs Hepatic 5-8 mg/kg/day Not known 8-12 hourly

2. Nosocomial FUO: Temperature of > 38.3°C develop-
ing on several occasions in a hospitalized patient who
is receiving acute care and in whom infection was
not manifest or incubating on admission. Three days
of investigations, including at least 2 days incubation
of cultures is the minimum requirement for this
diagnosis, e.g. sinusitis, clostridium difficile colitis,
drug fever, septic thrombophlebitis.
3. Neutropenic FUO defined as a temperature of 38.3°C
on several occasions in a patient whose neutrophil
count is < 500/uL. The diagnosis of neuropenic FUO
is invoked if a specific cause is not identified after 3
days of investigation including at least 2 days
incubation of culture. For example candidiasis,
Aspergillosis, perianal infection
4. HIV Associated FUO defined as temp of > 38.3°C on
several occasions over a period of > 4 weeks for out
patient or 3 days for hospitalized patient with HIV
infection.
The diagnosis is invoked if appropriate investi-
gation over 3 days including 2 days incubation of
culture reveals no organism.
E.g. Mycobacterium avium intracellularae,
Tuberculosis, Non-Hodgkins Iymphoma, drug fever.
Etiology
There are a good number of causes for FUO. Incidence
of diseases causing FUO varies depending upon the age
of the child. In children less than 6 years of age most
common is infective cause accounting for 65% followed
by neoplastic 8% and autoimmune 8%. In the age group
between 7 to 12 years, infective causes accounts for 38%,
neoplastic 4%, autoimmune 23%.
Etiology of FUO can be classified into infective causes
and noninfective causes.
Table 9.7.4 lists the etiology for FUO.
DIAGNOSTIC APPROACH TO FUO
The diagnostic approach for each child has to be
individualized. It has to be kept in mind that in most
cases the cause of FUO is a familiar disease with an
uncommon presentation, rather than a rare disease. For
most patients diagnostic evaluation may be initiated on

Side effects of Antipyretics

Drug GI Peptic CNS Tinnitus Hepatic Renal Bone Bronchial Reyes

irritation ulcer effects marrow reactivity syndrome

Aspirin +++ ++ + ++ ++ + + ++ ++
Paracetamol + + + + + + + – –
Ibuprofen ++ + + + + + + + +
Mefenamic acid ++ + + – – + + + –
Nimesulide ++ – – – + + – – –
300 IAP Textbook of Pediatrics

Choosing the right drug TABLE 9.7.4: Etiology for FUO

Cooling methods Indications 1. Infective cause

A. Specific infection
Tepid sponging + H/O neurological disease Bacterial:
antipyretic drugs H/O cardiopulmonary disease • Salmonella • Tuberculosis
H/O fever > 40 degree • Brucellosis • Yersiniosis
Septic shock • Meningococcemia • Actinomycosis
Tepid sponging alone Very young infant • Mycoplasma pneumonia
Severe liver disease Spirocheteal
H/O hypersensitivity to antipyretics • Borrelia Burgdorferi • Relapsing fever
Cold sponging Heat illness • Leptospirosis • Syphilis
Parasitic diseases:
• Amebiasis • Babesiosis
an outpatient basis. However young infants, children • Giardiasis • Malaria
• Toxoplasmosis
who appear toxic or chronically ill and children who have
Fungal disease
been febrile for a prolonged period should be • Blastomycosis • Coccidiomycosis
hospitalized for evaluation. Hospitalization helps in • Histoplasmosis
documenting the fever, exploring the history further, Clamydial
repeating the physical examination and maintaining • Lymphogranuloma venereum
constant observation along with lab evaluation. • Psittacosis
Rickettsial
• Q Fever • Rocky mountain
History
• Tick born typhus spotted fever
Carefully taken , detailed history is the most important Viruses
tool in the diagnosis of FUO. • CMV • Hepatitis
• Age: Neonates and young children are susceptible to • HIV
specific organisms like L monocytogenes, Group B B. Local septic infections
• Dental abscess • Hepatic abscess
Streptococcus. Adolescents are susceptible for N
• Sub phrenic abscess • Bronchectasis
gonorrhea infection. Connective tissue disorders are • Sinusitis • Mastoditis
4 times more common in children who are more than • Tonsillitis
6 years old. C. Local infection without pus formation
• Sex: Chronic granulomatous disease and Brutons • UTI • Phlebitis
agammaglobulinemia are restricted to boys. Pelvic • Ulcerative colitis • Regional enteritis
inflammatory disease occurs more often in females. • Diverticulitis
• History of fever in the family members or neighbours 2. Noninfectious cause
Collagen vascular disorder
may point towards infectious cause of fever.
• JRA • Behcet’s disease
• Contact with tuberculosis and past history of • Juvenile dermatomyositis • SLE
exanthematous illness may suggest the possibility of Neoplastic
tuberculosis. • Leukemia • Lymphoma
• Pets in the house raise the possibility of toxoplasmosis, • Neuroblastoma • Wilm’s tumor
visceral larva migrans, cat scratch disease. Metabolic
• Gout • Porphyria
• History of pica, ingestion of dirt provides clue to the
Endocrine
diagnosis of toxoplasma infections. • Thyrotoxicosis • Addison’s disease
• Note should be made about the presence of epidemics Hypersensitive reaction
in the community like dengue, enteroviral and • Serum sickness
leptospira infections for considering appropriate Drug fever
diagnosis. Miscellaneous
• Cirrhosis of liver • Sarcoidosis
• Take details regarding travel to areas with endemic • Familial mediterrean fever • Whipples diseases
illnesses. • Poisoning
• Recent history of surgery suggest possibility of occult Fictitious fever malingering
infection.

• A history of abdominal pain or diarrhea even weeks
before the onset of fever may be a clue for enteric
infection or intra-abdominal abscess.
• Medication history should be looked into and should
include over the counter preparation, topical agents
including atropine (Atropine induced fever).
• Genetic background of the patient is important for
conditions like Riley-Day syndrome.
Physical Examination and Clues to
the Diagnosis Of FUO
Careful and meticulous physical examination is
mandatory in all children with FUO. Repetitive
examinations, preferably daily examination is important
to pick-up subtle or new signs which appear during the
course of illness and help in identifying the etiology.
Following are the clinical parameters which give clues
to the diagnosis.
Temperature
Temperature pattern during hospitalization may give
clues to the diagnosis e.g. (1) Intermittent: Malaria, acute
pyelonephritis (2) Continuous: Typhoid, Miliary TB,
Subacute bacterial endocarditis (SABE), Pneumonia, (3)
Periodic/undulating: Hodgkins, brucellosis.
Pulse rate: Relative bradycardia (Typhoid, meningitis,
dengue, Weil’s disease).
Anemia: Malaria, Kala-azar SABE, ALL, chronic diseases.
Lymph node: All lymph nodes should be described and
recorded.
Generalized lymphadenopathy: Hodgkins disease, TB,
ALL, Secondary syphilis.
Localized lymphadenopathy: Glandular fever.
Jaundice: Infectitious hepatitis, Weil’s diseases, malaria,
liver abscess, infectious mononucleosis.
Skin rash: Viral exanthematous illnesses like measles and
varicella, meningococcemia, dengue, septicemia, SABE,
rickettsial illness.
Clubbing: Lung abscess, bronchiectasis, SABE, liver
abscess.
Arthritis: Rheumatic fever, SABE, meningococcemia,
leukemia.
Bony tenderness: Arthritis, leukemia.
Fundus: Choriod tubercules in tuberculosis.
Immunization and Infectious Diseases 301
CVS
CVS should be examined for murmurs daily.
The presence of sick and toxic look may suggest
bacterial etiology. A child who otherwise looks well in
spite of fever may have a non-infective cause of fever.
Investigations (Table 9.7.5)
Investigations should be appropriate and based on
clinical history and physical findings.
Following table lists the investigations which are
routinely done for patients with FUO. Further investi-
gation depends upon the child’s presentation which is
listed as advanced investigation.
Routine investigations should include total and
differential counts, peripheral smear, ESR urine analysis,
blood culture. Total count greater than 11,000/ mm3 have
a high likelihood of bacterial infection. Conversely,
absolute neutrophil count of less than 5,000/mm3 is
against indolent bacterial infection except typhoid fever.
Periperal eosinophilia provides clue to parasitic
infestation, immunodeficiency disorder or occult
malignancies. Direct smear examination with Giemsa or
Wright stain reveals organisms of malaria, toxoplasma,
relapsing fever, etc.ESR exceeding 30 mm per hour
indicates inflammation and need for further evaluation.
TABLE 9.7.5: Routine and Advanced investigations
Routine Investigations
Complete blood counts
ESR, CRP
Liver biopsy
Chest X-ray
Peripheral smear (night smears for filaria)
Mantoux test
Urine analysis
Blood and urine cultures
Stool examination (occult test also)
Liver function test
CSF analysis
Ultrasonography
Bone marrow aspiration and biopsy
Lymph node biopsy
Advanced Investigations
Serum for virological studies
Autoimmune work up (RA factor, ANA factors)
ECG/ECHOCT/MRI
Barium studies
Isotope scans
Lymphangiography to localize retroperitoneal, aortic and iliac
lymphnodes.
Exploratory laparotomy.
302 IAP Textbook of Pediatrics
ESR greater than 100 mm/hour may suggest tuber-
culosis, Kawasaki’s disease, autoimmune or malignant
diseases. Blood culture should include aerobic and
anerobic cultures. Chest X-ray should be an initial
investigation. X-ray of the sinuses, mastoids or GI tract
may be indicated by specific history or physical findings.
Other investigations like ultrasonography, CT scan, bone
marrow examination must proceed stepwise. Lumbar
puncture is necessary in young infant or child with
meningeal signs, altered mental status, etc.
Isotope scans with technetium-99m, gallium citrate,
indium-111 labeled leukocytes help in localizing
inflammatory processes.Bronchoscopy, laparoscopy,
gastrointestinal endoscopy and mediastinoscopy may be
warranted on individual merits of the case. Lymphangio-
graphy is resorted to localize aortic, iliac and retro-
peritoneal lymph nodes. Exploratory laparotomy is
performed when all the other diagnostic procedures fail.
Treatment
As far as possible any treatment for FUO should be
started only when sufficient grounds for diagnosis are
available. Mild antipyretics are given for the patient
comfort. Empirical trial with antibiotics may mask the
diagnosis of infective endocarditis, osteomyelitis or
meningitis. Exception may be the use of ATT in a critically
ill child with possible disseminated TB. In general
observation of the temperature pattern, repeated clinical
examination, careful laboratory evaluation and interpre-
tation of the results might throw a light on the diagnosis.
Specific treatment depends on the diagnosis.
9.8 An Approach to a Child with
Fever and Skin Rash
Skin rashes in a child with fever is always a cause for
great concern. They can be caused by a drug reaction, an
infection, or an allergic reaction. The skin can only react
to injury in a few ways, and many different agents can
cause rashes that look the same. Often, the symptoms in
addition to the rash help make the diagnosis, such as a
history of insect bites, exposure to other ill children or
adults, recent use of medication, environmental
BIBLIOGRAPHY
1. Campbell AGM. The child with fever. In Campbell AGM,
Neil Macintosh (Eds). Forfar and Arneil’s text book of
Pediatrics, 5th Edn, 1998;1282-4.
2. Chandra J. Antipyretics in children. Indian Journal of
Pediatrics 2002;69:69-74.
3. Chandrashekhar PH. Pyrexia of Unknown origin. Arch
Int Med 1994;154:841-9.
4. Cunha BA. fever of unknown origin. Infect Dis Clin
North Am 1996;111-27.
5. Gelfand JA, Dinarell CA. Fever and Hyperthermia. In
Fauci AA, Braunwald E, et al (Eds). Harrison’s principles
of internal medicine, 14th edn: 1998;84-90.
6. Krishnan S. FUO, IAP J Pract Ped 1994;2:289-91.
7. Martin I Lorin. Fever of unknown origin, In McMillan,
Deangelis, Feigen et al (Eds). Oski’s Principles and
Practice of Pediatrics 1999;3:844-8.
8. Martin I Lorin. Pathogenesis of fever and its treatment.
In McMillan, Deangelis, Feigen, et al (Eds). Oski’s
Principles and Practice of Pediatrics 1999;3:848-50.
9. Mieler ML, et al. Fever of unknown origin. Pediatr Clin
N Am 1995;42.
10. Powell KR. Fever of unknown origin Part 16, section 2,
Nelson Textbook of Pediatrics, 16th edn 2000;142-7.
11. Robinson MJ, Roberton DM. FUO.Practical Pediatrics
1995;3:301-4.
12. Sarah S, et al. Distinguishing among prolonged,
Recurrent and periodic fever syndromes. Pediatr Clin N
Am 2005;52:811-35.
13. Singh M. Fever of acute onset: A practical approach. IAP
J Prac Ped 2002;4:85-90.
14. Singh M. Fever with out focus. IAP J Prac Ped 1997;5:
139-42.
15. Singh M. Symptomatic management of fever in children:
A rational approach. IAP J Prac Ped 1999;1:75-80.
Jayakar Thomas
exposures, or prior immunizations. Most rashes caused
by viruses do not harm the child and go away over time
without any treatment. However, some childhood rashes
have serious or even life-threatening causes. A physician
should be familiar with these rashes. Many rashes can
look the same, making it difficult to know the exact
diagnosis. About 10% of all febrile children have a
dermatological problem.
 Immunization and Infectious Diseases 303

• Pattern of fever
Some examples of skin rash in a febrile child
• Type of skin lesions
Drug rash • Configuration
Kawasaki’s disease
• Arrangement
Systemic lupus erythematosus
Erythema infectiosum
• Distribution
Dermatomyositis • Site of first appearance
Measles • Evolution
Urticaria • Tenderness
Rubella • Mucosal involvement
Allergic vasculitis
• Palms/soles/hair/nails
Varicella
EMF • Other systems.
Herpeszoster (disseminated) The morphology of the skin lesions may contribute
Toxic epidermal necrolysis reasonably to its cause in relation to the fever. It is
Typhoid common to see more than one type of morphology at a
Staphylococcal scalded skin syndrome
given point of time. Drug reactions are classical examples
Erythema marginatum
Scarlet fever
of such presentation. At times the lesions go through
Meningococcemia stages, and in such cases the presenting lesion along with
Erysipelas relevant evidence from the history on evolution will help
Bacterial endocarditis clinch the diagnosis. Yet others may start in a particular
form and continue the same morphology, as in measles
The approach to such a situation is a challenge and and rubella. Therefore it is mandatory that the physician
in clinical practice, physicians “lean” on their eyes in no familiarizes himself with a sound knowledge of the
other situation more than they do when confronted by morphology of skin lesions in the different disorders.
an acutely ill child with fever and a skin eruption. Definitions of these patterns are given in the Chapter on
An algorithmic or stereotyped approach to a child Skin Diseases in Children.
with fever and skin rash would not sound meaningful. Some examples are shown below. These are only
Prudence, however, demands a systematic approach. It guidelines and should not be considered as complete and
will comprise of: comprehensive.
1. Careful history taking
2. Astute clinical examination Macules, papules, Macules and Macules only
and blisters blisters
3. Relevant laboratory work-up
History taking with regard to the fever, the points to Dermatomyositis
be considered include: Urticaria
Drug rash EMF Allergic vasculitis
• Duration of fever
SLE TEN Scarlet fever
• Variation with time of day Erysipelas SSSS Kawasaki’s Disease
• Drug intake Meningococcemia Varicella Erythema infectiosum
• Itching/burning/pain Bacterial endocarditis Measles
• Other symptoms Rubella
With regard to the skin rash, the points to be Erythema marginatum
Typhoid
considered include:
• Distribution of rash
Laboratory Work-up
• Morphology or pattern of skin rash
• Evolution Essential investigations include:
• Prodrome, if any. • Complete hemogram
• Urine microbiology
Clinical Examination • Blood biochemistry
This will include: • Smear examination from skin lesion
• Grade of fever • Gram/Leishman/AFB
304 IAP Textbook of Pediatrics
• Dark field microscopy
• LE cell test
• Blood serology
• Skin biopsy.
Many childhood diseases have bacterial or viral
causes and include a rash of some type. As study
continues and more and more vaccines become available,
these diseases become less of a threat to the child’s long-
term health. A rash of any kind should be taken seriously,
however, and may require a laboratory work-up for
evaluation.
Viral and Bacterial Disorders
Chickenpox
The characteristic rash appears in crops. An otherwise
healthy child usually has 250-500 lesions but may have
as few as 10 or as many as 1500. Each lesion starts as a
red macule and passes through stages of papule, vesicle,
pustule, and crust. Redness or swelling around a lesion
should lead to suspicion of secondary bacterial infection.
The vesicle on a lesion’s erythematous base leads to its
description as a pearl or dewdrop on a rose petal.
Varicella’s hallmark is the simultaneous presence of
different stages of the rash. Some lesions may appear in
the oropharynx. Eye lesions are rare. New lesions
continue to erupt for 3-5 days. Lesions usually crust by 6
days (2 to 12-d range), and heal completely by 16 days
(7 to 34-d range). Prolonged eruption of new lesions or
delayed crusting and healing can occur with impaired
cellular immunity. Fever usually is low-grade (100-102°F)
but occasionally may be as high as 106°F. In otherwise
healthy children, fever typically subsides within 4 days.
Prolonged fever should prompt suspicion of compli-
cation or immunodeficiency. Outcomes of in utero
varicella infections vary, based upon the timing of the
infection. Neonatal varicella can be a serious illness,
depending upon the timing of maternal varicella and
delivery. If the mother develops varicella within 5 days
before or 2 days after delivery, the baby is exposed to
the secondary viremia of the mother. The baby acquires
the virus transplacentally but acquires no protective
antibodies because of insufficient time for antibodies to
develop in the mother. In these circumstances, neonatal
varicella is likely to be severe and disseminated.
Prophylaxis or treatment is required with varicella-zoster
immune globulin (VZIG) and acyclovir. Without these
drugs, mortality rates may be as high as 30%. The
primary causes of death are severe pneumonia and
fulminant hepatitis. Onset of maternal varicella more
than 5 days antepartum provides the mother sufficient
time to generate and pass on antibodies along with the
virus. Full-term neonates of these women usually have
mild varicella because of the attenuating effect of the
transplacentally acquired antibodies. Treatment with
VZIG is not recommended in such cases, but acyclovir
may be used, depending on individual circumstances.
Laboratory studies are unnecessary for diagnosis because
varicella is obvious clinically. Most children with
varicella have leukopenia in the first 3 days, followed by
leukocytosis. Marked leukocytosis may indicate a
secondary bacterial infection, but this is not a dependable
sign. Most children with significant secondary bacterial
infections do not have leucocytosis. A Tzanck smear
involves scraping the base of the lesions, then staining
the scrapings to demonstrate multinucleated giant cells.
This finding, however, is not sufficiently sensitive or
specific for varicella and should be replaced by the more
specific immunohistochemical staining of such scrapings,
if available. Serology mainly is used to confirm past
infection to assess a patient’s susceptibility status. This
helps determine preventive treatment requirements for
an adolescent or adult who has been exposed to varicella.
Among the many serologic studies, the most sensitive
are the indirect fluorescent antibody (IFA), fluorescent
antibody to membrane antigen (FAMA), neutralization
test (NT), and radioimmunoassay (RIA). These time-
consuming tests require specialized equipment that
renders them unsuitable for routine use. Commercially
available latex agglutination (LA) and enzyme-linked
immunosorbent assay (ELISA) tests are sensitive and
rapid. Although the complement fixation test often is
used, its sensitivity is low. Children with high tempe-
ratures and respiratory signs should have a chest x-ray
to confirm or exclude pneumonia. Chest X-ray findings
may be normal or may show diffuse bilateral nodular
infiltrates in primary varicella pneumonia. X-rays also
may detect focal infiltrates suggestive of secondary
bacterial pneumonia. Children with neurological signs
should have their cerebrospinal fluid (CSF) examined.
The CSF of patients with varicella encephalitis may have
few or as many as a hundred cells that are polymor-
phonuclear or mononuclear, depending on the timing
of the lumbar puncture. Glucose levels are normal.
Protein levels are normal or slightly raised. Treatment is
mainly directed to manage pruritus with cool compresses

and regular bathing. Scratching is discouraged to avoid
scarring. Trimming the child’s fingernails and having the
child wear mittens while sleeping may reduce scratching.
Some children with varicella have reduced appetite and
should be encouraged to take sufficient fluids to maintain
hydration. Adequate hydration is especially important
if the child is receiving acyclovir, as the drug can
crystallize in the renal tubules if administered to
dehydrated individuals. Chickenpox is not always
benign. In certain well-defined groups, varicella can be
severe and even fatal. Antiviral drugs are recommended
for adolescents, adults, and children on steroid or
salicylate therapy and for children who are otherwise
immunocompromised. Acyclovir is the only adequately
studied drug of this class.
Measles
The incubation period from exposure to onset of
symptoms ranges from 8-12 days. The prodromal phase
is marked by malaise, fever, anorexia, conjunctivitis,
cough, and coryza. The entire course of uncomplicated
measles, from late prodrome to resolution of fever and
rash, is 7-10 days. Cough may be the final symptom to
appear. Fever: A temperature exceeding 101°F begins
with the prodrome and persists 7-10 days. Koplik spots
(i.e., bluish-gray specks or “grains of sand” on a red base)
appear on the buccal mucosa opposite the second molars
near the end of the prodrome, just prior to appearance
of rash. This enanthem begins to slough as the rash
appears. An erythematous and maculopapular rash that
becomes confluent begins on the face, then proceeds to
the trunk, extremities, palms, and soles and lasts for about
5 days. Patients appear most ill during the first or second
day of the rash. Desquamation, which spares the palms
and soles, may occur after 1 week. The rash may be absent
in patients with underlying deficiencies in cellular
immunity. Generalized lymphadenopathy, mild hepato-
megaly, and appendicitis may occur because of generali-
zed involvement of lymphoid tissue. Laboratories can
confirm measles by demonstrating more than a 4-fold
rise in immunoglobulin G (IgG) antibodies between acute
and convalescent sera. IgG antibodies may be detectable
4 days after the onset of the rash, although most cases
have detectable IgG antibodies by about a week after rash
onset. Thus, take specimens on the seventh day after rash
onset and repeat 10-14 days later to confirm the case as
soon as possible. Patients with SSPE have unusually high
titers of measles antibody in their serum and
Immunization and Infectious Diseases 305
cerebrospinal fluid. The earliest confirmation of measles
using IgG antibodies takes about 3 weeks from the onset
of illness, a delay too long to permit implementation of
effective control measures. Myxovirus (MV) can be
isolated from nasopharyngeal swabs. Viral genotyping
in a reference laboratory may determine whether an
isolate is endemic or imported. In immunocompromised
patients, who may have poor antibody responses that
preclude serologic confirmation of measles, virus
isolation from infected tissue or identification of measles
antigen by immunofluorescence may be the only method
to confirm the diagnosis. Leukopenia occurs in the late
stages of viremia. Elevated hepatic transaminase levels
may be detected in patients with MV hepatitis.
Administration of antibiotics (if evidence exists of otitis
media or bacterial pneumonia), vitamin A supplements
(particularly for children aged 6-24 mo), or ribavirin
(experimental) is considered treatment modalities. To
prevent or modify measles in exposed susceptible
individuals, administering MV vaccine or human
immunoglobulin is tried. Vitamin A treatment for
children with measles in developing countries has been
associated with a marked reduction in morbidity and
mortality. The World Health Organization recommends
vitamin A administration to all children with measles in
communities where vitamin A deficiency is a recognized
problem and where the MV-related mortality rate
exceeds 1%. Of note, low serum concentrations of vitamin
A are found in children with severe measles. Thus,
supplemental vitamin A in patients aged 6 months to 2
years who are hospitalized with measles and its
complications (e.g. croup, pneumonia, diarrhea) is found
useful. Also vitamin A supplementation is given for any
patient who meets the following criteria:
1. Is older than 6 months and has measles
2. Is not already receiving vitamin A supplementation
3. Is immunodeficient
4. Has clinical evidence of vitamin A deficiency
5. Has moderate-to-severe malnutrition
6. Has recently emigrated from an area with high
mortality rates due to measles.
Rubella (German measles)
Rubella virus is transmitted from person to person via
the aerosolized particles from the respiratory tract. A
history of exposure may not be present. Individuals may
acquire the infection from a completely asymptomatic
patient or from an individual shedding the virus during
306 IAP Textbook of Pediatrics
the incubation period. The incubation is usually 14-21
days after exposure to a person with rubella. Prodromal
symptoms are unusual in young children but are
common in adolescents and adults. The following signs
and symptoms usually appear 1-5 days before the onset
of rash:
• Eye pain on lateral and upward eye movement (a
particularly troublesome complaint)
• Conjunctivitis
• Sore throat
• Headache
• General body aches
• Low-grade fever
• Chills
• Anorexia
• Nausea
• Tender lymphadenopathy (particularly posterior
auricular and suboccipital lymph nodes)
• Forchheimer sign (an enanthem observed in 20% of
patients with rubella during the prodromal period;
can be present in some patients during the initial
phase of the exanthem; consists of pinpoint or larger
petechiae that usually occur on the soft palate).
The laboratory diagnosis of rubella can be made either
though serologic testing or by viral culture. The serologic
diagnosis consists of demonstrating the presence of
rubella-specific immunoglobulin M (IgM) antibody in a
single serum sample or observation of a significant rise
in rubella-specific immunoglobulin G (IgG) antibody titer
between the acute and convalescent serum specimens
drawn 2-3 weeks apart. False-positive rubella IgM test
results have been reported in persons with other viral
infections (e.g. acute Epstein-Barr virus [EBV], infectious
mononucleosis, cytomegalovirus [CMV] infection,
parvovirus B19 infection) and in the presence of
rheumatoid factor (RF). To demonstrate a 4-fold rise in
rubella-specific IgG antibody, a serum sample should be
obtained as soon as possible during the acute phase of
infection and tested for rubella-specific IgG antibody. An
aliquot of this serum should be frozen and stored for
repeat testing later. Then, a second serum specimen is
collected at 2-3 weeks and tested in the same laboratory
at the same time with the first serum sample. The levels
of rubella-specific IgG are compared between the first
and the second sample to show a significant rise in
antibody titers. Rubella viral cultures are time consum-
ing, expensive, not readily available, and used mainly
for tracking the epidemiology of rubella virus during an
outbreak. Complete blood count: CBC may reveal
leukopenia and thrombocytopenia. It is used to monitor
the course of thrombocytopenia. Histologically cutaneous
lesions are nonspecific and demonstrate only a mild,
superficial, perivascular, lymphocytic infiltrate.
Treatment is supportive. No specific antiviral agent for
rubella is currently available. Starch baths and antihista-
mines may be useful for uncomplicated rubella and
troublesome itching. For complicated cases, treatment is
as follows:
• For severe arthritis affecting weight-bearing joints,
encourage rest. Nonsteroidal anti-inflammatory
drugs (NSAIDs) may be helpful, but corticosteroids
are not indicated.
• For patients with encephalitis, provide supportive
care with adequate fluid and electrolyte maintenance.
• Thrombocytopenia usually is self-limited but, if
severe, consider intravenous immunoglobulin (IVIG).
Corticosteroids have not demonstrated any specific
benefit. Splenectomy is not indicated.
Drug therapy is currently not a component of the
standard of care for rubella.
Scarlet Fever (Scarlatina)
Thought not to be common in India scarlet fever is an
infection caused by toxin-producing group A beta
hemolytic streptococci (GABHS) found in secretions and
discharge from the nose, ears, throat, and skin. It may
follow streptococcal wound infections or burns, as well
as upper respiratory infections. The mucous membranes
usually are bright red, and scattered petechiae and small
red papular lesions on the soft palate are often present.
During the first days of infection, the tongue is heavily
coated with a white membrane through which edema-
tous red papillae protrude (classic appearance of white
strawberry tongue). By day 4 or 5, the white membrane
sloughs off, revealing a shiny red tongue with prominent
papillae (red strawberry tongue). Red, edematous,
exudative tonsils are typically observed if the infection
originates there. The characteristic exanthem consists of
a fine erythematous punctate eruption that appears
within 1-4 days following the onset of the illness. It first
appears on the upper trunk and axillae and then becomes
generalized, although it is usually more prominent in
flexural areas, such as the axillae, popliteal fossae, and
inguinal folds. It may also appear more intense at
dependent sites and sites of pressure, such as the

buttocks. Capillary fragility is increased, and often,
transverse areas of hyperpigmentation with petechiae
in the axillary, antecubital, and inguinal areas (Pastia
lines) can be observed. The face is usually flushed, and
circumoral pallor is observed. The eruption imparts a
dry rough texture to the skin that is reported to resemble
the feel of sandpaper. The cutaneous rash lasts for 4-5
days, followed by fine desquamation, the extent and
duration of which is directly related to the severity of
the eruption. Cultures of the infected oropharynx or other
infected areas should be obtained. CBC commonly
reveals a leukocytosis. An increase in anti–streptolysin
O (ASO) titers can be observed but is a late finding and
usually of value only in retrospect. Patients whose
bacterial source may suggest another process (e.g. a
patient with a suppurative leg wound who may have
osteomyelitis) should be evaluated accordingly. The
microscopic findings of the eruption of scarlet fever are
nonspecific and have an appearance similar to that of
other exanthematous eruptions. A sparse perivascular
infiltrate usually consisting of lymphocytes primarily
with a slight amount of spongiosis in the epidermis is
present. Slight parakeratosis may be present, which
probably correlates with the sandpaper like texture of
the skin.
Antibiotic therapy is the treatment of choice for scarlet
fever. Cultures should be obtained where organisms
other than streptococcal bacteria are suspected. The
desquamating rash that follows is self-limited, with only
emollients necessary for care.
The drug of choice is benzathine penicillin G
administered IM or penicillin VK administered orally for
10 days. First-generation cephalosporins may also be
used. Erythromycin should be considered in patients
allergic to penicillin.
Fifth Disease
Fifth disease, also known as erythema infectiosum or
“slapped cheeks” disease, is caused by a virus
(parvovirus B19). This disease tends to occur in the winter
and spring but can happen year-round. Erythema
infectiosum typically has an incubation period of 4-14
days and is spread primarily via aerosolized respiratory
droplets. Transmission also occurs through blood
products and from mother to fetus. The prodromal phase
often is mild enough to be noticed only rarely but may
include headache, coryza, low-grade fever, pharyngitis,
and malaise. Infrequently, nausea, diarrhea, arthralgias,
Immunization and Infectious Diseases 307
and abdominal pain may occur. In hosts who are
immunocompetent, the patient is viremic and capable
of spreading the infection only during the incubation
period. Classic cutaneous findings follow within 3-7 days
for some patients, while other patients may manifest no
findings. Pertinent physical findings predominantly are
limited to the skin and joints. The exanthem begins with
the classic slapped-cheek appearance. The bright red
erythema appears abruptly over the cheeks and is
marked by nasal, perioral, and periorbital sparing. The
exanthem may appear like sunburn, occasionally is
edematous, and typically fades over 2-4 days. Within 1-
4 days of the malar rash, an erythematous macular-to-
morbilliform eruption occurs primarily on the extre-
mities. While the eruption tends to favor the extensor
surfaces, it can involve the palms and soles. Pruritus is
rare. After several days, most of the second stage eruption
fades into a lacy pattern, with particular emphasis on
the proximal extremities. Despite its synonym, slapped-
cheek disease, the reticulate pattern is distinctly
characteristic for erythema infectiosum and may be the
only manifestation of the illness. The third stage lasts
from 3 days to 3 weeks. After starting to fade, the
exanthem may recur over several weeks following
physical stimuli, such as exercise, sun exposure, friction,
bathing in hot water, or stress. In adults, an acute
polyarthropathy is more likely to result than classic
erythema infectiosum. Polyarthropathy may start with
a typical prodromal illness and some cutaneous aspect
of erythema infectiosum but more often manifests simply
by a new onset of symmetric joint pain. Arthropathy is
more common in women and can last for days to months.
Sites most commonly affected include joints of the hands,
wrists, knees, and ankles. Unlike rheumatoid arthritis,
joint pain worsens over the day, and no joint destruction
occurs. The synovial fluid is acellular and devoid of viral
particles. The diagnosis of erythema infectiosum usually
is based on clinical presentation alone, and a workup for
patients with the classic presentation is not necessary.
For patients with other PV-B19–associated signs or
symptoms, or for exposure in a woman who is pregnant,
confirmation of infection may be helpful and can be
accomplished with the following specialized tests:
• IgM assays (enzyme-linked immunoassay, radio-
immunoassay)
• Dot blot hybridization
• Polymerase chain reaction
308 IAP Textbook of Pediatrics
Skin biopsy is not necessary or does not aid in
diagnosis but may reveal nonspecific changes, including
mild basilar vacuolarization, dyskeratotic cells, and a
sparse perivascular infiltrate.
Since erythema infectiosum most often is a benign
self-limited disease, reassuring the parents often is the
only intervention necessary. For patients with arthralgias
or pruritus, symptomatic relief can be obtained using oral
analgesics and antihistamines or topical antipruritic
lotions (e.g. alum lotion or calamine lotion). Symptomatic
relief of erythema infectiosum may be provided using
nonsteroidal anti-inflammatory drugs (NSAIDs),
antihistamines, and topical antipruritics. For an acute
aplastic crisis, supplemental oxygen and blood trans-
fusions may be necessary. Intravenous immunoglobulin
(IVIG) is helpful for chronic anemia in patients who are
immunocompromised.
Roseola Infantum
Roseola is also called exanthem subitum and is a common
childhood virus caused by the human herpes virus 6.
The disease usually occurs in children younger than 4
years. The classic patient with roseola is a 9- to 12-month-
old infant in previously good health and who has an
abrupt onset of high fever (40°C), which lasts for 3 days
with nonspecific complaints. A febrile seizure occurs in
15% of patients. Rapid defervescence is striking with the
onset of a mild, pink, morbilliform exanthem. In patients
who are immunocompromised, the onset of symptoms
is usually abrupt, with fever, malaise, and CNS and other
organ system involvement. Despite the high fever, few
clinical findings are observed early in the course. The
lack of upper respiratory infection is notable, and
meningeal signs and encephalopathy are not present.
Gastrointestinal symptoms, signs of electrolyte
imbalance, or evidence of dehydration are rarely present.
A febrile seizure, with no residual findings, may have
occurred. After cessation of fever, the characteristic rash
appears. The eruption is generalized and subtle. It is
composed of either discrete, small, pale pink papules or
a blanchable, maculopapular exanthem that is 1-5 mm
in diameter. This rash may last 2 days. The characteristic
enanthem (Nagayama spots) consists of erythematous
papules on the mucosa of the soft palate and the base of
the uvula. The enanthem may be present on the fourth
day in two thirds of patients with roseola. In response to
the early acute febrile presentation, laboratory studies
may include CBC, urinalysis (UA), blood culture, and
cerebrospinal fluid examination. If the patient presents
with a febrile seizure, a seizure workup may be indicated.
Diagnosis may be confirmed by virus isolation,
seroconversion (immunoglobulin M [IgM]), or detection
of viral DNA sequences in peripheral blood mononuclear
cells. Typical ballooning cells may be seen histologically
in any organ system affected with HHV-6 infection. At
present, no medical antiviral therapy is available for
HHV-6 infection that causes roseola. Thus, treatment is
supportive. Acute or chronic antiseizure medications are
not recommended for infants who have had a febrile
seizure secondary to roseola.
Coxsackieviruses and Other Enteroviruses
The enteroviruses, including the coxsackieviruses, are a
very common cause of fever and rash in children. Two
diseases are caused by coxsackieviruses, called hand-
foot-and-mouth disease and herpangina. Coxsackievirus
infections are more common in the summer and autumn.
In hand-foot-and-mouth disease, the children develop
fever and rash. The rash includes blisters to the mouth
and tongue and to the hands and the feet. Herpangina
causes a fever, sore throat, and painful blisters or ulcers
to the back of the mouth. No specific treatment is
available except acetaminophen or ibuprofen for fever.
The diseases are not harmful but can be prevented with
good hand washing and not eating off someone else’s
plate or sharing straws.
Impetigo
Impetigo is a superficial skin infection with streptococcal
or staphylococcal bacteria. It is often found around the
nose and mouth but can occur anywhere. The rash is
more common in the warmer months. It can also be an
additional infection to skin that has been damaged, such
as in scabies, poison ivy, eczema, or drug reactions. It
begins as small superficial blisters that rupture leaving
red, open patches of skin. Often a honey-colored crust
forms over this rash. The rash is very itchy. Impetigo is
also highly contagious. A child can spread the infection
to other parts of the body or to other people. This infection
of the skin is easily treated with topical or oral antibiotics.
The child usually is no longer contagious after 2-3 days
of therapy, and the rash begins to heal in 3-5 days. When
the impetigo occurs in addition to poison ivy or scabies,
the child may benefit from an anti-itch medication while
the antibiotics are taking effect.

Life-threatening Rashes
Life-threatening rashes are uncommon, and your child
usually appears quite ill if he or she has a life-threatening
rash. Fever and petechiae are the common symptoms.
These two symptoms are present with many rashes and
are often signs of a more serious condition. Children can
develop petechiae from a number of causes. It is not
unusual for forceful coughing or vomiting to cause
petechiae on the face and chest. Petechia with fever is
more concerning, although most of these children have
a viral illness that does not require any therapy. A small
percentage (2-7%) may have diseases that need imme-
diate evaluation. Petechiae are red dots on the skin that
do not fade when pressure is applied. The dots represent
bleeding from the capillaries leaving a small, temporary
blood blister in the skin.
Meningococcemia
Meningococcal disease is a communicable infection
caused by Neisseria meningitidis. It is transmitted from
person to person via respiratory secretions. N meningitidis
infection can be clinically polymorphic. The most
common disease presentation is meningitis. Rarely, N
meningitidis infection may manifest as chronic meningo-
coccemia that resembles the arthritis-dermatitis
syndrome of gonococcemia; however, acute meningo-
coccal septicemia (also called meningococcemia) is the
most devastating form of the disease. Meningococcemia
can kill more rapidly than any other infectious disease.
Early recognition is critical to implement prompt
antibiotic therapy and supportive care. Treatment must
be instituted rapidly because irreversible shock and death
may occur within hours of the onset of symptoms.
Cutaneous manifestations in meningococcemia may be
important clues to the diagnosis. Skin involvement can
be the most dramatic aspect of the disease and is often
the first sign that leads to the clinical consideration of
meningococcemia. It follows an upper respiratory
infection and is associated with headache, nausea,
vomiting, myalgias, and arthralgias. Not all children
appear toxic. The initial presentation may be difficult to
distinguish from a viral syndrome. While a slower clinical
presentation can occur in persons with a milder form of
disease, fever may increase dramatically with rapid
clinical deterioration. In fulminant meningococcemia, a
hemorrhagic eruption, hypotension, and cardiac
depression may be apparent within hours of the initial
Immunization and Infectious Diseases 309
presentation. Cutaneous manifestations of meningo-
coccemia are common and can be the presenting sign of
disease. Petechiae are the most common sign, occurring
in 50-60% of patients with meningococcemia; however,
urticarial and maculopapular lesions also may occur
initially. Petechiae are most often located on the
extremities and trunk but may progress to involve any
part of the body. Petechiae may appear in groups under
areas of pressure. With progression of meningococcemia,
pustules, bullae, and hemorrhagic lesions with central
necrosis can develop. Stellate purpura with a central
gunmetal-gray hue is characteristic and should be
considered highly suggestive of meningococcemia. Large
maplike purpuric and necrotic areas related to the
development of DIC are characteristic of fulminant
meningococcemia. Noncutaneous physical findings are
altered mental status, neck stiffness, irritability, seizures,
nerve palsies, gait disturbance, nausea, vomiting, and
unstable vital signs. Meningococcemia can be confirmed
with blood culture, lumbar puncture, and a Gram stain
of lesional skin biopsy or aspirate specimens. In
meningococcemia, organisms have been isolated by
blood culture in almost 100% of patients, yet the results
are not available for 12-24 hours. A throat culture should
be obtained; however, the diagnosis of meningococcemia
cannot be made solely based on a positive result from
throat culture because asymptomatic colonization is not
uncommon. Complement deficiencies should be sought
for complicated infections and recurrent or familial
disease. Meningococcal meningitis causes a polymor-
phonuclear leukocytosis in the cerebrospinal fluid, which
can be evaluated using lumbar puncture. In meningococ-
cemia, Gram stain results of the cerebrospinal fluid are
often negative. Detection of N. meningitidis capsular
polysaccharide antigen in cerebrospinal fluid and urine
with rapid serologic tests based on latex particle
agglutination is commercially available. In an effort to
obtain a more rapid diagnosis, several studies have
concentrated on the identification of meningococci from
skin specimens. Up to 50-80% of rigorous skin scrapings,
lesional aspirates, or punch biopsy samples from bullous
or pustular lesions reveal gram-negative N. meningitidis
with Gram staining or Brown-Hopp–modified Gram
stain; however, these results must be interpreted with
caution because many gram-negative commensals are
possible on the skin. Hitologically cutaneous petechiae
and purpura correspond to thrombi in the dermal vessels
composed of neutrophils, platelets, and fibrin. Acute
310 IAP Textbook of Pediatrics
vasculitis with neutrophils and nuclear dust present
within and around vessels leads to hemorrhage into the
surrounding tissue. Meningococci can often be seen in
the luminal thrombi and vessel walls. Intraepidermal and
subepidermal neutrophilic pustules also may be present.
The most important measure in treating meningo-
coccemia is early detection and rapid administration of
antibiotics. Penicillin G is the antibiotic of choice for
susceptible isolates. A third-generation cephalosporin
(e.g. cefotaxime, ceftriaxone) can be used initially in septic
patients while the diagnosis is being confirmed or in
countries such as the United Kingdom or Spain, where
penicillin-resistant strains of N. meningitidis have been
isolated. Intensive supportive care is required for patients
with fulminant meningococcemia. Components of
treatment include antibiotic therapy, ventilatory support,
inotropic support, and intravenous fluids. Central venous
access facilitates the administration of massive amounts
of volume expanders and inotropic medications needed
for adequate tissue perfusion. If DIC is present, fresh
frozen plasma may be indicated. Treatment is indivi-
dualized depending on the severity of hemodynamic
compromise of the patient. Many experimental and
alternate therapies have been tried with varying success.
Currently under study are treatments to inhibit
inflammatory mediators (e.g. monoclonal antibodies to
endotoxin, tumor necrosis factor, interleukin-1,
interleukin-6, and interferon-gamma). Anecdotal reports
show removal of inflammatory mediators by dialysis
may offer some benefit. Fibrinolytic treatment using
recombinant tissue plasminogen activator or the
administration of highly purified protein C concentrate
may prove to be helpful adjuncts to conventional therapy
to improve tissue perfusion in the presence of DIC. The
goals of therapy are to eradicate the microorganism, to
reduce morbidity, and to prevent complications.
Lyme Disease
Lyme disease is caused by the spirochete Borrelia
burgdorferi, which is transmitted by Ixodes species of tick,
mostly Ixodes scapularis (the common deer tick). The
presenting signs and symptoms depend on the stage at
which the disease is recognized, as follows:
• Early disease—Usually 7-14 days after a tick bite. Two
thirds of patients with Lyme disease present with the
typical rash, erythema migrans (EM). The rash may
be a confluent patch of erythema or may have central
clearing. The rash typically expands over days and is
not evanescent. During early disease, with or without
the rash, patients may complain of fever, chills,
myalgias, arthralgias, headache, and malaise. In the
area of the tick bite, tender adenopathy may be noted.
• Early disseminated disease—Usually develops 3-10
weeks after inoculation. Approximately 25% of
individuals infected with B. burgdorferi have signs and
symptoms of disseminated disease at presentation.
Multiple EMs are relatively small erythematous
macules (1-5 cm) and often are oval. Unlike primary
single EMs, these lesions can be evanescent and do
not show the typical expansion over days. Patients
with early disseminated disease may complain of
fever, myalgias, arthralgias, malaise, and headache.
Aseptic meningitis may develop at this stage.
Cranioneuropathies, especially peripheral seventh
nerve (Bell palsy), are common (3% of Lyme disease).
Encephalitis is rare. Carditis may present as complete
heart block.
• Late disease—Weeks to months after inoculation.
Arthritis is the hallmark of late disease. It tends to
involve large joints (knee involved in 90% of cases).
Arthritis needs to be differentiated from arthralgia,
which is common in early disease. Most patients
presenting with late disease do not have a history of
EM because the rash would have led to earlier
treatment and, therefore, prevention of late disease.
Laboratory investigations play a vital role in
diagnosis. WBC count can be normal or elevated.
Erythrocyte sedimentation rate usually is elevated.
Serum glutamic-oxaloacetic transaminase (SGOT) may
be elevated. C3 and C4 generally are normal or slightly
elevated. Antinuclear antibody (ANA) and rheumatoid
factor test results are negative. Microscopic hematuria
and mild proteinuria also have been described. Joint fluid
in patients with arthritis may have 25,000-125,000 WBCs
per mm3, often with a polymorphonuclear predomi-
nance. Cerebral spinal fluid (CSF) in patients with
meningitis has mild pleocytosis (<1000 cells per mm3)
with lymphocyte predominance. Diagnosis can be made
clinically in the early stages of disease by the presence of
EM rash. Culturing B. burgdorferi is impractical; the
organism is difficult to culture and requires an invasive
procedure, such as biopsy or lumbar puncture, to obtain
adequate samples. Serology is the standard of diagnosis
in later stages of the disease. Reported specificity of Lyme
serology is only 90-95%. Therefore, the positive predictive
value of the test is highly dependent on the prevalence

of disease. Lyme serology should not be performed in
children with nonspecific symptoms and no history of
exposure or in children in nonendemic areas. Antibodies
are known to persist for many years despite eradication
of the infection. Hence, diagnosis of repeat infection or
evidence of cure can be difficult. Treatment for all stages
of Lyme disease requires antibiotics. Facial nerve palsies
improve without treatment; however, antibiotic
(doxycycline) therapy should prevent late disease.
Similarly, arthritis improves without treatment but tends
to recur in the same joint or other new joints. Administer
antibiotic therapy to patients who develop a flulike illness
within 3 weeks postexposure to a deer tick (in an area
endemic for Lyme disease).
Kawasaki Disease
Kawasaki disease (also called mucocutaneous lymph
node syndrome) is of unknown cause, although it is
suspected to be caused by a bacteria or virus. It usually
affects children younger than 9 years. It can have serious
effects on your child’s heart if not diagnosed and treated
correctly. Patients with classic Kawasaki disease must
have 5 of the following symptoms, with fever an absolute
criterion:
• Fever, lasting more than 5 days and refractory to
appropriate antibiotic therapy
• Polymorphous erythematous rash
• Nonpurulent bilateral conjunctival injection
• Oropharyngeal changes, including diffuse
hyperemia, strawberry tongue, and lip changes (e.g.
swelling, fissuring, erythema, bleeding)
• Peripheral extremity changes, including erythema,
edema, induration, and desquamation
• Nonpurulent cervical lymphadenopathy.
Other findings may include irritability, coronary
artery aneurysms (CAA), pericardial effusion, myocar-
ditis, congestive cardiac failure, stiff neck secondary to
aseptic meningitis, facial palsy, cerebral infarction, sterile
pyuria, proteinuria, nephritis, acute renal failure,
arthralgias or arthritis, pleural effusion, diarrhea,
hepatitis, obstructive jaundice, hydrops, pancreatitis, gall
bladder distention, meatitis, vulvitis, urethritis,
conjunctivitis, and uveitis. Dermatological manifesta-
tions include peripheral extremity gangrene, pustules,
erythema multiforme-like lesions, perianal desquama-
tion, macules, papules, measles like rash, scarlet fever-
like erythema, and induration at the site of Bacille
Calmette-Guérin (BCG) inoculation (commonly observed
Immunization and Infectious Diseases 311
in Japan). Up to 10-45% of published cases have
incomplete or atypical clinical presentations. The 2 most
commonly missing findings are cervical lymphadeno-
pathy and polymorphous rash. Mucous membrane
changes, on the other hand, are the most common
manifestations of Kawasaki disease, occurring in more
than 90% of patients with either typical or atypical forms
of the disease. No specific laboratory test exists; however,
certain abnormalities coincide with various stages. Mild-
to-moderate normochromic anemia is observed in the
acute stage along with a moderate-to-high WBC count
with a left shift, which is a predominant sign of immature
and mature granulocytes. Many of the acute phase
reactant markers, such as the erythrocyte sedimentation
rate (ESR), C-reactive protein, and serum α-1-antitrypsin
are elevated. Culture results are all negative. Antineutro-
phil cytoplasmic antibodies, antiendothelial cell
antibodies, antinuclear antibody, and rheumatoid factors:
These are within the reference range. Thrombocytosis
typically develops during the second or third week of
illness, with an average of 700,000 per microliter.
Thrombocytopenia is associated with severe coronary
artery disease and MI. Chest radiography should be
performed to assess baseline findings and to confirm
clinical suspicion of CHF. Echocardiography is the study
of choice to evaluate for CAAs. Ultrasonography: Gall
bladder ultrasonography may be necessary if any
suggestion of liver or gall bladder dysfunction is present.
Obtain a scrotal ultrasound in males to evaluate for
epididymitis. Although epididymitis is generally an
inflammatory process that affects boys aged 9-14 years,
it can be observed in younger males with Henoch-
Schönlein purpura and Kawasaki disease.
The main goal of treatment is to prevent coronary
artery disease and relieve symptoms. Full doses of
salicylates (aspirin) and intravenous gammaglobulin are
the mainstays of treatment. All patients are hospitalized
for intravenous gammaglobulin and observation until
fever is controlled. Patients with small aneurysms must
take aspirin. Dipyridamole is indicated in patients with
larger aneurysms. Patients taking long-term aspirin
therapy should receive an influenza vaccination to
protect against Reye syndrome.
The pathophysiology in Kawasaki disease involves
inflammation. The patient’s own immune system
probably causes the vasculitis that leads to morbidity and
mortality in Kawasaki disease. Early and aggressive
intervention improves outcome. Standard treatment
312 IAP Textbook of Pediatrics
includes aspirin and intravenous immunoglobulin to
treat inflammation and prevent consequences of
coronary artery disease. Other anticoagulants or anti-
platelet agents (e.g. warfarin, dipyridamole) are
occasionally used.
Vascular Reactions and Drug Reactions
Toxic Epidermal Necrolysis
Toxic epidermal necrolysis (TEN) is a severe mucocuta-
neous exfoliative disease with an uncertain pathogenesis
and a high mortality rate. It can usually be distinguished
from the morphologically similar, but more benign,
staphylococcal scalded skin syndrome (SSSS) according
to historical and epidemiological factors. While
controversy exists regarding the classification of TEN as
a separate entity or a severe form of erythema multiforme
(e.g., Stevens-Johnson syndrome), the clinical distinction
is of little significance in an emergency clinical setting,
because the etiology and immediate treatment of these
potentially life-threatening diseases are similar. The
primary manifestation of TEN is the appearance of an
erythematous confluent morbilliform eruption that
rapidly evolves into exfoliation of the skin at the dermal-
epidermal junction, resulting in large sheets of necrotic
epidermis and the underlying shiny, denuded dermal
surface. This process seems to be immune-complex
mediated. Although the exact pathogenesis of TEN is not
understood, most experts agree that it represents an
idiosyncratic reaction to a drug or chemical agent. Graft-
versus-host reaction, viral infections, measles immuni-
zation, lymphoma, leukemia, radiotherapy, and contact
with toxic fumigant have been associated with TEN.
Idiopathic causes, as in erythema multiforme, account
for a significant percentage of TEN. Drugs related to TEN
may include the following:
• Sulfonamides and sulfones
• Pyrazolone derivatives (e.g. phenylbutazone,
oxyphenbutazone, phenazone)
• Antibiotics (e.g. aminopenicillins, trimethoprim,
cephalosporins, ciprofloxacin, doxycycline, erythro-
mycin, tetracycline)
• Anticonvulsants (e.g. phenytoin, phenobarbital, and
carbamazepine)
• Nonsteroidal anti-inflammatory drugs
• Allopurinol
• Antituberculosis drugs (e.g. thiacetazone, isoniazid)
TEN is estimated to occur in 0.22-1.23 cases per
100,000 population. Septicemia, GI hemorrhage,
leukopenia, pneumonia, fluid and/or electrolyte
imbalance, and renal insufficiency are the major
complications that contribute to a mortality rate of
approximately 15-40%. Old age, extensive skin lesions,
neutropenia, and impaired renal function are poor
prognostic factors. The recovery period usually is
prolonged. While SSSS occurs predominantly in children,
TEN affects more adults more than children. The
prognosis in geriatric patients is unfavorable. In addition
to characterizing the physical, constitutional, and
mucocutaneous symptoms, a detailed history should
focus on known etiologies of TEN, such as medication
or chemical agent use, maternal-fetal transfusion, blood
product administration, recent infections, measles
immunization, or recent radiotherapy. Prodromal
symptoms may precede skin lesions by 1-2 weeks. Fever
is the most common symptom. Upper respiratory
infection-like symptoms, such as malaise, anorexia,
headache, sore throat, cough, nausea, vomiting, and
diarrhea, are present. The skin is diffuse, erythematous,
and painful, and tender skin lesions are present. The scalp
usually is spared. Mucous membranes have painful
inflammation and blisters on the mucosal surfaces,
especially the oropharynx. These symptoms may limit
oral intake. Pain and photophobia are common ocular
findings and result from purulent conjunctivitis. These
usually begin 1-2 days prior to the onset of the rash.
Physical examination may show the following:
• Pyrexia may be present.
• Skin lesions may begin as hot, tender, erythematous
morbilliform or discrete macules that rapidly coalesce
and become patches of loose skin. These patches may
wrinkle, slide laterally, and separate with slight
pressure (Nikolsky sign).
• The oral mucosa especially is susceptible to inflam-
mation, blistering, and erosion. The vaginal tract
epithelium also may be involved.
• Eye involvement may result in bilateral purulent
conjunctivitis, which manifests as edema, crusting,
and ulceration with pain and photophobia.
• Pulmonary involvement leads to bronchopneumonia
in approximately 30% of all cases. Many patients
require ventilatory support because of respiratory
failure.
Differential diagnosis should include Stevens-
Johnson syndrome and staphylococcal scalded skin
syndrome. No definitive or specific emergent laboratory

tests are indicated. Basic laboratory tests may be helpful
in planning symptomatic or supportive therapy. The CBC
may reveal leukopenia of uncertain cause. Significant
fluid loss may occur. Fluid and electrolyte status must
be monitored. Regarding BUN and creatinine levels,
elevated serum creatinine levels occur in a significant
portion of patients, because of dehydration. Urinalysis
may reveal hematuria and proteinuria, which indicate
renal involvement. Positive culture findings for
Staphylococcus aureus from the conjunctiva, nose, throat,
perineum, and skin suggest an infectious cause. In the
correct clinical setting, this finding may be used to
differentiate SSSS from TEN. Chest radiography may be
performed to detect possible pneumonia, as clinically
indicated. While excisional or punch biopsy can be
performed to determine the level of dermal and/or
epidermal separation to differentiate SSSS from TEN, this
may not be a procedure to be undertaken in most
emergency situations. It is, however, the diagnostic
procedure of choice to be performed as soon as feasible.
Prehospital care is similar to that of burns. In severe TEN
in which the barrier function of the skin is compromised,
contamination and evaporation must be minimized. The
patient should be treated as one with extensive burns is
treated, that is, with the application of dry, sterile
coverings. Fluid and pulmonary status must be carefully
monitored. No specific definitive therapies for TEN exist;
therefore, intensive care is supportive. Care is given to
minimize fluid and electrolyte loss and prevent
secondary infection. Volume and electrolyte replacement,
along with respiratory stabilization, are the primary
concerns. Adequate analgesia should be provided. Silver
sulfadiazine should be avoided because it may preci-
pitate TEN. Antibiotics are of no proven benefit if biopsy
findings prove the presence of TEN and not SSSS. Use of
systemic steroids is controversial; most experts do not
recommend their use. Silver nitrate 0.5% wet dressing
may be used. Discontinuation of the offending agent (if
identified) should be immediate. Internal medicine or
critical care specialists should be consulted, depending
on severity of disease. Ophthalmologists may manage
ocular manifestations and help prevent sequelae.
Further inpatient care includes continuance of supportive
care and meticulous wound care to prevent secondary
infection. Transfer to intensive care unit or burn unit may
be necessary for those patients with involvement of a
large body surface area or with hemodynamic instability.
Immunization and Infectious Diseases 313
Numerous complications appear to be unfavorable
prognostic signs. These include the following:
• Neutropenia
• Renal insufficiency
• Septicemia (Pseudomonas aeruginosa, S aureus, gram-
negative species, and Candida albicans)
• GI hemorrhage
• Pneumonia
The overall prognosis of TEN is poor, with a mortality
rate as high as 40%. Major sequelae include Sjögrenlike
syndrome, symblepharon (adhesion between the
palpebral and conjunctiva), entropion (inward curling
of eyelid), ectropion, trichiasis (inversion of the
eyelashes), corneal opacity, blindness, esophageal and
vaginal stenosis, anonychia (loss of the nails), and
hypopigmentation or hyperpigmentation. Patient
education is directed to emphasize avoidance of any
identified causative factors
Erythema Multiforme
It is a reaction of the skin to different causes as viral
infections (commonly herpes simplex), bacterial, mycotic
or parasitic infections, drugs, or systemic diseases
(rheumatic fever, systemic lupus erythematosus, etc.).
This reaction pattern of blood vessels in the dermis with
secondary epidermal changes is exhibited clinically as
characteristic erythematous iris-shaped papules and
vesicobullous lesions typically involving the extremities
(especially the palms and soles) and the mucous
membranes. The characteristic lesions are also known
as target lesions. The eruption begins rapidly with
varying degrees of constitutional symptoms. It is
distributed bilaterally and symmetrically in a centrifugal
pattern. Stevens-Johnson syndrome is a severe bullous
form of erythema multiforme; the mucous membranes
are severely involved and there are severe general
constitutional symptoms. The duration of lesions is
several days; lesions develop over 10 days or more.
Patients may have a history of prior episode of erythema
multiforme. Skin lesions may be pruritic or painful.
Mouth lesions are painful and tender. Constitutional
symptoms may be present in the form of fever, weakness,
and malaise. Skin lesions consist of macules (48 hours)
evolving to papules, 1 to 2 cm; lesions may appear for 2
weeks. Vesicles and bullae (in the center of papule
forming the so-called iris or target lesions) are typical.
314 IAP Textbook of Pediatrics
Lesions are dull red. Iris or target lesions are typical (see
above). Lesions may be localized to the hands or
generalized. They are usually bilateral and often
symmetrical. The sites of predilection include the dorsa
of hands, palms, soles, forearms, feet, elbows and knees;
the penis (50%) and vulva may be also involved. Over
the mucous membranes, lesions may occur in the mouth
and on the lips (99%). Pulmonary manifestations may
be present; the eyes may be affected with corneal ulcers
and anterior uveitis. Histological changes are observed
in the epidermis and dermis. An inflammatory process
is seen characterized by perivascular mononuclear
infiltrate, and edema of the upper dermis; in lesions with
bulla formation, there is eosinophilic necrosis of
keratinocytes with subepidermal bulla formation. All
attempts must be made to rule out occult viral, fungal,
and bacterial infections. In severely ill patients, systemic
corticosteroids are usually given (prednisolone 50 to 80
mg daily in divided doses, quickly tapered), but their
effectiveness has not been established by controlled
studies. Control of herpes simplex using oral acyclovir
may prevent development of recurrent erythema
multiforme.
Staphylococcal Scalded Skin Syndrome
Staphylococcal scalded-skin syndrome (SSSS) is a toxin-
mediated epidermolytic disease characterized by
erythema and widespread detachment of the superficial
layers of the epidermis, resembling the effects of scalding.
It occurs mainly in newborns and infants under 2 years
of age. Severity ranges from a localized form, bullous
impetigo, to a generalized form with extensive epidermo-
lysis and desquamation. Clinical spectrum of SSSS
includes:
1. Bullous impetigo,
2. Bullous impetigo with generalization,
3. Scarlatiniform syndrome,
4. Generalized scalded-skin syndrome.
Synonyms: Pemphigus neonatorum, Ritter’s disease.
A low-grade fever may be present. The child is
irritable.
Skin findings: Bullous impetigo: Lesions are often
clustered in an intertriginous area and consist of intact
flaccid, purulent bullae. Rupture of the bullae results in
moist red and/or crusted erosive lesions.
Generalized SSSS: A very tender, ill-defined erythema
occurs initially. With epidermolysis, the epidermis
appears wrinkled. The unroofed epidermis forms
erosions with red, moist base. Initially, lesions are present
on the face (periorificially), neck, axillae, and groins,
becoming more widespread in 24 to 48 hours. The initial
erythema and later sloughing of the epidermis are most
pronounced periorificially on the face, and in the flexural
areas and pressure points: on the neck, axillae, groins,
antecubital area, and back.
Scarlatiniform syndrome: Presentation is like scarlet fever
but without pharyngitis, tonsillitis, and strawberry
tongue.
Nikolsky’s sign (gentle lateral pressure causes shearing off of
superficial epidermis): Positive.
Mucous membranes: are usually uninvolved.
Investigations include:
Grams’s stain:
Bullous impetigo: findings include pus in bullae and
clumps of gram-positive cocci within PMNL.
Generalized SSSS: Gram-positive cocci are only observed
at colonized site, not in areas of epidermolysis.
Bacterial culture:
Bullous impetigo: Staph. aureus is isolated.
Generalized SSSS: Staph. aureus is only present in colonized
site of infection, i.e. umbilical stump, conjunctiva, or
external ear canal; culture of sloughing skin or bullae
usually yields no pathogens.
For a newborn, hospitalization and treatment with
IV cloxacillin, 200 mg per kg body weight per day in
divided every 4 hours, are preferable.
Hospitalize infants with extensive sloughing of skin
or if parental compliance to treatment is questioned.
With reliable home care and mild involvement,
cloxacillin, 30 to 50 mg per kg body weight per day, can
be given orally. Topical care includes baths or compres-
ses, and mupirocin ointment, bacitracin, or silver
sulfadiazine.
The reader is reminded that the above description is
narrated only as guidelines and is advised to refer to other
standard books of dermatology for more comprehensive
information.

9.9 Tuberculosis in Children
Childhood tuberculosis is neglected in endemic areas
with resource constrainsts in high-burden countries as
in India, because the children
i. Are considered to develop mild forms of disease
ii. Mostly the lesions are sputum-negative and
contribute little in the transmission of disease.
In endemic areas, children contribute a significant
proportion of the disease-burden and suffer severe
tuberculosis related morbidity and mortality particularly
when associated with HIV infection, severe malnutrition
and are above the age of 10 years.
The common perception that children rarely develop
severe forms of tuberculosis is true in nonendemic areas
but not so in endemic areas. Because of the difficulty of
establishing an accurate diagnosis of childhood
tuberculosis, the true extent of morbidity and mortality
related to tuberculosis in endemic areas is not available.
Despite the huge burden, the access to antituberculosis
treatment in children remains poor, as tuberculosis control
program focuses predominantly on the treatment of
sputum smear-positive adults. However, now in Revised
National Tuberculosis Control Program (RNTCP) i.e.
Directly Observed Therapy Short-course (DOTS), separate
algorithms have been prepared for the diagnosis of
childhood tuberculosis. In these algorithms, besides X-ray
chest and tuberculin test, lot of emphasis has been given
to signs and some symptoms in relation to pulmonary
and extrapulmonary tuberculosis. In the latter, the
commonest is lymphadenitis followed by neuro-,
abdominal-, and skeletal tuberculosis, to name a few.
Tuberculosis (TB) is caused by Mycobacterium
tuberculosis. It mainly infects the lungs, though it can
affect other organs as well.
When a patient with sputum positive untreated TB
disease coughs or sneezes, the air is filled with droplets
containing bacteria. Inhaling these infected droplets is
the usual way a person gets TB.
Children are not considered infectious, and usually
get the infection from an infectious adult. The incubation
period varies from weeks to years, depending upon the
health status of the individual and whether the infection
is primary, progressive or reactivation TB. It is a chronic
disease that can persist for years if not treated.
Immunization and Infectious Diseases 315
Vimlesh Seth
The most common type is human type. The genus
Mycobacterium includes the species responsible for
causing tuberculosis. M.tuberculosis, M.bovis, M.african is
also called Mycobacterium tuberculosis complex.
There are several other types of mycobacteria that are
collectively called “Non-tuberculosis mycobacteria” (NTM),
and were called atypical mycobacteria in the past. They
have been increasingly recognized to cause pulmonary
and non-pulmonary infections which is partly explained
by the increase in the number of susceptible/immuno-
compromised individuals such as those suffering with
AIDS. They are also called mycobacterium other than
tubercule bacilli (MOTT).
Epidemiology
Tuberculosis has become one of India’s worst enemies.
Women and children are worst effected. Studies
conducted on the socio-economic impact of TB have
projected that over three lakh children are orphaned by
the disease every year and over a lakh women are rejected
by their families once they contract the disease, inspite
of the illness being treated free of cost from Government
funds.
Fear of becoming homeless and social isolation, leads
over 75% of women diagnosed with TB, to dismiss their
constant coughing as seasonal. Thousands of children
drop out of school, while over 20% of them take up jobs
in order to supplement income especially if the father
has TB, thereby adding already to the unwieldy problem
of child labor. Several studies conducted by Tuberculosis
Research Centre (TRC) Chennai, between 1997-2006,
confirmed that TB had tremendous impact on patient’s
households in-terms of decrease in income and affecting
therapy, health, education, nutrition particulary if the
patient was a wage earner.
As per TRC study over 35% of patients admitted were
not able to afford to buy adequate food, clothing and
books for children due to lack of income. TB’s greatest
impact is on productive adults, in the age group of 15-59
years. They are also the parents on whom the survival
and development of children depends. Thus as very
316 IAP Textbook of Pediatrics
rightly said TB has the potential to have impact on the
development of both individual and society.
It is further emphasized that TB results in more stigma
in women than in men. The man abandons his wife,
remarries. On the other had no body marries a single
girl who develops TB.
Impact of TB-killer disease in India
• India has 3.8 million TB patients at any time
• India estimates 3% of new cases of MDR
• Till date, 6.7 million patients in India have received DOTS
treatment thus averting more than 1.22 million deaths
• Over the last 10 years, 26 million patients have been placed
on effective TB treatment globally
• But the disease still kills 4,400 people every day.
The clinical profile of childhood tuberculosis in
developing countries is different in comparison to Europe
and North America or so called low-burden disease
countries. The extent of tuberculosis in children is a
reflection of Tuberculosis Control Program in a particular
area. Epidemiological data regarding the extent of
tuberculosis in children is lacking globally, India being
no exception. It is due to difficulty in diagnosis.
Udani1 has described tuberculosis in children as a
pyramid in three categories:
Group I
These patients are admitted in the hospital and constitute
6 to 10 percent of total pediatric admissions, majority of
them have serious disease like meningitis, miliary disease
or severe pulmonary involvement. They constitute the
apex of the pyramid.
Group II
Majority of patients in this group have non-specific
symptoms, some may have characteristic symptoms.
They are either undiagnosed, untreated or inadequately
treated.
Group III
This group constitutes the base of the pyramid. These
children are either asymptomatic or have nonspecific
symptoms, hence are usually undiagnosed and remain
untreated. They constitute the reservoir of primary
infection from which various post-primary complications
(group I and group II) develop. These are forerunners of
a large percentage of chronic pulmonary tuberculosis in
adults.
Children are usually infected with tuberculosis by an
adult or an older child with sputum smear-positive
pulmonary tuberculosis, often a family member. They
are less likely to be infected with a smear-negative
contact. In younger children less than two years who are
not ambulatory outside the household, the source of
infection is in the house unlike an older child whose
contact is from the community. The best way to prevent
tuberculosis in children is the proper identification and
treatment of tuberculosis in adults with sputum smear-
positive disease. The case notification in children due to
tuberculosis has been 6-20 percent of all TB cases
registered with National Tuberculosis Control Program.
In India the prevalence of primary tuberculosis infection
in children is alarming. The annual risk of TB infection
is 1.5, and 40 percent of children by 16 years acquire
infection, and nearly 10 percent infected eventually
develop disease. Five percent of these develop disease
in the 1st two years of infection. This large pool of infected
children means that TB will continue to be a major
problem in the foreseable future.
Data on all forms of TB amongst children is not
available in India. Most surveys conducted have focused
on pulmonary tuberculosis and no significant population
based studies on extrapulmonary tuberculosis are
available.
Chakraborty has summarized the incidence and
prevalence of tuberculosis in NTP data as given below:
TABLE 9.9.1: Annual incidence and prevalence of
tuberculosis infection (NTP data)
Age (Years) Incidence of infection Prevalence of
(%) infection (%)
<5 0.8 2.8
5-9 1.1 13.4
10-14 1.3 —
All ages 1.6 38.0
The risk of infection in children depends on the extent
of exposure to infectious droplet nuclei. If a mother has
sputum smear-positive pulmonary tuberculosis, her
infant is more at risk of developing the disease because
of the chance of inhalation of large number of infectious
droplets.
The majority of infected children do not develop TB
disease in childhood. The only evidence of infection may

be a positive tuberculin skin test. The likelihood of
developing disease is greatest shortly after infection. This
declines steadily with time. Infants and young children
under five are more likely to develop the disease. The
majority of children will present with symptoms within
one year of infection. For infants particularly the time-
span between infection and disease may be as little as
6-8 weeks. Various immunosuppressive illnesses
facilitate the progress of infection to disease, such as HIV-
infection, measles, whooping cough, protein energy
malnutrition.
Types of Strain
An untreatable TB strain causes alarm. A survey
conducted by WHO and the US Centre for Disease
Control (CDC, Atlanta) analysed the data from 2000-2004
and found that XDR-TB is most frequent in the countries
of former Soviet Union and Asia. A virtually untreatable
form of tuberculosis—extreme drug resistant TB (XDR-
TB) is spreading all over the world, including India,
causing nearly 100% mortality. WHO’s coordinator for
TB/HIV and drug resistance programme Paul Nunn
called it an explosive combination.
Nunn told that 52 of 53 patients with XDR-TB in South
Africa died with in 210 days between January 2005 and
March 2006. Even in US which has the best medicines
available, 33% diagnosed to be suffering from this strain
died.
At present the problem of XDR-TB in India is small
but there is severe burden of HIV patients. The
combination of two is almost lethal. He recommends
India must undertake a survey to gauge the extent of
XDR-TB particularly in Mumbai because there is very
large burden of HIV over there. Nunn has the following
other suggestions for India:
i. Increase the number of laboratories to diagnose TB
cases.
ii. Improve management of clinical cases.
iii. Strengthen basic TB care to prevent emergence of
resistance by ensuring good compliance.
iv. Increase collaboration between HIV-TB control
program to provide necessary prevention and care
of coinfected patients.
According to Health Ministry records, over 30% of
the fresh cases are suffering from XDR-TB while over
12% of old cases undergoing treatment have acquired
this strain. This new strain is not only resistant to the
Immunization and Infectious Diseases 317
two first-line drugs isoniazid and rifampicin, but also
are resistant to the six other drugs used for second-tier
in therapy. TB has become the 2nd largest killer of AIDS
patients in India. Over 60% of all AIDS patients contract
and ultimately die of TB. National AIDS Control
Organization (NACO) has now decided to scale up and
integrate the National AIDS and TB Control Programs
from 2006. Director of the TB control program (Ministry
of Health and Family Welfare) has stated that every year
1.8 million new cases of TB occur in India, of which 0.8
million are infectious. Unless these are treated properly,
each TB infectious case can infect 10 to 15 persons a year.
Not properly treated TB patients can become incurable.
Since no new drug has been discovered since 1968, the
germs have started developing drug resistance.
As per data available nearly 40 million children are
likely to be exposed to the risk and nearly 3-4 million
under five years are estimated to be infected and may
progress to disease. In a study conducted in Chengalput
in South India, it was found that prevalence rate was
very high. There were 420 active cases of tuberculosis
per 1,00,000 population. This survey did not include
children under five years. In India the annual rate of
infection is 20 to 25 times higher than in developed
countries.
Trends in Tubercular Disease
At a referral hospital in India, an increase in the
proportion of cases of extrapulmonary tuberculosis has
been observed over the last three years. The increase was
reported to be due to increase in tubercular lymph-
adenitis. The severe form of tubercular disease such as
meningoencephalitis has shown a decline. However, the
kind of picture is not so in other medical schools where
still a significant proportion of indoor admissions due to
tuberculosis is because of meningooencephalitis. A point
which needs to be emphasized is that when suspected
tuberculosis does not respond to the usual drugs,
infection with a resistant strain has to be kept in mind
and investigated from the very beginning. However, it
is a difficult situation because tuberculosis in children
still is paucibacillary. Here lies the importance of
screening the children of a sputum smear-positive adult.
Family survey of an index case in a given child gives,
only 20-30% contact positivity available in the best hands.
318 IAP Textbook of Pediatrics
Pathogenesis
Ghon’s lesion results at the site of initial organisms
depositon. Initially (for the first 4-6 weeks) unrestrained
multiplication occurs with in the Ghon-focus and bacilli
drain via local lymphatics to the regional lymph nodes
and beyond. The upper lobe lymph nodes drain to
ipsilateral-paratracheal nodes, whereas the rest of the
lung drains to perihilar and subcarinal nodes with
dominant lymph flow from left to right. The Ghon
complex is represented by both the Ghon focus, with or
without some pleural reaction and the affected regional
lymph nodes.
Occult dissemination frequently occurs during this
early proliferative phase before cell-mediated immunity
is fully activated. Therefore, with active contact tracing
and aggressive screening (collection of specimens in
asymptomatic patients) is expected to find some positive
cultures before the onset of the disease.
Uncomplicated hilar adenopathy remains the most
common disease manifestation in children and is
considered the hallmark of primary tuberculosis. The
progression to disease is indicated by the onset of
persistent, nonremitting symptoms.
In terms of pathophysiology, microbiology and
natural history, asymptomatic hilar adenopathy is more
indicative of recent primary infection than active disease
(Figs 9.9.1 to 9.9.4).
Within the Ghon’s focus, containment is usually
successful. Poor containment and unrestrained organism
Figure 9.9.1: Types of pulmonary tuberculosis
proliferation may cause progressive parenchymal
damage with ultimate breakdown of Ghon’s focus.
Infants and HIV-positive children who have poor cell-
mediated immune response are most vulnerable to this
type of cavitation. In contrast immune-competent
adolescents seem to mount an “excessive” (damaging)
immune response in an attempt to contain the organism.
Children with adult-type of disease are frequently
sputum smear-positive and they contribute to disease
transmission particularly in congregate settings such as
schools.
Exuberant lymph node enlargement, associated with
edema and small airway size in children less than 5 years
cause most of the complications of extraluminal
compression.
Polyps or granulomatous tissues secondary to
inflammatory changes in the bronchial wall cause
intraluminal obstruction. This type of obstruction can
also result when caseous material is deposited into an
airway after lymph node eruption. Hence, radiological
signs should be interpreted with caution in the absence
of clinical data. Hilar adenopathy can be very sensitively
deducted by high resolution computerized tomography
(CT). It is important to point out that CT has got no role
in the evaluation of asymptomatic, immune competent
children exposed to tuberculosis.
In everyday practice, distinguishing between the
signs and symptoms of recent primary infection and
active disease is less relevant in high-risk children (less
 Immunization and Infectious Diseases 319

Figure 9.9.2: Progression (local) in lymphatic nodes (complicated lymph node TB)

Figure 9.9.3: Hematogenous spread

320 IAP Textbook of Pediatrics
Figure 9.9.4: Chronic pulmonary tuberculosis (CPT) (CPT seen mainly in adolescents and adults)
than 3 years of age and or immune compromised). In
this group infection frequently progresses to disease,
sometimes with rapid progression.
Radiological signs vary from segmental to lobar
hyperinflation, with partial obstruction and segmental
to lobar collapse can result due to total obstruction and
resorption of distal airway. Dose and virulance of the
bacilli determine the extent of pathology due to aspiration
of caseous material. Pure hypersensitivity response to
dead bacilli and or toxic products can result in transient
parenchmal consolidation. Continued pneuomonic
process can result in progressive caseating pneumonia.
This type of caseating pneumonia frequently results in
parenchymal destruction and cavity formation.
The following factors are responsible for cavitary
disease in children:
1. Poor containment at the site of organism deposition
(very young and or immune—compromised children).
2. Aspiration of live bacilli when a diseased lymph node
ruptures into an airway with destructive caseating
pneumonia in the distal segment or lobe. (Children
less than 5 years of age).
3. Mainly children older than 10 years of age, develop
adult-type disease.
Children between 5 and 10 years of age are
immune competent and at lowest risk to progression
of disease.
4. Disseminated miliary disease occurs predominantly
in very young (immune-immature) and immune-
compromised such as HIV-infected or severely
malnourished. These children have poor containment
of organisms both with in the regional lymph nodes
or at multiple sites of occult dissemination. 20 to 30%
of cases develop tuberculous meningitis (TBM) which
is the most dangerous complication of disseminated
disease (it is usually meningoencephalitis, which
affects the mental development of child).
Natural History of Disease
The prechemotherapy literature is not so well documen-
ted hence the natural history of tuberculosis in children
is also not known. Clinician and researchers have limited
access to the important studies which were conducted
before 1950 and not available in the electronic database.
After the availability of safe and effective antituberculosis
agents, the studies on the natural course of disease could
not be conducted.
Case Definition
The most important variable that determines the risk to
progress to disease after M.tuberculosis infection in
immune competent children is the age. The infants are
at the highest risk. The risk drops but remains signifi-
cantly high in the second year. It reaches its lowest level
in children infected between 5 and 10 years of age. The
other factors which determines the progression is HIV
infection and degree of malnutrition. 95% of children
who progress from infection to disease do so with in 12
months. Hence, it is prudent to categorise children less
than 3 years as high risk category. Active disease is
accompanied by persistent, non-remitting symptoms and
disease progression is slow which provides opportunity
for symptoms based diagnosis.

DISEASE DIVERSITY
Profile of Tuberculosis in Children
Based on clinicoimmunological study by Seth, the
following profile of tuberculosis in children has emerged:
i. Tuberculin positive, asymptomatic with no manifest
radiological tuberculous lesion. The asymptomatic,
Mantoux positive (ASMP) group.
ii. Tuberculin positive, with symptoms of tuberculosis
but without any manifest tuberculosis lesion. The
symptomatic positive (SMP) group.
iii. Pulmonary primary complex (PPC) which is of three
types (a) nodal, (b) parenchymal) and (c) parenchy-
mal plus nodal.
iv. Tuberculous lymphadenitis (TBL) with or without
pulmonary lesion (nodal, parenchymal or nodal
plus parenchymal).
v. Progressive primary disease (PPD)
vi. Miliary tuberculosis (MTB)
vii. Meningeal tuberculosis (TBM) more precisely
meningo-encephalitic type tuberculosis.
viii. Tuberculosis of other organs (abdominal, bones and
joints). Accurate disease classification is important
because of its prognostic significance and decision
to be taken about the regimen whether RNTCP,
intermittent or continuous.
In tuberculosis in children, it is always not possible
to put every child on RNTCP recommended regimens
due to logistics difficulties. At times parents can afford
the therapy with the help of some NGO’s and it is more
cost effective and practical to use continuous therapy.
Immunology of Tuberculosis
It is well-known that outcome of infection with
Mycobacterium tuberculosis in man varies enormously
from person to person. In one group of subjects, it evokes
no response at all. The infection is contained and there is
no disease but the subject may have a positive tuberculin
test. In an another group, the infection produces slow
development of host response with development of
primary complex, tuberculin positivity, cell-mediated
immunity and containment of infection but no progres-
sion. However, with lowering of immunity there may
be progressive disease from primary comlex. In other
group of subjects, there is aggressive response against
the bacilli and there is no containment or control of the
first infection which results in progressive disease,
Immunization and Infectious Diseases 321
whether in the lungs, mediastinal lymph nodes, their
local complications or hematogenous spread and
involvement of various organs. Another group of
patients, who had primary infection usually in childhood
may develop granulomatous but necrotizing or destruc-
tive cavitary form of tuberculosis at a later date as
happens in adolescents, adults and in old age. There is a
fourth type of subjects in which there is no cavity but
rapidly progressing pneumonic form with widespread
dissemination as seen in malnourished children or HIV
infection in whom immunity is compromised. It may be
noted that bacilli do not produce endo- or exotoxins. The
result depends upon their ability to withstand and
survive the onslaught by the host defence mechanisms.
It is important to understand the fact that various clinical
and pathological manifestations of tuberculosis are
directly due to tissue damaging host responses.
This host response leads to infection in two directions,
one cell-mediated protective response leading to
immunity and other causing inflammatory illness and
tissue destruction mediated by products elaborated by
host cells while trying to contain the bacilli. Though these
responses are mainly dependent on genetic makeup, with
severe infection and with large number of bacilli, the
child is likely to get progressive disease.
Mechanism of Lysis of Mycobacteria by
CD4 T-cells, Lymphokine-activated (LAK)
Cells and TNF Alpha
T-cells and natural killer (NK) cells: NK-cells are stimulated
by cytokine, interleukin 2 (IL-2). Moreover, sensitized
mycobacteria show increased susceptibility to lysis by
TNF alpha. These cells control the infection by releasing
various enzymes in the host tissues like proteinases,
nucleases and lipases. These enzymes produce local
inflammation which reduces the caseation or cavitation.
As mentioned earlier CD4 + T-cell functions are depen-
dent on replication to secretion of cytokine interleukin 2.
When there is dysfunction of the CD4 + T-cells as happens
in severe malnutrition in children and progressive HIV
disease, tuberculous disease progresses further with
further depletion of CD4 + T-cells. There is reduced
cytotoxic function, decreased IL-2 production which leads
to reduced LAK cells and as well as TNF alpha function.
Thus, in malnourished children there is adverse effect on
CMI and DTH. There are various probable practical
implications in immune deficient children and in these
322 IAP Textbook of Pediatrics
infants and young children with severe PEM because of
poor CD4 + T-cell function the infection is progressive.
There is high incidence of life-threatening disease like
miliary tuberculosis, hematogenous tuberculosis and its
various local complications, more often tuberculosis
meningoencephalitis, tuberculous meningitis, etc. The
delayed hypersensitivity in the skin is impaired and leads
to negative tuberculin test. The other implication of
immune deficiency in malnourished children is in liver
histology, with the presence of few tubercles and many
histiocytic nodules. Moreover, the incidence of hepatic
tuberculosis is high in malnourished adults at autopsy.
Diagnosis
A high degree of suspicion is essential because of high
prevalence of tuberculous infection and disease in
children in India. The prechemotherapy literature that
describes the natural history of disease in children
identifies three factors:
• The need for accurate case definition.
• The importance of risk stratification
• The diverse spectrum of disease pathology.
Due to the absence of a gold standard, the diagnosis
of childhood tuberculosis presents a major challenge.
1. Bacteriological Confirmation
The accepted gold standard is of limited use in children
because of the paucibacillary nature of the disease and
poor yield of bacteria.
Sputum-smear microscopy: Often it is the only diagnostic
test available in endemic area, positive in less than
10-15% of children with probable tuberculosis. In adult-
type of disease the yield is high and sputum – smear
microscopy has definite value in older children (>10
years).
Poor bacteriological yields are also due to the problem
of collection of bacteriologic specimens. Two or three
fasting gastric aspirates collected on consecutive days
(usually requiring hospital admission) are routinely
performed in young children who cannot cough up
sputum. The gastric aspirate can be collected early
morning on out patients basis after over night fast.
2. Culture Yields
Culture yields are also low (<30 to 40%) in probable
tuberculosis. Culture positivity depends on the specific
intrathoracic manifestations. Hence, sensitive bacterio-
logical – based diagnostic approaches are particularly of
use only in endemic areas where children frequently
present with advanced disease.
Bronchoalveolar lavage It requires the use of a flexible fiber-
optic bronchoscopy and has additive value when used
in combination with gastric lavage. However, this
technique is highly specialized and is not easily available
in most of the endemic areas.
Gastric aspirate provides a slightly better yeild than
nasopharyngeal aspiration. The latter does not require
hospitalization and fasting and is minimally invasive.
Induced-sputum collection By using hypertonic saline the
yield of bacilli is similar to three gastric aspirates.
There is difficulty in achieving bacteriological
confirmation of the diagnosis of childhood tuberculosis
in non-endemic areas and younger age group in endemic
area where the disease is paucibacillary. Presentation is
due to dissemination of disease and location of primary
lesion is difficult. The following criteria are used:
• Known contact with an adult index case frequently
with in the household
• A positive tuberculin skin test (TST)
• Suggestive signs on the chest radiograph
This triad provides a fairly accurate diagnosis in
settings where exposure to M.tuberculosis is rare and often
documented. However, its accuracy is reduced in
endemic areas where exposure to M.tuberculosis is
common and often undocumented as the exposure is
mostly outside the household except in children less than
two years. A positive TST reaction remains a fairly
accurate measure of infection with M.tuberculosis inspite
of National Program of BCG vaccination and exposure
to mycobacteria other than tuberculosis (MOTT).
In endemic areas a positive TST is induration > 10
mm. Clinical features and the chest radiography are
given due importance in diagnosis. Even the latter is not
easily available in endemic areas like India, particularly
in remote or not so remote areas (urban health clinics).
Despite this limitation, chest radiogram in symptomatic
children is the most widely used diagnostic criterion in
clinical practice.
Scoring System
Various scoring systems have been developed as a
scapegoat for suggested diagnosis in endemic areas. A

critical review of these indicates that they are of limited
value and lack standard symptom definitions and
adequate validation. Developing standard symptom
definitions through consensus of expert opinions are
difficult. Better guidance can be achieved by objective
measurement of the potential diagnostic value of
different value of these fairly-defined symptoms. This
requires validation in prospective, community based
studies that include children from all relevant risk
groups. Children showing neurological symptoms like
irritability, refusal to feed, headache, vomiting or altered
sensorium can be highly suspected to have TBM.
These symptoms based diagnostic approaches have
less value in high-risk children (less than 3-yr of age and
or immune compromised). In the latter, there is a definite
role of early diagnosis, and preventive therapy and even
treatment of latent tuberculosis.
Clinical Features
Clinical features are variable depending upon the age of
the child, immune competence, dose of infection,
nutrition of the child and genetic factors. However, the
child may develop progressive primary disease usually
in the lungs and lymph nodes and may develop
extrathoracic complications with mild, moderate or
serious clinical manifestations. Following are some of the
presenting clinical features:
• Typhoid like fever in infancy and early childhood,
which may often be missed as pyrexia of unknown
origin.
• Pneumonia which fails to resolve, even though the
symptoms may be controlled with or without even
non-tuberculosis drugs.
• A prolonged pyrexia not due to other detectable
causes like typhoid or urinary tract infection, or heat
pyrexia in summer.
• Persistent cough particularly pertussoid type or
stridulous cough with whistling sound, indicating
endobronchial tuberculosis and bronchial obs-
truction.
• Persistent wheezing in the chest more commonly due
to allergic bronchitis is also seen with endobronchial
or endotracheal disease. Recent studies have revealed
that the hyperreactivity of a bronchial mucosa can be
caused by tuberculoprotein, from pulmonary or
mediastinal nodes, and the symptoms of persistent
or recurrent bronchitis, pertussoid cough and/or
Immunization and Infectious Diseases 323
asthma, which do not respond well or recurs in spite
of conventional treatment. Studies have proved the
relation between pulmonary TB and asthma.
Precipitation of asthma with provocative dose of PPD,
given by insufflation will not only produce an attack
of asthma, but also raise the basal specific serum lgE
value to significant high lgE levels after PPD
provocative dose.
• Pain in the chest in an older child with pleurisy.
• General symptoms like weakness, fatigue, poor
appetitie and/or unexplained loss of weight.
• Fever of vague illnesses following measles, or
whooping cough.
• Respiratory distress of different severity with minimal
or no signs in the lungs, can be caused be enlarged
subcarinal nodes due to compression of the carina
(tracheal bifurcation), while chronic cough can be
caused by various mediastinal nodes, hilar, more so
by paratracheals and subcarinal nodes (SCLN), which
are in contact with or which indent the trachea. The
lymph node enlargement is much more common in
BCG vaccinated children than nonvaccinated and
would be the main diagnostic problem in infants
covered by BCG vaccination.
• Child with abdominal pain, distention of abdomen,
steatorrhea, chronic diarrhea, malabsorption and
doughy abdomen with hepatosplenomegaly with or
without abdominal mass due to mesenteric adentitis,
matted intestine or rolled up omentum. At times they
present with subacute intestinal obstruction (see in
Chapter 9.10 on Abdominal Tuberculosis).
• Tuberculosis of the nervous system is the most
important cause of death in a tuberculous child. The
presenting features in early stages are persistent fever,
headache, vomiting, anorexia, constipation and
apathy alternating with irritability (see Chapter 9.11
on Neurotuberculosis).
Immunology (Diagnostic Evaluation)
Serological Tests
These are currently unable to diagnose childhood
tuberculosis with accuracy. Sputum-based polymerase
chain reaction (PCR) tests have shown variable results
and hence are of limited utility. Heminested PCR
technique using uninfected children as control group
limits its utility for the diagnosis of latent infection from
the active disease.
324 IAP Textbook of Pediatrics
Immunological Tests
Novel T-cell based assays (T-SPOT-TB Oxford Immuno-
tec Antigen UK) and Quanti FERON – TB Gold (Cellestis,
velencia, CA) may improve the ability to diagnose
M.tuberculosis infection. This has particular relevance in
immune compromised malnourished children (parti-
cularly less than 3 years) in whom TST programs poorly.
T-SPOT-TB assay is more sensitive than traditional TST,
has better performance in associated HIV-infection which
has to be treated for probable tuberculosis. It is
independent of CD4 + T-cell count. The use of M.
tuberulosis specific antigents such as ESAT-6 and CFP-10
provides superior specificity as these tests are not
influenced by BCG vaccination and rarely by environ-
mental mycobacteria. It is important to emphasize that in
the absence of symptoms, or radiological signs indicative
of disease, qualitative T-cell assays like TST fail to make
the distinction between infection and disease.
Problem of Associated HIV in Diagnosis
The specificity of symptoms based diagnostic approaches
is reduced by the presence of chronic HIV-related
symptoms and is further limited due to rapid progression
of the disease.
Chest radiography interpretation is complicated by
HIV-related morbidity and atypical presentation. Hence,
in this group there is more value of microbiological
diagnosis. HIV will not only lead to rapid progression of
disease but may precipitate i.e. reactivate the latent
infection. The traditional TST has poor diagnostic ability,
as only 50% or less children with HIV infection and
bacteriological confirmed tuberculosis have TST positive
despite using an induration of 5 mm as only a cut off
point for positivity. This is a major limitation and a more
reliable measure of infection will be to identify children
with infection who will benefit from preventive
chemotherapy.
These new diagnostic tools are of value in non-
endemic areas for contact and immigrant screening and
in endemic areas with limited resources to assess their
ability to detect M.tuberculosis infection in HIV-infected
individuals.
Pattern of Disease in BCG Vaccinated Children as
Compared to the Nonvaccinated Children
The type of tuberculosis seen in BCG vaccinated children
is commonly intrathoracic tuberculosis, particularly
mediastinal lymph node tuberculosis and its local
complications. The higher incidence of intrathoracic
disease in vaccinated children is because intradermal
BCG vaccination cannot prevent lodgment of natural
virulent tubercule bacilli in the lungs and development
of primary infection and its progressive local compl-
ications. However, BCG vaccination reduces the
hematogenous dissemination of infection in vaccinated
children. In nonvaccinated children, relative incidence
of intrathoracic lesion is less compared to vaccinated
because there is hematogenous spread of the bacilli to
various organs and systems with development of
metastatic foci. Hence, miliary tuberculosis, tuberculous
meningitis and hematogenous TB are much more
common in nonvaccinated than in vaccinated children.
Mediastinal lymph node tuberculosis is one of the
important manifestations in BCG vaccinated children.
The enlarged nodes may be missed on X-ray film of chest
but can be identified by newer imaging techniques such
as CT and MRI scans.
Changing Clinical Presentation of Neurotuberculosis
(Refer to Chapter 9.11 on Neurotuberculosis)
The incidence of clinical manifestations of various types
of neurotuberculosis are different in vaccinated than in
nonvaccinated children. For example, serous tuberculous
meningitis is two to three times more common in
vaccinated children than in nonvaccinated children.
Because of better T-cell function in vaccinated children,
generalized or characteristic tuberculous meningoence-
phalitis is less common in these children unless they are
severely malnourished. Localized tuberculous disease of
the brain or meninges is more common in vaccinated
children. In children with serous tuberculous meningitis
there is no diffuse brain involvement and hence child
may present with fever, headache, vomiting and
meningeal signs and he is usually conscious and alert.
He may have evidence of raised ICT demonstration by
Macewen’s sign being positive and papilledema. He may
develop neurological deficit by involvement of blood
vessels and nerves and/or develop hydrocephalus by
exudate at the base of the brain blocking the basal
cisterns. Hence, there is never clinical picture of serious
tuberculous meningitis but there is higher incidence of
tuberculoma in vaccinated children. These diagnostic
possibilities should be kept in mind as this is going to be
a common presentation.

Treatment
Basic Principles
Antituberculosis treatment aims to cure the individual
patient and to prevent the emergence of drug-resistant
strain with in the community by following principles:
• Rapid reduction of organism load
• Effective eradication of dormant and intermittently
metabolizing (persistent) bacilli.
• Achieving this with minimal side effects in the child.
Bactericidal Drugs
Ensure rapid reduction of the organism load which
(i) improves clinical symptoms, (ii) limits disease prog-
ression, (iii) terminates transmission and (iv) prevents
the emergence of drug resistance.
Sterilizing Drugs
Ensure the effective eradication of dormant and
intermittently metabolizing (persisters) bacilli, thus
preventing disease relapse. These principles provide the
rationale behind the intensive and continuation phases
of current antituberculosis treatment regimens.
Assuming that there is complete drug susceptibility
and there is no immune compromised state, each of the
first-line drugs makes a specific contribution during
different periods of drug action.
Period 1
Lasts 2 to 3 days during which time fast growing
extracellular bacilli which comprise the vast majority of
the organisms load are killed. This is achieved mainly
by the excellent bactericidal activity of isoniazid.
Period 2
It lasts 4 to 8 weeks. Slower growing extracellular bacilli
are killed. The rate of killing is determined more by the
physiological state of the bacilli and less by the
bactericidal activity of the drug. During this period
bactericidal activity of rifampin (RMP) is important and
pyrazinamide (PZA) contributes by killing extracellular
bacilli that persist in acidic areas of inflammation.
Period 3
It lasts 4 to 6 months. Persistant intracellular bacilli are
eradicated mainly by RMP, although INH continues to
Immunization and Infectious Diseases 325
offer protection against the development of resistance.
It may also assist in the eradication of organisms
especially in fibrocaseous tissues with poor drug
penetration. Host immunity plays an important role
throughout. It is of particular importance in (i) eradi-
cation of organism and thus (ii) preventing relapse. Due
to poor host immunity relapse rates are very high in
children with associated HIV-infection.
When the mycobacterial load is very high, any
antituberculosis drug used in isolation is vulnerable to
resistance from naturally occurring mutants. Random
resistance is extremely rare to multiple drugs. Therefore,
is recommendation of the use of multiple drugs in
combination, during the intensive phase of treatment. It
drastically reduces the risk of treatment failure inspite
of heavy bacillary load.
Intensive Phase
Bulk of the organism load is eliminated with the virtual
elimination of risk of drug resistance. To prevent the
emergence of drug resistance, good adherence is very
necessary as several cycles of mycobacterial killing (when
drugs are taken) and regrowth (when drugs are not
taken) favors selection of drugs-resistant mutants. These
mutants may accumultate additional random mutations
resulting in the emergence of multiple drug resistance.
Operational issues in treatment include:
• Access to early and accurate diagnosis.
• Uninterrupted provision of quality-assured drugs
and appropriate regimen.
• System to ensure good treatment adherence.
• Fixed-dose combination should be used whenever
possible to reduce the risk of drug resistance.
• Adherence must be ensured.
• Quality assurance is essential to ensure optimum
bioavailability of all constituent drugs.
With proper implementation of the World Health
Organisation’s directly observed therapy, short-course
(DOTS) strategy, all the above mentioned operational
issues are addressed. However, the main emphasis on
sputum smear-positive disease excludes the vast majority
of children. There is desperate need to improve service
delivery to children with tuberculosis, particularly in
endemic areas with limited resources.
Use of BCG for Prevention Strategy
Variable results are obtained for the efficacy of BCG
vaccination due to variation in strain-specific immuno-
326 IAP Textbook of Pediatrics
genicity, timing and technique presence or absence of
environmental mycobacteria (MOTT) and the effect of
multiple reinfection events as occurs in endemic areas.
BCG vaccination offers little or no protection against
adult-type of disease but helps in the protection against
disseminated (miliary) disease in young infants less than
two years. However, when the environmental mycobac-
terial exposure is low and the adolescent is TST -ve, BCG,
is protective.
BCG is contraindicated in HIV-infected children.
However, in asymptomatic HIV exposed infants, WHO
recommends the use of BCG vaccination.
The treatment in children needs description as
follows:
1. Preventive therapy
2. Treatment of latent tuberculosis
3. Curative treatment.
1. Preventive Therapy
As recommended by Indian Academy of Pediatrics the
following groups of children are considered for
preventive therapy.
• Asymptomatic Mantoux positive < 3 years
• Asymptomatic Mantoux positive < 5 years with grade
IIII or IV malnutrition
• Mantoux positive – recent converter/no signs
Healed lesion – normal chest X-ray or calcification/
fibrosis
• Children < 3 years with history of sputum smear
positive contact with in the household
• Children < 5 years – grades III or IV malnutrition
with sputum smear positive contact with in the
family
The recommended regimen is 6HR.
2. Treatment of Latent Tuberculosis
Young children with tuberculosis infection are more
likely than adults to develop serious forms of disease.
Exposure at any early age to infectious tuberculosis is
common in less developing countries like India. There
are many children with subclinical infection.
Among the interventions which can control the
spread of tuberculosis is “preventive chemotherapy or
chemoprophylaxis”. These terms are often a source of
confusion for patients and providers and the majority of
candidates are infected with TB and the role of therapy
is secondary rather than primary prevention.
In an effort to most accurately describe this inter-
vention, the American Thoracic Society (ARS) supports
the replacement of both these terms with “treatment of
latent tuberculosis infection (LTBI)”. Case detection and
cure of active disease are critical to reducing transmission.
Treatment of LTBI intervenes at an earlier point in the
cycle, by preventing the development of disease in those
who were previously infected.
In India it is time that recommendation of single drug
5 mg/kg of isoniazid for 6 months in children under five
exposed to sputum positive in the household be changed
to the use of two drugs (6HR) when the exposure is to a
contact with MDR organism. Doctor looking after the
adult sputum positive should be able to decide which
regimen the concerned child need to be put on.
3. Curative Treatment
Bacterial load and anatomic distribution of bacilli apart
from primary drug resistance are the major determinants
of success of chemotherapy.
In sputum-smear positive disease, it is often
cavitatory with high bacillary load and an increased risk
of random drug resistance against individual drugs.
Miliary disease can be often associated with penetration
of the bacilli into central nervous system. In this, the
adequate drug penetration against blood-brain barrier
is essential for treatment.
The main variables that influence the success of chemotherapy
is to identify following groups of children with tuberculosis:
1. Those with sputum smear-negative disease.
2. Those with sputum smear-positive disease (cavitary)
3. Those with disseminated (milliary and meningoencephalitis)
disease.
4. Special organs/systems: Gastrointestinal, bone and joint
DOTS Strategy
DOTS is the recommended strategy for treatment of TB
and all pediatric TB patients should be registered under
RNTCP.6 Intermittent short-course chemotherapy given
under direct observation as advocated in the RNTCP
should be used for children.
Table 9.9.2 shows the RNTCP treatment regimens.
In patients with TBM on category I treatment, the four
drugs used during the intensive phase should be HRZS
or HRZE. Continuation phase of treatment of TBM and
spinal TB with neurological complications should be
given for 6-7 months extending the total duration to 8 to
 Immunization and Infectious Diseases 327

TABLE 9.9.2: Treatment regimens for children under RNTCP

Treatment Type of patients TB treatment regimens
category
IP CP
CAT I New sputum smear-positive PTB, 2H3R3Z3E3*** 4H3R3
Seriously ill* sputum smear-negative
PTB, seriously ill EPTB
CAT II Sputum smear-positive relapse, 2S3H3R3Z3E3/ 5H3R3E3
Sputum smear-positive treatment 1H3R3Z3E3
Failure, sputum smear-positive treatment
after default.

CAT III Sputum smear-negative and EPTB 2H3R3Z3 4H3R3

not seriously ill**

IP – Intenstive phase, CP – continuation phase

* Seriously ill sputum smear-negative PTB includes all forms of PTB, other than primary complex. Seriously ill EPTB include TB
meningitis (TBM), disseminated/milliary TB, TB pericarditis, and TB peritonitis and intestinal tuberculosis, bilateral or extensive pleurisy,
spinal tuberculosis, with or without neurological complications, genitourinary tract tuberculosis, bone and joint tuberculosis.
** Not seriously ill EPTB include lymph node tuberculosis and unilateral pleural effusion.
***Prefix indicates months and subscript indicates thrice weekly.
PTB – Pulmonary tuberculosis
EPTB – Extrapulmonary tuberculosis
* For details see the chapter on RNTCP

9 months. There should be well controlled studies in a Clinical or symptomatic improvement is to be

larger number of children with neuro-tuberculosis. Seth
has shown the efficacy of intermittent therapy in
tubercular meningoencephalitis in a well controlled
study but in a small number of cases and needs a larger
controlled study to confirm the same.
Steroids
Should be used initially in hospitalized cases of TBM and
TB pericarditis and reduced gradually over 6 to 8 weeks.
In all instances before starting a child on category II
treatment, she/he should be examined by a pediatrician
or a TB expert, and in view of the growing evidence that
the use of ethambutol in young children is safe, ethambutol
is to be used as per RNTCP regimens for all age group.
To assist in calculating required dosages and
administration of anti-TB drugs for children, medication
is available in the form of combipacks in patientwise
boxes limited to child’s weight in four categories.
Monitoring and Evaluation
Pediatric-focused monitoring is an integral part of the
program. Wherever possible, follow-up sputum exami-
nation is to be performed with the same frequency as in
adults.
assessed at the end of the intensive phase of treatment.
Improvement should be judged by absence of fever or
cough, a decrease in the size of lymph nodes and weight
gain. Radiological improvement is assessed by chest
X-ray examination in all smear-negative pulmonary TB
cases at the end of treatment.
Continuous Therapy in Pediatrics
Although it is recommended that all children should be
treated under RNTCP but in some circumstances
treatment can be continuous when it can be afforded
easily but it is difficult to follow adherence as in the
program. This will ensure better adherence.
For poor parents, the wage loss and travel time
involved are limitations because in real-life situation, one
cannot assure 100% coverage of all cases. This is true of
all National Programs in India. At least the drug regimen
can be decided by a doctor at the Primary Health Centre
in case of non-neurological tuberculosis, i.e. the types
described above. Pediatric-focused monitoring is an
integral part of the program. Wherever possible, follow-
up sputum examination is to be performed with the same
frequency as in adults.
328 IAP Textbook of Pediatrics
Clinical or symptomatic improvement is to be
assessed at the end of the intensive phase of treatment.
Improvement should be judged by absence of fever or
cough, a decrease in the size of lymph nodes, weight gain.
Radiological improvement is assessed by chest X-ray
examination in all smear-negative pulmonary TB cases
at the end of treatment.
DRUG RESISTANT TUBERCULOSIS
DEFINITION
Drug resistance in mycobacteria is defined as insensi-
tivity of mycobacteria to a sufficient degree to be
reasonably certain that the strain concerned is different
from a sample of wild strains of human type that have
never come in contact with the drugs.
Types of Drug Resistance
Drug resistance in TB may be broadly classified as
primary or acquired. When drug resistance is demons-
trated in a patient who has never received anti-
tuberculosis treatment previously, it is termed primary
resistance. Acquired resistance occurs as result of
specified previous treatment.
The level of primary resistance in the community is
considered to reflect the efficacy of control measures in
the past while the level of acquired resistance is a measure
of ongoing TB control measures. However, the World
Health Organization (WHO) and the International Union
Against Tuberculosis and Lung Disease (IUATLD), in the
light of discussion in several International fora, have
replaced the term “primary resistance” by the term “drug
resistance among new cases” and “acquired resistance”
by the term “drug resistance among previously treated
cases”.
Causes of Drug Resistance
A variety of factors namely management, health provider
and patient related, are responsible for the emergence of
drug resistance in M.tuberculosis. These include:
i. Deficient or deteriorating TB control programs
resulting in inadequate administration of effective
treatment.
ii. Poor case holding.
iii. Administration of sub-standard drugs, inadequate
or irregular drug supply and lack of supervision.
iv. Ignorance of health care workers in epidemiology,
treatment and control of the disease.
v. Improper prescription of drug regimens.
vi. Interruption of chemotherapy due to adverse effects
of drugs.
vii. Non-adherence of the patient to the prescribed drug
therapy.
viii. Availability of anti TB-drugs over-the-counter
without prescription.
ix. Massive bacillary load.
x. Illiteracy and low socio-economic status of the
patients.
xi. Epidemic of HIV infection.
xii. Laboratory delays in identification.
xiii. Use of non-standardized laboratory techniques,
poor quality active pharmaceutical ingredient, lack
of quality control measures, and
xiv. Use of anti-TB drugs for causes other than tuber-
culosis.
Multidrug resistant tuberculosis (MDR-TB) requires
treatment with second-line drugs. These drugs have
limited sterilizing capacity and not useful for short-course
chemotherapy. Thus the problem of transmission is
crucial to the disease in children. It is of grave concern
when there is contact of a child with MDR tuberculosis
in the family resulting in primary resistant infection.
MDR-TB has important implication both for individual
patient and tuberculosis control program.
The modern era of tuberculosis is characterized by a
rise in the number of cases of infection with MDR-TB.
This has also lead to outbreaks of MDR-TB and individual
cases that are only marginally treatable and often fatal.
World Health Organization (WHO) in 1993 on World
Tuberculosis Day declared tuberculosis as a global
emergency. MDR-TB has been described as the third
epidemic, complicating the epidemic of HIV.
Diagnosis
Since the clinical presentation of both the sensitive and
drug resistant tuberculosis is the same, the only certain
way of diagnosing tuberculosis is by isolating the
infective strain and assessing its susceptibility pattern.
AFB isolation in tuberculosis, in children except in
cavitary disease is low (25-44%) even in the most
advanced centers. Adult contacts of children should be
assessed for history of prior antituberculosis therapy with
persistent sputum-positivity. Since, this is a pointer
towards drug-resistance, children with such adults

should be watched for any (i) lack of response or
(ii) deterioration on treatment.
Diagnosis of drug resistance is further confounded
by certain peculiarities of the disease. The resolution of
radiographic abnormalities of chest can take months or
years even after successful treatment. Also post-
tuberculosis hyperreactivity, bronchiectasis and other
residual lesions can cause symptoms with persistence of
radiological shadows.
In 15-20 percent infection with susceptible organisms,
lymph nodes of considerable size persist even after
complete therapy. These may fluctuate intermittently.
Histopathology in such cases may show sterile granu-
loma. AFB can be isolated in cases of drug-failure or
relapse.
Tuberculomas of brain may increase in number, as
well as size, even on successful treatment. Anatomically
they heal over a period of months or years. A patient can
have recurrence of convulsions during the healing phase.
Such symptoms do not necessarily imply a relapse or
resistance to antituberculosis chemotherapy.
Various reasons may be responsible for delay in
diagnosis of MDR-TB. In a recent report of tuberculosis
in children when the emphasis was on the isolation of
Mycobacterium tuberculosis by rapid methods using
induced sputum, the delay in starting the therapy was a
median of two days when the MDR-TB source case was
taken into account. It was a delay of 246 days if the drug
susceptibility pattern of the source case was not
considered. Correlation between the isolate of the child
and source case was 68 percent. This suggests that there
is a need to define the resistant tuberculosis in children.
If a child has had a contact with an adult patient
particularly in the household with documented MDR-
TB, he can be considered to be suffering from MDR-TB.
He should be started on an appropriate therapy after
taking the requisite samples for culture and sensitivity
for M.tuberculosis.
If a patient fails to improve after appropriate
antituberculosis drugs with good compliance, he may
be suffering from resistant tuberculosis and should be
referred to an appropriate center dealing with drug
resistant tuberculosis. The primary care physician should
not start the child on a regimen for drug resistant
tuberculosis.
Predictors of Drug Resistance in Children
Pattern of drug-resistance among children with tuber-
culosis tend to reflect those found among adults.
Immunization and Infectious Diseases 329
Predictors of drug-resistance in children are given in
Table 9.9.3:
TABLE 9.9.3: Predictors of drug resistance
• Previous antituberculosis therapy
• HIV infection in the child or source case of adult
• Known contact with an adult patient with MDR-TB
• In children with HIV infection or cavitary lesion, treatment
is extended upto 24 months in children with HIV infection
or cavitory lesions
• Intermittent regimens are not recommended.
If patient’s M.tuberculosis culture remains positive
after 4 to 5 months of treatment, it should be retested for
susceptibility to both first and second-line drugs. If this
is not available, as is often the situation in India, at least
two new drugs should be added while continuing
original medication if available. Addition of new drugs
should be based on susceptibility testing.
If patient develops an adverse drug reaction, the
offending drug can be removed and rest of the regimen
continued. Alternatively, a new medication can be
substituted. In general first-line drugs are well tolerated
by children and the adverse effects are more often by
second-line drugs. Children on second-line drugs must
be monitored for liver, renal and hearing tests periodi-
cally.
Management
The management of MDR-TB in adults has been
extensively documented including India. However, little
is known about its diagnosis and management in
children. After the streptomycin was introduced in the
treatment of TB, very early it was found that there were
frequent relapse and emergence of a population of
streptomycin resistant M.tuberculosis.
The current threat is due to emergence of strains
resistant to the two most potent anti-TB drugs viz.,
isoniazid(H) and rifampicin (R) (MDR-TB). The response
of patients with MDR-TB to treatment is poor and
mortality rate is usually high.
The number of MDR-TB patients has increased in
India and the concern of the government of India is to
prevent the increase in the incidence of XDR or extremely
drug resistant cases which have no cure.
The Health Ministry is dolling out the DOTS Plus
program to manage MDR-TB in several states by early
June 2008 and in 17 other states by May 2009.
330 IAP Textbook of Pediatrics
TB infects 8 lakh people in India every year and when
treated inappropriately (the administration of drugs is
stopped prematurely or is not done properly), the patient
not only remains sick, but the bacteria that causes the
illness may develop resistance to drugs ordinarily used
to treat tuberculosis.
MDR-TB is difficult to treat and drugs used cause side
effects. The people infected spread it readily to others.
In India’s TB control program, laboratories to diagnose
MDR-TB are being accredited in states like Delhi, West
Bengal, Kerala, Rajasthan, Tamil Nadu, Andhra Pradesh
and Haryana.
The Stop TB Partnership opined that plans to combat
drug-resistant TB need to be prioritized by the
Government, which should increase the number of
laboratories to diagnose MDR-TB and introduce rapid
methods to quickly identify drug-resistant patients.
Drug Therapy of MDR-TB
The treatment of MDR-TB is a challenge since it
involves the use of second-line reserve drugs which
are not only more expensive but are also more toxic
and less effective than the standard drugs. These drugs
include aminoglycosides (capreomycin), thionamides,
fluoroquinolones, cycloserine and para-aminosalicylic
acid (PAS).
When to Suspect Drug Resistance
Drug resistance should be suspected whenever:
• Therapeutic progress is not maintained
• Bacterial relapse occurs during treatment
• Recurrence occurs in a patient previously treated for
tuberculosis and their contact including children.
• Associated HIV infection.
Once there is strong possibility of drug resistance
complicating therapy:
i. All treatment should be reconsidered.
ii. Culture and sensitivity studies should be under-
taken using rapid methods of identification of AFB
on smear and culture.
Repeated examination of gastric lavage and induced
sputum specimen, examination of fine needle aspiration
(FNA) material in non-resolving lymphadenitis must be
undertaken. Further, drugs should not be added
piecemeal to the existing regimen as this will lead to
decrease of drugs for use in an effective alternative
therapeutic regimen.
Principles of Treatment of MDR-TB
• MDR-TB should always be treated in consultation
with a clinician who is experienced in treating the
disease.
• Patients should be treated with at least 2 or preferably
3-4 drugs to which the strain isolated from the patient
or adult source-case is known to be sensitive.
• Aminoglycosides or capreomycin should be one of
the medications as studies have shown that its use is
a good predictor of culture conversion and survival.
• Bactericidal drugs should be used as far as possible
• Treatment should be given for at least 12 months after
culture of bacilli has converted to negative.
Some important features of anti-TB drugs used in
chemotherapy of MDR-TB are given in Table 9.9.4.
Treatment of Drug Resistant Tuberculosis Disease
Even under ideal conditions, M.tuberculosis is isolated
from induced sputum or gastric aspirate in 50% of
children with pulmonary tuberculosis. Culture yields
from other anatomic sites are lower. For this reason the
clinician should be aware of the resistance pattern in the
community since, in vast majority of cases of resistant
tuberculosis in children, it is primary. Susceptibility
information can be obtained from the M.tuberculosis
isolated from the adult who transmitted the infection.
The treatment can be as follows depending upon the
disease in the child from known contact or unknown
source.
1. Children with Resistant Disease with Known Adult
Patients with MDR Tuberculosis
All children with MDR-tuberculosis need individualized
treatment regimen (ITR). The children in this category
should first receive any oral first-line drugs to which the
isolate from the adult source case is sensitive. Second,
all regimens must include an injectable agent for a
minimum of six months after culture conversion, and
an oral quinolone for the duration of therapy. Children
who yet do not have five drugs in their regimen should
receive additional second-line drugs (ethionamide,
cycloserine or PAS). If a strain is highly resistant and the
child’s regimen still contains less than five drugs,
additional agents with known antituberculosis acitivity
(e.g. amoxicillin/clavulanic acid or clofazimine) can be
added.
 Immunization and Infectious Diseases 331

TABLE 9.9.4: Antituberculosis drugs for the treatment of MDR tuberculosis

Drugs Average Routes Tolerance Toxicity Type of antimico-
daily dose bacterial activity
(mg/kg)
• Aminoglycosides
– Streptomycin 15 Injection Moderate Medium Bactericidal against actively
multiplying bacteria
– Kanamycin Injection Poor Medium Bactericidal against actively
multiplying bacteria
– Amikacin Injection Medium Medium Bactericidal against actively
multiplying bacteria
– Capreomycin Injection Moderate Medium Bactericidal against actively
multiplying bacteria
• Thionamides
– Ethionamides 10-20 Oral Good to moderate Medium Bactericidal
– Prothionamides
• Pyrazinamide 20-30 Oral Good Low Bactericidal at acid pH
• Ofloxacin 7.5-15 Oral Good Low Weak bactericidal
• Ethambutol 15-20 Oral Good Low Bacteriostatic
• Cycloserine 10-20 Oral Moderate High Bacteriostatic
• PAS 10-12 g Oral Tabs Low Bacteriostatic
Granules

2. Children with Tuberculosis Disease TABLE 9.9.5: Suggested drug regimen for proven drug
without Known Contact resistance in relation to HIV status

These are children who fail to respond to appropriate HIV status Isoniazid Rifampicin Multi-drug
antituberculosis treatment. The treatment failure may be HIV-ve 12RZE 18-24 HRZ 3 sensitive
due to several reasons, including inappropriate regimen, drugs for 2
poor adherence, or wrong diagnosis. It is recommended years after
culture-ve
that attempt should be made to ascertain the diagnosis
of TB again by subjecting appropriate specimens for HIV+ve 18 RZE or 18-24 HZE 3 sensitive
isolation of M.tuberculosis and category 2 treatment 12 months after or 12 months drugs for 2
should be started (2SHRZE, 1HRZE, 5HRE). culture-ve after culture-ve years after
culture-ve
The family should be counselled to achieve 100%
compliance. Children who are already on this regimen
for 3 months but show no improvement, should be
Preventive therapy for children likely to be infected
considered for treatment for MDR-TB in a specialised
with resistant strain, a combination of PZA and EMB or
centre of WHO.
PZA and a fluoroquinolone for 12 months is recom-
The recommendations of Indian Academy of
mended. Children should be followed up carefully
Pediatrics for management of drug resistant tuberculosis
during and after treatment for the development of signs
in children are given in Table 9.9.5.
and symptoms of tuberculosis disease. All children
infected with MDR-TB should be treated for disease.
Treatment of Drug Resistant Infection
In children less than 2 years of age who have high
Isoniazid alone has been recommended for children who risk of developing a life threatening disease all possible
have a contact with a drug-susceptible adult. In areas attempts should be made to isolate the organism. Any
with high rates of isoniazid resistance, rifampicin child who has AIDS has to be treated as associated
(10 mg/kg) for 6-12 months is recommended. tuberculosis disease.
332 IAP Textbook of Pediatrics
Concept of DOTS Plus
Two basic approaches to DOTS Plus have been proposed:
i. Individualized treatment regimen and
ii. Standardized regimen including second and third-
line drugs. In pediatric practice, it is still recom-
mended to individualize the regimen as described
above.
Newer Drugs
This is amoxicillin-clavulanic combination showing
promise for treatment of MDR-TB. Imipenem, amoxy-
cillin-clavulanic acid, interferon gamma via aerosol,
newer rifamycins (rifabutin, rifatazil) and recombinant
interleukin are some of the drugs under investigation. A
recently investigated compound which appears encoura-
ging is oxazolidinone.
Immunotherapy
M.vaccae vaccine used in small trials in adult patients,
has shown some benefit. Mode of action is possibly by
regulation of cell-mediated immunity with enhancement
of Th1 and down regulation of Th2 cells. It is shown by
faster bacteriologic conversion, reduction in ESR, increase
in body weight, resolution of radiological opacities,
leading to betterment in clinical status.
9.10 Abdominal Tuberculosis
Tuberculosis is still common in the tropics and continues
to figure in the differential diagnosis of medical and
surgical emergencies of acute abdomen.
DEFINITION
It is defined as tuberculosis infection of the abdomen
including gastrointestinal tract (GIT), peritoneum,
omentum, mesentry, lymph nodes and other solid organs
of the abdomen like liver, spleen and pancreas. It has
been well described in adults. There has been paucity of
literature on abdominal tuberculosis in children due to
its protean manifestations and difficulty in diagnosis.
Prevention
The prevention of MDR-TB depends upon an effective
use of the principles of tuberculosis control. The timely
identification and adequate treatment in a special TB
center is of formost importance in preventing further
spread. Due emphasis has to be given for contact tracing
of children of an adult with suspected or proven MDR-
TB.
BIBLIOGRAPHY
1. Chakraborty AK. Prevalence and incidence of tuber-
culosis infection and disease in India: a comprehensive
review. World Health Organisation, Geneva, Switzerland
1997, WHO/TB/97/33.
2. Kabra SK, Lodha R, Seth V. Tuberculosis in children –
what has changed in 20 years? Indian J Pediatric 2002;
69 (suppl)1:55-10.
3. Mariais BJ, Rober P, Gie H, Donald P, et al. Childhood
pulmonary tuberculosis, old wisdom and new
challenges. Am J Rep Crt Care Med 2006;173:1048-90.
4. Seth V. Revised National Tuberculosis Control-Program-
management of tuberculosis in children. In IAP Text Book
of Pediatrics. Jaypee Brothers medical Publishers (P) Ltd,
New Delhi, 2009;351-58.
5. Seth V, Lodha R, Kabra SK. Pulmonary tuberculosis. In:
Seth V, Kabra SK (Eds): Essentials of Tuberculosis in
Children, (3rd edition). Jaypee Brothers Medical
Publishers (P) Ltd: New Delhi 2006;109-33.
6. Treatment of Childhood Tuberculosis: Consensus
Statement Recommendations of Indian Academy of
Pediatrics, India Pediatr 1997;37:1093-6.
7. Udani PM. Tuberculosis in children in India. Pediatric
Clin India 1903;25:125-31.
Saroj Mehta, Vimlesh Seth
Etiopathology
Mycobacterium tuberculosis, M.bovis and mycobacteria
other than tuberculosis (MOTT) can cause abdominal
tuberculosis. Due to pasteurisation of milk and the
custom of boiling it before consumption, tuberculosis due
to M.bovis is rarely seen in India. The likely mechanism
for the infection of the bowel include direct infection of
tubercule bacilli from either infected sputum or dairy
products. The other mechanism is hematogenous spread
through the bile from focus elsewhere in the body or
direct extension from the other organs. Tuberculous
peritonitis can occur due to ulceration of an abdominal
 Immunization and Infectious Diseases 333

TABLE 9.10.1: Sites of involvement in TABLE 9.10.2: Abdominal tuberculosis—

abdominal tuberculosis clinical features at presentation
• Intestine Clinical features % of patients
– Ulcerative; hypertrophic;
• Symptoms
– Ulcerohypertrophic; miliary
– Pain abdomen 88
• Peritoneum
– Anorexia 77
– Exudative (generalized or localized)
– Fever 68
– Dry plastic, fibroblastic, miliary
– Chronic diarrhea 64
– Omental adhesive
– Loss of weight 84
• Lymph node
– Diarrhea 18
– Mesenteric, other local nodes;
– Vomiting 31
– Retroperitoneal
– Constipation 5
– Cough 57

lymph node, or a tubercular ulcer, or as a result of • Signs

transmural infection of the bowel without perforation.
Primary infection of the intestines can occur due to
involvement of peritoneal lymph nodes.
Clinical Features
Abdominal tuberculosis can be of the following types:
• Classic plastic form
• Ascitic form
• Involvement of mesenteric lymph nodes.
In children nearly two-third cases have predomi-
nantly involvement of GIT. Peritoneal involvement
occurs only in one-third cases. Isolated nodal involve-
ment (Tabes mesenterica) is uncommon (about 4%). The
sites of involvement in gastrointestinal tract, in order of
frequency are, ileum, colon, ileocecal region, jejunum and
duodenum. The types of lesions in various organs are
given in Table 9.10.1.
Table 9.10.2 the shows the possible clinical symptoms
and signs of abdominal tuberculosis in children.
Peripheral lymphadenopathy (33%) and some
pulmonary signs may provide significant pointers to
etiology of abdominal findings. Abdominal disease is
more often disseminated in children, unlike adults in
whom it tends to localize, often resulting in subacute
obstruction.
Clinical presentation of abdominal tuberculosis is
very variable and may mimic common childhood
illnesses like diarrhea, fever, pain abdomen, etc. The most
common symptoms are abdominal pain followed closely
by anorexia and weight loss and chronic or recurrent
diarrhea. Association of low grade pyrexia and cough
may arouse suspicion. Duration of symptoms may vary
from, as short as two weeks, to as long as a few years.
The clinical signs include distention of abdomen, visible
peristalsis, doughy feel on palpation of abdomen, ascites
– Distension of abdomen 69
– Ascites 19
– Peritonitis —
– Doughy abdomen 39
– Enterocutaneous fistula 4
– Hepatomegaly 52
– Splenomegaly 21
and vague lump in abdomen accompanied by hepato-
megaly and splenomegaly. Evidence of tuberculosis
elsewhere in body should always be looked for.
Diagnosis
The investigations which are needed to establish the
diagnosis can be divided into two categories:
Definitive Diagnosis
Definitive diagnosis is accepted only when acid-fast
bacilli (AFB) are demonstrated in the tissue, or typical
tuberculosis granuloma with caseating necrosis has been
established. However, this is not always possible in
abdominal tuberculosis. Many techniques are now
available which have improved diagnosis. Previous
methods of culture were painstaking and took 6 to 10
weeks to yield results. Rapid methods of culture on
modified culture media are now available which have
vastly improved the yield of AFB. Methods of identifi-
cation of AFB have also improved a lot. Further, methods
to obtain material from lesions in gastrointestinal tract,
peritoneum and masses in abdomen have also improved.
Some of these techniques are given below (Table 9.10.3).
Investigations
• Fine needle aspiration cytology (FNAC) from
palpable mass in abdomen or ultrasound guided
334 IAP Textbook of Pediatrics
TABLE 9.10.3: Definitive diagnosis of
abdominal tuberculosis
Criteria
• Demonstration of AFB in lesion/ culture
• Tuberculous granuloma with caseating necrosis
Material
• Surgical specimen
• Fine needle aspiration
• Endoscopic biopsy
• Peritoneoscopic biopsy
• Liver biopsy
• Ascitic fluid
Supportive diagnosis
• Identification of contact (adult patient)
• Mantoux test/Tuberculin test
• Radiology (contrast and double contrast meal and enema
techniques), chest and abdomen skiagram
• Ultrasound abdomen
• CT scan for nodal involvement
• Adenosine deaminase (ADA) in ascitic fluid
• Serological tests
aspirated material can be used to identify AFB, typical
cell reaction and caseation material and for culture.
It is a safe and quick method of definitive diagnosis.
• Upper and lower GI endoscopy has provided an
access to direct visualization of mucosal lesions. At
the same time, biopsy can be obtained from the lesion
under direct vision. With the help of fine needle
threaded through endoscope, aspiration of material
can be obtained from deeper part of the lesion.
• Peritoneal biopsy with the Vim-Silverman needle or
under direct vision through peritoneoscope can
provide requisite material for AFB, cytology and
culture.
• Ascitic fluid obtained from free or localized collection
is useful for culture and cytology by concentration
methods.
• Liver biopsy gives varied changes such as granulo-
matous hepatitis, miliary tubercules, conglomerate
tubercles, and nonspecific hepatitis, fatty inflamma-
tory cell infiltrate, portal inflammation, portal fibrosis,
Kuppfer cell hyperplasia, tuberculomas, abscesses
and cholangitis in abdominal tuberculosis.
• Laparotomy may now be rarely needed and only
when other methods fail. It is indicated when
diagnosis of tuberculosis is strongly being considered,
particularly if subacute obstruction or fistula exist.
Surgical specimen with characteristic gross appear-
ance of hypertrophy, peritoneal and regional lymph
node involvement with caseation are highly
suggestive. Histopathology, demonstration of AFB
and culture of bacilli provide the most accepted
definitive diagnosis.
Supportive Diagnosis
More often than not, diagnosis of abdominal tuberculosis
rests on supportive or circumstantial evidence. These
include:
• Mantoux test is likely to be positive (more than 10 ×
10 mm) in 50 to 60 percent cases. Negative test does
not exclude tuberculosis.
• Radiology
— Skiagram of chest as an evidence of co-existing
pulmonary disease is variable (as low as 6% to a
high of 90%)
— Plain skiagram of abdomen may reveal multiple fluid
levels suggestive of subacute intestinal obstruction
(nearly 20%) or calcification in lymph nodes (intra-
abdominal) or mass shadow of omentum, lymph
nodes single or matted together, etc.
— Barium meal with follow-through is very useful to
determine the nature, the site, extent of involve-
ment of GI tract, peritoneum and nodal masses.
Lesions like ulceration, stricture, hypertrophic
segments, malabsorption pattern, matted intesti-
nal coils (indicating peritoneal involvement),
compression or separation of coils due to enlarged
lymph nodes and fistulous tract can be delineated.
This technique of barium contrast study has been
vastly improved by double contrast (provided by
air pushed along-with thin barium). The precision
to pin-point lesions in small intestine has been
greatly enhanced.
— Barium enema is indicated when colonic lesions are
suspected. Ulcerations, hypertrophic segments
and strictures can be diagnosed. Double contrast
with air has improved this technique of diagnosis.
In our experience radiological investigations in
clinically suspected cases, have served as best
supportive evidence of diseases.
• Ultrasound and CT scan. CT scan has been useful in
locating pockets of ascites, and outlining typical
appearance of enlarged lymph nodes with radio-
lucent center indicative of caseation necrosis. MRI is
not of much value.

• Adenosine deaminase (ADA) in the peritoneal fluid
in tuberculous peritonitis is raised many folds.
Sensitivity and specificity of this test is 95 to 100
percent and 96 to 98 percent respectively. ADA in
the ascitic fluid is very helpful to differentiate
tuberculous peritonitis from other causes of
peritonitis. Thus, with high clinical index and
judicious employment of relevant tests, in most cases
diagnosis can be made.
To summarise, abdominal tuberculosis is a pauci-
bacillary disease and hence microbial evidence is not
easily available. For a definitive diagnosis, tissue
specimens can be obtained by one of the following
techniques:
i. Fine needle aspiration cytology (FNAC) from
intraabdominal masses which can be done only in
a palpable mass and biopsy can be guided by an
ultrasound or CT. Endoscopic biopsy can be done
of the submucosa.
ii. Ascitic fluid collection for cytology, chemistry and
AFB culture.
iii. AFB culture in the tissue biopsy specimen. Ascites,
and outlining typical appearance of enlarged lymph
nodes with radiolucent center indicative of caseation
necrosis. MRI is of not much value.
iv. Adenosine deaminase (ADA) in the peritoneal fluid.
Complications
The relatively common complications of tuberculous
enteritis include obstruction, fistula formation, perfo-
ration with abscess, hemorrhage, enterolithiasis and
traction diverticula. Rarely perforation may occur, with
resultant peritonitis. Early institution of antituberculosis
therapy prevents complications.
Treatment
WHO has prepared guidelines for National Programs
with the objective of effective treatment. Effectiveness
of treatment is determined by two major factors: (i) the
cure rate, and (ii) lower drug resistance. In order to
achieve these objectives, treatment is divided into (a) an
intensive phase to effect prompt bactericidal effect
(b) and a continuation phase to sterilize the lesion of
bacteria to prevent relapse.
Abdominal tuberculosis including peritoneal,
gastrointestinal and nodal involvement has been
included under category 1 by WHO. Category I is
Immunization and Infectious Diseases 335
2R3H3Z3/4R3H3 (For details refer to the Chapter on
RNTCP).
At times one can use a continuous regimen using the
same drugs. Some pediatricians and pediatric surgeons
still are comfortable using a regimen containing
ethambutol, 2HRZE 4HR. Current information suggests
that 90 percent of patients with enteric tuberculosis, and
even a higher percentage of peritoneal tuberculosis cases
respond to this regimen. Less frequently the continuation
phase may have to be extended for 7-10 months. In
populations with low probability of drug resistance,
initial phase may be managed with three drugs only.
Hepatotoxicity due to drugs should be monitored
with transaminases periodically in first 6 to 8 weeks of
therapy. If hepatotoxicity occurs, both the drugs isoniazid
and rifampicin should be stopped and ethambutol
(15 mg/kg) is given till the time there is complete recovery
of hepatic injury. At this point, INH and rifamipicin can
be restarted. In most cases hepatotoxicity does not recur.
If hepatotoxicity recurs, isoniazid and ethambutol
combination may be used for continuation phase.
Role of Surgery in Abdominal Tuberculosis
The role of surgery is limited to tissue diagnosis and is
needed for management of complications such as
obstruction, perforation, fistula formation or rarely
significant bleeding.
Summary
Abdominal tuberculosis remains significant problem in
the developing world. The clinical manifestation can be
protean and nonspecific and hence diagnosis requires a
high index of suspicion. Only 15 to 20 percent of patients
with abdominal tuberculosis have concominant lung
disease. Treatment of this type of tuberculosis is
essentially by chemotherapy, and only rarely surgical
intervention is required.
BIBLIOGRAPHY
1. Bajpai M, Gupta DK. Abdominal tuberculosis. In Seth V,
Kabra SK (Eds): Essentials of Tuberculosis in Children.
3rd edition. Jaypee Brothers Medical Books Publishers
(P) Ltd. New Delhi 2006;143-56.
2. http://www.pediatriciancall.com 10.2.06
3. Seth V. Revised National Tuberculosis Control Program
(RNTCP) Directly Observed Treatment, in IAP Textbook
of Pediatrics, Ed: Jaypee Brothers Medical Publishers (P)
Ltd. New Delhi 2009;351-58.
336 IAP Textbook of Pediatrics
9.11 Neurotuberculosis
Neurotuberculosis (tuberculosis of the central nervous
system) is represented by different and possibly
concomitant forms of which the most important are
tuberculous meningitis (TBM) and tuberculoma. It is the
result of complex mechanisms that operate to produce
multifarious changes in all structural and cellular
components of the cerebrum, cerebellum, brainstem and
spinal cord. Considering all ages, TBM is a more frequent
manifestation of neurotuberculosis than brain
tuberculoma.
TUBERCULAR MENINGITIS (TBM)
Introduction
Tuberculous meningitis (TBM) is a potentially curable
disease of the central nervous system. A complete
neurological recovery will depend upon early confirma-
tive laboratory diagnosis along with institution of
appropriate chemotherapy. M.tuberculosis demonstration
by conventional methods is not only less sensitive but
also yields false negative results. TBM was first described
by Robert Whytt in 1769 as dropsy of the brain. Charles
Moorhead, described its pathology in 1847.
Human tuberculosis still remains one of the major
public health problems in most of the developing
countries despite world wide tuberculosis control and
eradication program along with availability of newer
shorter duration diagnostic techniques and therapeutic
modalities. Childhood tuberculosis, a reflection of adult
tuberculosis is a problem with limitation of application
of newer diagnostic techniques due to non-availability
and maintenance of adherence to treatment (short-course
chemotherapy of RNTCP) in India.
Increasing evidence of HIV-infection has added to
the increase in the problem of tuberculosis, equally
applicable to children as in adults. Every year, estimated
eight million new cases are added with 2 million deaths.
TBM is the most important cause of death in children
amongst all types of neurotuberculosis. Inspite of BCG
vaccination and antituberculosis drugs, malnourished
children die of TBM. If they recover they are left with
severe residual sequelae. Though BCG vaccination
reduces the life-threatening complications of childhood
Vimlesh Seth
TB, there are newer manifestations of tuberculosis in BCG
vaccinated children.
Neurotuberculosis is a more important problem in
developing countries due to:
I. Ineffective TB control program for adults.
• Poor contact tracing in children < 5 years of adult
sputum +ve pulmonary tuberculosis (PTB) and
failure of preventive therapy in this high risk age
group.
• Failure of timely treatment of latent tuberculosis
in the age group of < 5 years.
II. Emergence of drug resistant strains.
III. Increasing prevalence of HIV/AIDS.
IV. Overcrowding, poor nutritional status and poverty.
Before HIV, the most important determinants for the
development of tuberculosis meningitis (TBM) were age
and poor nutritional status. HIV predisposes to the
development of TBM among the extrapulmonary
tuberculosis. The risk increase as the CD4 count declines.
Epidemiology
Tuberculous meningitis (TBM) is the most important
cause of death in children amongst all types of
neurotuberculosis. In an autopsy study of 3646 children1
from Mumbai, of the 356 deaths due to all types of
tuberculosis, 190 had TBM without tuberculoma, 32 had
TBM with tuberculoma and 11 had tuberculosis who had
miliary TB with brain edema. In a recent study between
1990 and 1992, deaths due to TBM had come down to
40 percent.
In spite of BCG vaccination and antituberculosis
drugs, malnourished children die of TBM and if they
recover, they have severe residual sequelae. There is no
doubt that BCG vaccination has been effective in
reducing the life-threatening complications of childhood
TB, yet one has to recognize newer manifestations of
tuberculosis in BCG vaccinated children.
Pathology
Mycobacterium tuberculosis is responsible for most
tuberculous infections of the CNS. M.bovis and
M. africanum are the less frequent causative organism.

It is believed that the bacilli reach the CNS by the
hematogenous route secondary to disease elsewhere in
the body. Mycobacteria filter from the blood by lungs,
liver, spleen and bone marrow, while they get trapped
in organs like brain where there is no reticuloendothelial
system.
The classic work of Rich and McCorduck forms the
basis for its current understanding. CNS tuberculosis is
accepted to occur as a three step process.
1. Initially, hematogenous seeding of the meninges
occurs either during the stage of bacteriemia of
primary tuberculous infection or shortly afterwards.
These initial lesions (Rich’s foci) may be in the
meninges, subpial or subependymal surface of the
brain or the spinal cord.
2. This is followed by a quiescent phase which may last
from few weeks to many decades.
3. In the third step, the mycobacteria in these Rich’s foci
multiply and then a immune or traumatic stimulus
causes them to rupture resulting in the clinical
manifestations of neurotuberculosis.
Tuberculous meningitis develops when the Rich’s
focus which has been established in the brain, meninges
or spinal cord during hematogenous dissemination from
primary infection, bursts in the subarachnoid space and
produces generalized meningitis. The pathology is
characterized by exudates specially at the base of the
brain, edema of the brain, infarction due to large or small
vessel obstruction or presence of small or large
tuberculoma in the cerebral hemispheres, cerebellum or
brainstem. The exudate in TBM is predominantly at the
base of the brain as infection spreads in the subarachnoid
space and particularly in basal cisterns. The exudates in
the middle cranial fossa produces obstruction of the basal
cisterns which are glued by the exudate, leading to
hydrocephalus. Apart from the exudate, there is edema
of the brain, affecting white matter more than the gray.
Basal exudates by obstructing the large arteries like
middle cerebral and its branches cause infarction of the
areas of brain supplied by these arteries. Engulfment of
the cranial nerves at the base of the brain by exudates
produces various types of cranial nerve palsies. The
exudates at the base of the brain may track upwards to
subthalamic nucleus with contralateral hemiballismus
or along the Sylvian fissure, involving the middle cerebral
arteries.
Immunization and Infectious Diseases 337
Classification of Neurotuberculosis (Udani)
• Tuberculous meningitis with characteristic CSF
findings
• Serous tuberculous meningitis with,
— normal CSF
— mild increase of proteins and cells but normal
sugar and chloride
• Tuberculous encephalopathy without clinical
evidence of meningitis, usually normal CSF
• Acute infantile hemiplegia due to ischemic focal
lesion in the brain and perifocal edema or due to
lesion in the internal capsule
• Localized meningitis
— Localized basal meningitis
— Posterior fossa meningitis
– Cerebellar syndrome with clinical features of
midline cerebellar syndrome with hemispheric
cerebellar signs
– Cerebellar syndrome with hemispheric
cerebellar signs
– Mixed type
• Isolated spinal tuberculous meningitis (without
cranial meningitis or cerebral involvement)
• Tuberculous polyneuritis (Guillain-Barre syndrome),
before, during, or when the child is recovering from
serous TBM (rare)
• Tuberculous radiculomyelopathy (not uncommon
and usually associated with TBM)
• Tuberculous neuritis (rare)
• Tuberculoma
— Intracranial, cerebral, cerebeller; single or
multiple; small or large usually with edema
— Associated with TBM.
Clinical Features
It will be desirable to describe the clinical features of
classical tuberculous meningitis before various modified
clinical pictures of neurotuberculosis in BCG vaccinated
children are described, as more than 90 percent of infants
have been vaccinated by the year 2000.
Age and Sex Incidence
TBM is commonly seen in the first 5 years of life with
more than 65 percent of the cases belonging to this age
group. TBM is usually more common in males than
females.
338 IAP Textbook of Pediatrics
Clinical Stages of TBM
The three traditional stages of TBM are not sharply
defined, and clinical features often overlap.
First Stage
The first stage symptoms are of nonspecific illnesses.
When symptoms persist or if there is a contact with an
adult whose sputum is positive for AFB, diagnosis should
be suspected. The first stage is known as the stage of
meningeal irritation. The child has fever often with a
typhoid-like temperature, associated with headache,
vomiting, constipation and apathy alternating with
irritability. Often a shrill cry is present when child is
disturbed. Deep tendon reflexes are usually brisk. The
apathy may progress to drowsiness but still the child can
be awakened to take feeds. In infants and young children,
onset may be acute and may simulate pyogenic
meningitis. In older children when onset is subacute,
there may be behavior disturbances, and the child may
mistakenly be referred for psychiatric evaluation.
Second Stage
In stage II, symptoms of cerebral involvement are present
characterized by convulsions, neurological deficits and
cranial nerve palsies, such as squint, disturbances of
vision, facial asymmetry, ptosis and dilated irregular
pupils. Convulsions occur in almost 65 percent of the
cases at some stage of the disease. Paralytic forms include
hemiplegia, monoplegia and at times, spastic quadri-
plegia. Hemiplegia on one side and hemiballismic
movements on the other side are common. Features of
increased intracranial tension including severe headache,
vomiting and visual disturbances and meningeal signs
may be present. In infants and young children, there is
bulging fontanellae and separation of sutures with
Macewen sign or cracked pot sound on tapping the head.
The child becomes semicomatose and can be aroused
only with difficulty with painful stimuli. Cutaneous
manifestations of autonomic nervous system disturbance
may be present.
Third Stage
Third stage is heralded by deep coma, well-marked
meningeal signs, progressive neurological deficits,
dilated and almost fixed pupils to light. Signs of
brainstem compression may be present with marked
neck retraction, opisthotonous, decorticate and decere-
brate spasms. Decerebrate rigidity may appear followed
by spasticity. Child may develop irregular or Biot’s
breathing. In the terminal stage, pupils are dilated and
fixed. Patient may develop hyperpyrexia of central origin
and may die.
Modified Clinical Pictures of TBM-Usually Seen in
BCG Vaccinated Children
Atypical clinical pictures in vaccinated children are being
observed because of the localization of lesions in
meninges, brain, spinal cord and peripheral nervous
system. This is presumed to be due to presence of
activated “T” lymphocytes which are lodged in the organ
or the tissue after intradermal BCG vaccination. The
localized lesions in various parts of the brain in a
vaccinated child may be isolated or present with different
combinations of pathological lesions with varied clinical
features. However, as the number of “T” cells or their
function is not adequate enough to prevent the
complications, they only modify the picture by localiza-
tion of lesions in various parts of the nervous system
(Table 9.11.1).
It can be appreciated that depending upon the
localized lesion in the meninges or any part of the brain,
spinal cord or peripheral nervous system, the patients
may present with protean clinical manifestations.
Diagnosis
The onset of the disease is generally insidious with a
vague symptomatology that makes the diagnosis
difficult.
Clinical diagnosis of TBM is easy if:
i. There is characteristic clinical presentation
(symptoms and sign of meningial irritation)
ii. Characteristic CSF (cytology and biochemical
changes)
iii. Imaging abnormalities (CT, MRI, and PET).
Confirmation of diagnosis of TBM rests on the
isolation of Mycobacterium tuberculosis. The bacilli are
seldom seen by staining and culture which takes several
weeks and is associated with a low yield. This leads to a
delay in starting treatment for this potentially treatable
disease. Early treatment can reduce the morbidity and
mortality.
The following criteria could prove to be helpful in
early diagnosis of TBM in children.

TABLE 9.11.1: Modified neurotuberculosis in
BCG vaccinated children
A. Localized lesions in the meninges
i. Meningeal tuberculoma
ii. Serous tuberculous meningitis at the base of the brain
which results in severe hydrocephalus, hemiparesis with
or without cranial nerve palsies
iii. Localized meningitis on the superolateral surface of the
brain.
iv. Localized meningitis in the posterior fossa with unilateral
or bilateral cerebellar hemispheric signs or lesions in the
vermis of the cerebellum with signs of disturbance of
equilibrium
v. Isolated or localized spinal tuberculous meningitis with or
without compression of the spinal cord or involvement of
the spinal cord
B. Localized lesions in the brain and spinal cord
i. Internal capsule due to lacunar infarct resulting in
hemiplegia in conscious and alert patients
ii. Thalamic nuclei with or without involvement of adjacent
structures
iii. Basal ganglia, caudate nucleus, putamen and globus
pallidus
iv. Subthalamic nucleus-development of hemiballismic
movements and hemiplegia on the opposite side
v. Optic nerve by the exudate or tuberculoma-primary or
secondary optic atrophy
vi. Aqueduct with dilatation of third and lateral ventricles
vii. Geniculate bodies and/or superior colliculi with impairment
of vision particularly involvement of eye movement like
upward gaze
viii. Brainstem with development of locked in syndrome
ix. Midbrain with cranial nerve palsy particularly 3, 4 and 6
cranial nerves and nucleus and other areas in midbrain
x. Lower part of the brain and medulla with involvement of 7,
8, 9, 10, 11, and 12 cranial nerves.
xi. Lateral columns, spinothalamic tract, posterior columns in
the spinal cord with signs of lateral column involvement
below the site of the lesion, signs of anterior horn cell
damage at the site of lesion and attacks of severe pains
with involvement of sensory tracts, and there may also be
loss of sense of position.
Essential Features
1. Fever for two weeks.
2. Abnormal CSF findings (pleocytosis with more than
20 cells, predominantly lymphocytes (greater than
60%), protein greater than 100 mg percent, sugar less
than 60 percent of the corresponding blood sugar.
Plus any two of the following:
1. Evidence of extraneural tuberculosis
2. Positive (family) history of exposure to a case of
tuberculosis.
Immunization and Infectious Diseases 339
3. Positive Tuberculin Skin Test (TST) (ITU, PPD)
(>10 mm induration)
Due to nonavailability of ITU of PPD, TST is done by
5TU of PPD.
4. Abnormal CT findings (two or more of the following):
i. Exudates in the basal cysterns or in the Sylvian
fissures.
ii. Hydrocephalus
iii. Infarcts
iv. Gyral enhancement.
Neuroimaging
• Skiagram of Skull: Sutural diastasis may be apparent
on radiograph of skull in infants with hydrocephalus.
• Computed tomography (CT), magnetic resonance
imaging of head, (MRI) or positron emission
tomography (PET) if available particularly when the
differential diagnosis is between neurocysticercosis
and tuberculosis.
CT scan and MRI are useful both for diagnosis and
monitoring of management of increased intracranial
pressure. CT and MRI have enhanced the diagnostic
accuracy of neurotuberculosis, but they are still not
pathognomonic for the diagnosis of the disease. They
may reveal thickening and intense contrast enhancement
of meninges especially in basilar region.
CT Findings
Thick basilar exudates appear as intensely enhancing
area in the basal cisterns. (spider leg appearance) and in
the sylvian fissures. Ventricular enlargement is present
in a majority of patients. Hydrocephalus is usually of
the communicating type due to blockade at the level of
cisterns. Periventicular ooze suggests high pressure.
Sensitivity of MRI and CECT
• Unenhanced MRI scans are relatively less sensitive
than contrast enhanced CT (CECT) in distinction of
diffuse meningitis.
• Contrast enhanced MRI is superior to CECT in
detecting diffuse and/or focal meningial granulo-
matous lesions.
• MRI is better than CT in detecting infarcts.
Angiography
The carotid or magnetic resonance angiogram (MRA)
shows changes in the circle of Willis including uniform
340 IAP Textbook of Pediatrics

narrowing of large segments, irregular beaded appear- TABLE 9.11.2: Drug regimens used by AIIMS, TRC
ance and complete occlusions. They are secondary either (Chennai) and recommended by IAP and RNTCP (DOTS)
to vasculitis or mechanical compression by basilar
Center Drug regimen Total
exudates. duration
Intensive Continu- (months)
Molecular Diagnosic Methods phase ation phase

These fall into three categories: • AIIMS, New Delhi ½ SHRZE 4-6 HRE 9
1. Biochemical tests detecting products released as a 1½ HRZE 12
result of the host response. • TRC Chennai 2 SHRZ 10 HE 12
2. Immunological test that detect mycobacterial antigen • IAP * 2 HRZE 10 HRE 12
or antimycobacterial antibody in the CSF. • DOTS (RNTCP)** 2H3R3 Z3E3 4 H3 R3E3 CAT I DOTS
3. Molecular biological tests that detect DNA fragments 6 months
of the organism. * IAP – Indian Academy of Pediatrics (consensus)
**RNTCP – Revised National Tuberculosis Control Program of
Electrophysiological Studies Government of India.

Electroencephalographic abnormalities have been

reported in upto three-fourth of patients with TBM. EEG TABLE 9.11.3: Recommended doses of drugs as per
abnormalities include diffuse theta to delta waves Indian Academy of Pediatrics
slowing (68.7%), intermittent rhythmic delta activity in
Drug Dose (mg/kg)
frontal region (46.8%), right to left asymmetry (15.6%)
and epileptic form discharges (12.5%). The EEG findings Daily Intermittent
correlate with the severity of meningitis, the degree of
• Isoniazid 5 15
coma and outcome at three months. • Rifampicin 10 15
Abnormal brainstem auditory evoked response • Pyrazinamide 25 30*
(BAER) have been reported in children having impaired • Ethambutol 20 30**
hearing. • Streptomycin 20 30
• Prednisone 1 —
TREATMENT * Never < 5 mg/kg, to be rounded to the closest higher dose
** No studies have been reported in children.
Chemotherapy
Drug regimens used for TBM at the All India Institute of TABLE 9.11.4: Suggested pediatric doses of antituberculosis
Medical Sciences (New Delhi), TRC Chennai, recom- drugs for intermittent therapy under RNTCP as combipacks
mended by Indian Academy of Pediatrics (IAP); and for different weight categories*
RNTCP (DOTS), are given in Table 9.11.2: Drug Dosage Weight of the child (kg)
Tables 9.11.3 and 9.11.4 give the recommended doses (mg/kg)
6-10 11-17 18-25 26-30
of various antituberculosis drugs.
• Isoniazid 10-15 For details see the chapter on
Supportive Measures • Rifampicin 10 RNTCP
• Pyrazinamide 30-35
i. Mannitol 20% (Intravenous) 5 ml/kg body weight • Ethambutol 30
followed by 2ml/kg every 6 hourly for two days • Streptomycin 15
• Oral glycerol given by nasogastric tube (50% in *Currently there are four age categories which are likely to be
2.5% dextrose) increased to five due to operational difficulties encountered in
ii. Intravenous fluids/nasogastric feed, vitamin and the program.
mineral supplements. Doses used by AIIMS and TRC Chennai are almost similar to
iii. Antiepileptic drugs, if needed. IAP.
 Immunization and Infectious Diseases 341

Hepatotoxicity v. Increased detection rate with the easy availability

of CT and MRI.
In case of overt toxicity there is pain in abdomen,
vomiting and hepatic enlargement. All hepatotoxic drugs
Diagnosis
should be stopped. Patient to be started on ethambutol
and streptomycin. The following flow diagram shows 1. Clinical features of raised intracranial tension
the management of hepatotoxicity. 2. Focal neurological signs.
3. Intractable epilepsy.
Hepatotoxicity
Investigations
Stop all hepatotoxic drugs • CT scan, MRI, PET
• PET helps the differential diagnosis better between
Institute for 7 days streptomycin and ethambutol cysticercosis and tuberculomas.

Repeat AST, ALT if they are normal or are
showing a declining trend.
Rifampicin 10 mg/kg/day
+ INH 2.5 mg/kg/day for 7 days
Repeat AST, ALT, if normal
Add PZA (30 mg/kg/day)
Increase INH (5 mg/kg/day)
Treatment
• Chemotherapy
Antituberculosis regimen
2 HRZE 10 HR with oral dexamethasone 0.15 mg/
kg/day
6 hourly for 6 to 8 weeks tapered over 2 weeks.
• Surgery rarely required
Cerebral Tuberculosis Abscess
It is diagnosed by:
i. Microscopic evidence of pus
ii. Inflammatory reaction in the abscess wall
iii. Demonstration of AFB in the purulent material or
in the abscess wall or positive culture of
M. tuberculosis.

Surgery
It has been shown that addition of ventriculo peritoneal
(VP) shunt in children who are in advanced, i.e. IIIrd
stage of TBM only adds to more morbidity as survival
leaves the child with lot of neurological deficits. Hence,
early diagnosis and prevention are more important than
heroic intervention by VP shunt.
Treatment
Cerebral TB abscess requires surgical excision/ stereo-
tactic aspiration along with chemotherapy in comparison
to tuberculoma which responds to antituberculosis
therapy alone.
TUBERCULAR ARACHNOIDITIS

Tuberculoma 2HRZE10HR is given for one year, surgical intervention

Intracranial tuberculoma is an important cause of space
occupying lesion in both the developed and developing
countries. The rising incidence of tuberculoma is
attributed to:
i. Emergence of drug resistant strains.
ii. Ineffective TB control program.
iii. Increasing prevalence of HIV infection.
iv. Overcrowding and poor nutritional status.
may be required where medical management fails.
TUBERCULAR ENCEPHALOPATHY
Spinal
• POTT’S spine and POTT’S paraplegia.
• Non-osseous spinal cord tuberculosis – management
is surgical.
• Spinal tuberculous meningitis.
342 IAP Textbook of Pediatrics
Diagnosis By MRI
For details of uncommon form of neurotuberculosis, the
reader is referred to Seth and Kabra.
Prevention
BCG does not prevent the development of primary
complex and its local complications, but it helps to reduce
hematogenous spread of infection. Incidence of tuber-
culous meningitis is 5 to 7 times higher in non-vaccinated
children than in vaccinated ones. As TBM is a compli-
cation of primary tuberculosis, prevention of tuberculosis
in children is very important.
BIBLIOGRAPHY
1. Rich MR, McCordock HA. The pathogenesis of tuber-
culous meningitis. Bull John Hopkins Hosp 1933;52:5-37.
2. Udani PM, Gulati S, Kabra V, Seth R, Seth V. Case studies
in Neurotuberculosis. In: Seth V, Kabra SK (Eds):
Essentials of Tuberculosis in Children, 3rd edn. Jaypee
Brothers Medical Publishers, New Delhi, 2006;228-47.
3. Udani PM, Parthasarathy A. Neurotuberculosis. In
Parthasarathy A (Editor in Chief): Indian Academy of
Pediatrics Text Book, 3rd edn. Jaypee Brothers Medical
Publisher 2006;225-30.
9.11.1 REVISED NATIONAL
TUBERCULOSIS CONTROL
PROGRAM (RNTCP) INCLUDING
DIRECTLY OBSERVED TREATMENT
Vimlesh Seth
Tuberculosis continues to be a major public health
problem. The number of persons infected with tubercle
bacillus worldwide is estimated to be 1.7 billion, of which
1.3 billion live in developing countries. The annual
incidence of new cases of all forms of tuberculosis
(pulmonary and extrapulmonary) worldwide is estima-
ted to be about 8 million, of which about 95 percent live
in developing countries. The total number of tuberculosis
cases at a given time worldwide is 16 to 20 million, of
whom about 8 to 10 million are sputum smear-positive
and highly infectious. In India, more than 40 percent of
adults are infected with tuberculosis. Approximately 1.5
million cases are put on treatment every year and more
than 1000 persons die of tuberculosis everyday in India.
It has been realized that tuberculosis control measures,
if rightly applied with political and administrative
commitment, have the potential to become one of the
most cost-effective health control intervention.
In India the fight against tuberculosis can be
successfully carried out within the framework of
National Tuberculosis Program (NTP). This program is
part of general health plan of the country.
In a comprehensive review of the outcome measures
of the NTP by the World Bank, the World Health
Organization (WHO), and the Government of India
(GOI) in 1992, it was concluded that the desired results
of tuberculosis control were not being achieved and this
culminated in a revision of NTP strategy.
The revised strategy to control tuberculosis was pilot-
tested in 1993 in a population of 2.35 million, and then
extended to 13.85 million populations in 15 states/ Union
Territories (UTs) in the country. With this strategy in
these areas, and quality sputum microscopy, cure rates
doubled as compared to conventional treatment. Thus,
the Revised National Tuberculosis Control Program
(RNTCP) was born with the following salient features:
i. A goal of achieving a cure rate of 85 percent along
with efforts to enhance case finding in order to detect
at least 70 percent of the estimated cases of smear-
positive pulmonary tuberculosis.
ii. Involvement of non-governmental organisations
(NGOs), information, education, communication
and improved operational research.
Epidemiological Basis of TB Control Activities
A simple model of pathogenesis of tuberculosis given
below helps in better understanding, the epidemiological
basis of TB.

The major factors that determine the risk of becoming
exposed to the tubercle bacilli include number of
infectious cases in the community, duration of their
infectiousness and the number and nature of interactions
between a case and a susceptible contact per unit time of
infectiousness.
The Revised National TB Control Program
After 1992, despite the National Tuberculosis Control
Program (NTCP) which was in existence since 1962, there
was no appreciable change in the epidemiological
situation in the country.
HIV/AIDS epidemic and the spread of multidrug
resistant TB (MDR-TB) were threatening to further
worsen the situation in India too, due to infection with a
new resistant strain (XDR).
In the light of recommendations and concern
expressed by the Central Health Council, steps were
taken since 1993 to improve the Revised National
Tuberculosis Control Program (RNTCP). In selected
areas with World Bank assistance, RNTCP adopted the
internationally recommended directly observed therapy
short-course (DOTS strategy), an acronym for direct
observed therapy, short-course. On March 24, 1997, the
Director General of the World Health Organization
declared that “The DOTS strategy represents the most
important public health breakthough of the decade, in
terms of lives which will be saved. In the revised
strategy, although passive case finding has replaced
active case finding, the responsibility of cure for the
patient has shifted from the patient to the health system.
DOTS is essentially a community-based systematic
strategy which ensures free of cost tuberculosis
treatment and cure, and has been acknowledged as a
breakthrough in our quest to “stop tuberculosis”.
RNTCP was started on a pilot basis for coverage of 18
million population. High treatment success rate was
observed. A rapid expansion of program began in 1998.
About 775 million population of country has been
covered till 2003. Remaining coverage was planned by
2005. Cure and completion rates of tuberculosis in
children have been above 90 percent under RNTCP, in
contrast to 80 and 70 percent for those outside the
program and 70 percent where the default rates lie
between 21 to 33 percent.
The five fundamental principles of the WHO
recommended DOTS strategies are:
Immunization and Infectious Diseases 343
i. Effective Political and Administrative Commitment:
Since tuberculosis is the leading infectious cause of
death among adults, which can be cured and the
epidemic reversed to topmost priority, which has
been accorded by the Government of India, must
be continued and expanded at state, district, and
local levels.
ii. Good Quality Diagnosis: Here the case finding is done
primarily by microscopic examination of sputum of
patients attending the health facilities with cough
of 3 weeks duration or more with sputum micro-
scopy using binocular microscopy and quality
reagents. All the microscopists of the designated
microscopy center are extensively trained. The
system also ensures multitier cross-checking and
quality assurance of sputum smear examination.
iii. Good Quality Drugs: This includes regular and
uninterrupted supply of drugs, the drugs being
supplied by the manufacturers to the project sites,
in boxes earmarked for each category of patient,
along with sufficient buffer stocks ensured.
iv. Short-course Chemotherapy given in a Program of DOTS:
This program uses the best anti-TB medications
available. However, unless treatment is taken by
patients, it will fail. This is why, the heart of the
DOTS program is directly observed treatment, in
which a health worker or other trained person, who
is not a family member watches as patient swallows
the anti-TB medicine in their presence. With short-
course it is easier to prevent drug resistance by using
directly observed treatment, and achieve high cure
rates.
v. Systemic Monitoring and Accountability: The cure rate
and other key indicators are monitored at every level
of the health system to identify areas requiring
intensified supervision. The outcome of the
treatment is systematically recorded at every level
of health system. If any area is not achieving
90 percent sputum conversion rate at the end of
3 months, and 85 percent cure rate, supervision is
intensified.
Another objective of the RNTCP is 70 percent
detection of new sputum smear-positive cases. However,
the target for case detection should only be attempted if
cure rate of already detected patients is more than
85 percent. One should remember to increase the cure rate
before attempting to achieve case detections target.
344 IAP Textbook of Pediatrics
Structure of the Revised National Tuberculosis
Control Program
The RNTCP has a central division, state, district and sub-
district levels, and health units. An additional structure
of the RNTCP is the district tuberculosis control society
(DTCS). DTCS is responsible for monitoring the program
implementation, arranging necessary logistics such as
transport and procuring materials such as laboratory
consumables.
In order to implement the RNTCP, the state tuber-
culosis headquarters and the state tuberculosis training
and demonstration center are being strengthened. In
addition, tuberculosis units are being established at the
sub-district level, covering a population of approximately
5 lakh. Each tuberculosis unit includes newly created
posts of one senior tuberculosis laboratory supervisor
(STLS). A designated medical officer-tuberculosis control
(MO-TC) is made responsible for all the program
activities at the tuberculosis units level.
Consensus Guidelines of Diagnosis and
Management of Tuberculosis in Children
Before the RNTCP, the national program lacked specific
guidelines for the management of children below 5 years
of age and the emphasis steered towards children in the
age group between 5 to 15 years.
In spite of the inherent difficulties in studying the
epidemiology of tuberculosis in children, because of
nonavailability of sputum, it must be emphasized that
pulmonary primary complex must be diagnosed at the
earliest, irrespective of the BCG status so as to prevent
hematogenous dissemination and its serious life-
threatening manifestation like miliary tuberculosis and
tuberculous meningitis in infants and young children and
cavitatory disease in the adolescent groups.
Preventive Therapy
Asymptomatic children under 6 years of age exposed to
an adult with infectious (smear-positive) tuberculosis
should be given isoniazid (5 mg/kg) for 6 months.
Management of Pediatric TB under RNTCP
Childhood TB is a reflection of the prevalence of sputum
smear-positive pulmonary tuberculosis (PTB) and the
extent of TB infection in the community. Children suffer
from more serious forms of TB and are more likely to die
if not treated properly and in time. It is estimated2 that
globally about 1.5 million new cases of TB occur and
130,000 children die annually due to TB. Due to
difficulties in diagnosis of pediatric TB under field
conditions, reliable data on disease incidence and
prevalence is not available.
Even young children are often found to be AFB smear-
positive. Although most pediatric tuberculosis cases are
smear-negative, it is always recommended to obtain three
sputum samples. A positive-smear establishes a firm
diagnosis and is an objective finding to be monitored
during treatment.
In the revised strategy, specific guidelines have been
laid down for the management of tuberculosis in children
and for the childhood contacts of sputum positive
patients.
Diagnosis
Suspected cases of pulmonary tuberculosis shall include
children having fever and or cough for more than
3 weeks, with or without weight loss or no weight gain,
and history of contact with a suspected or a diagnosed
case of active tuberculosis within last 2 years. Children
showing neurological symptoms like irritability, refusal
to feed, headache, vomiting or altered sensorium may
be suspected to have tuberculous meningitis.
The diagnosis of tuberculosis in a child should be
based on continuation of clinical presentation, sputum
examination (whenever possible) chest X-ray (PA view),
Mantoux test with 1TU PPD (RT23, with Tween 80,
positive if induration > 10 mm after 48-72 hours) and
history of contact. PPD would be supplied by CTD to
district headquarters. However, still 5TU (0.1 ml) of PPD
is being used. Existing RNTCP case definitions will be
used for all cases diagnosed. Use of currently available
scoring systems is not recommended for diagnosis of
tuberculosis in children.
Where diagnostic difficulties are faced, the child
should be referred to a pediatrician for further manage-
ment.
The diagnosis of tuberculosis in children rests largely
on the clinical history, contact history, X-ray chest
evaluation, and the tuberculin test. While the tuberculin
test is helpful in evaluating for tuberculosis in children,
a positive test does not confirm disease and a negative
test does not rule it out. Children (especially below
5 years of age) usually can not expectorate sputum to
 Immunization and Infectious Diseases 345

Figure 9.11.1.1: Diagnostic algorithm for pediatric pulmonary TB

allow a definite diagnosis until they are old enough.
Therefore, the RNTCP recommends that evaluation
of child contacts of sputum positive cases should be
done in consultation of a pediatrician to rule out active
disease and to decide chemoprophyaxis (Fig. 9.11.1.1).
Treatment of Tuberculosis in Children
DOTS is a recommended strategy for treatment of
tuberculosis and all pediatric tuberculosis patients should
be registered under RNTCP. Intermittent short-course
chemotherapy given under direct observation as
346 IAP Textbook of Pediatrics

advocated in the RNTCP, should be used in children. To TABLE 9.11.1.3: Suggested pediatric dosages for
assist in calculating required dosage and administration intermittent therapy
of antituberculosis drugs in children medication should
Drugs Therapy per dose
be made available in the form of combipacks in patients- (Thrice a week)
wise boxes linked to child’s weight (Tables 9.11.1.1 and (mg/kg)
9.11.1.2).
Isoniazid 10-15

TABLE 9.11.1.1: The new formulations Rifampicin 10

to be used in RNTCP Pyrazinamide 30-35

• Rifampicin 75/150 mg Streptomycin 15

• Isoniazid 75/150 mg Ethambutol 30
• Ethambutol 200/400 mg
• Pyrazinamide 250/500 mg
In patients with TBM on category I treatment, the four
drugs used during the intensive phase should be HRZS
TABLE 9.11.1.2: The pediatric population is divided into (instead of HRZE). Continuation phase of treatment in
four weight bands for purpose of treatment
TBM and spinal TB with neurological complications
• 6-10 kgs should be given for 6-7 months, thus extending the total
• 11-17 kgs duration of treatment to 8-9 months. Steroids should be
• 18-25 kgs
• 26-30 kgs used initially in hospitalized cases of TBM and TB
pericarditis and reduced gradually over 6-8 weeks. In
To assist in calculating dosages and administration all instances, before starting a child on Category II
of anti-TB drugs for children, the medication would be treatment, she/he should be examined by a Pediatrician
made available in the form of patient wise-boxes, linked or TB expert, wherever available.
to the child’s weight. The recommended dosages for As recommended by WHO, and in view of the
children, in mg/kg, are given in Table 9.11.1.3. growing evidence that the use of ethambutol in young
Treatment is given according to categories. These children is safe, ethmbutol is to be used as per RNTCP
categories must be strictly adhered to (Table 9.11.1.4). regimen for all age groups.

TABLE 9.11.1.4: RNTCP treatment categories and regimens for children

Treatment category Type of patients Treatment regimen**

IP CP

Category I New sputum smear-positive PTB 2H3R3Z3E3*** 4H3R3

New Sputum smear-negative PTB,
seriously ill*
New extra-PTB, seriously ill*

Category II Sputum smear-positive relapse 2H3R3Z3E3S3 + 5H3R3E3

Sputum smear-positive treatment failure 1H3R3Z3E3
Sputum smear-positive treatment after default

Category III New sputum smear-negative, not seriously ill** 2H3R3Z3 4H3R3
New extra-PTB, not seriously ill**

*In children, seriously ill sputum smear negative PTB includes all forms of sputum smear-negative PTB other than primary complex.
Seriously ill EPTB includes TB meningitis (TBM), disseminated TB, TB pericarditis, TB peritonitis and intestinal TB, bilateral
extensive pleurisly, spinal TB with or without neurological complications, genito-urinary TB, and bone and joint TB.
**Not seriously ill sputum smear negative PTB includes primary complex. Not seriously ill EPTB includes lymph node TB and
unilateral pleural effusion.
***Prefix indicates month and subscript indicates thrice weekly.

DETAILED DESCRIPTION OF TREATMENT
IN EACH CATEGORY
Category I
New cases who are sputum smear-positive, or seriously
ill-patients with smear-negative or extra-pulmonary
disease.
Treatment
In category I the treatment is given in two phases. The
first phase is intensive phase and consists of isoniazid,
rifampicin, pyrazinamide and ethambutol given under
direct observation thrice a week on alternate days and
lasts for 2 months. This is immediately followed by the
second phase, i.e. continuation phase, which consists of 4
months of isoniazid and rifampicin given thrice a week
on alternate days, the first dose every week being directly
observed. If the sputum smear is positive after 2 months
of treatment, the 4 intensive phase drugs are continued
for another 1 month before starting the 4-months
continuation phase. If the sputum smear is positive after
5 or more months of treatment, the patient is declared as
a failure and is placed on CAT II treatment afresh.
In patients with TBM on category I treatment, 4 drugs
used during intensive phase should be HRZS (instead
of HRZE). Continuation phase of treatment in TBM and
spinal tuberculosis with or without neurological
complications should be given for 6 to 7 months,
extending the total duration of treatment to 8 to 9 months.
Steroids should be used initially in hospitalized cases of
TBM and tuberculous pericarditis and reduced gradually
over 6 to 8 weeks. In all instances before starting a child
on category II treatment, the child should be examined
by a pediatrician or tuberculosis expert.
Category II
Category II have retreatment cases including patients
with relapse, failure, treatment after default and
others. Such patients are generally sputum smear-
positive.
Treatment
Category II also, the treatment is given in two phases.
The intensive phase consists of two months of isoniazid,
rifampicin, pyrazinamide, ethambutol and streptomycin
all given under direct observation thrice a week on
Immunization and Infectious Diseases 347
alternate days, followed by one month of isoniazid,
rifampicin, pyrazinamide and ethambutol, all given
under direct observation thrice a week on alternate days.
This is immediately followed by the continuation phase,
which consists of 5 months of isoniazid, rifampicin, and
ethambutol given thrice a week on alternate days. The
first dose of every week being directly observed part of
therapy. If the sputum smear is positive after 3 months
of treatment, the 4 oral intensive phase drugs are
continued for another one month before starting the
5 months continuation phase.
Category III
Caterogy III includes patients who are smear negative
or who have extrapulmonary TB and are not
seriously ill.
Treatment
In category III also, the treatment is given in two phases.
The intensive phase consists of isoniazid, rifampicin, and
pyrazinamide given under direct observation thrice a
week on alternate days and lasts for 2 months. This is
immediately followed by the continuation phase, which
consists of 4 months of isoniazid and rifampicin given
thrice a week on alternate days, the first dose of every
week being directly observed. If the sputum smear is
positive after 2 months of starting the treatment, the
patient is considered a treatment failure and begun afresh
on category II treatment.
Children are rarely sputum smear-positive and thus
generally receive category III treatment. Ethambutol
should not be given to children who are too young to
report reduced vision or have their visual acuity assessed.
Monitoring and Evaluation
Pediatric focused monitoring should be an integral part
of program. As much as possible, follow-up sputum
examination is to be performed at same frequency as in
adults. Clinical/asymptomatic improvement should be
at the end of intensive phase and also at the end of
continuation phase of treatment. Improvement should
be judged by absence of fever or cough, a decrease in
size of lymph nodes and weight gain. Radiological
improvement needs to be assessed by chest X-ray
examination in all smear-negative pulmonary tuber-
culosis cases at the end treatment (Fig. 9.11.1.2).
348 IAP Textbook of Pediatrics
Figure 9.11.1.2: Clinical monitoring
• DOTS is the recommended strategy for
treatment in adults as well as children
• All pediatric TB patients should be registered
under RNTCP.
Chemoprophylaxis
Recent infection with tubercle bacilli is one of the risk
factors for disease development. The younger the child,
the higher is the risk of breakdown of infection into
disease. Therefore, child contacts of smear-positive TB
cases, especially those below 6 years of age, must be
screened for symptoms of tuberculosis. In case of
symptoms being present, the diagnostic algorithm of
pediatric TB should be followed and the child should be
given a full course of anti TB treatment if she is diagnosed
as a TB case. For asymptomatic children and those who
are not found to be suffering from TB, chemoprophylaxis
with isoniazid (5 mg per kg body wt) should be adminis-
tered daily for a period of six months. This is regardless
of the BCG vaccination status.
To ensure that proper preventive chemotherapy is
given to children, enquire (or have the health workers
enquire) from all smear positive tuberculosis patients
under treatment, if they have children under 6 years of
age. Explain to them how children can acquire the
infection which may later develop into tuberculosis.
Make sure that the children are brought to a health unit
for screening.
The DOTS strategy has been rightly accorded the
highest priority in the current WHO promoted “Stop TB”
campaign since in the present era of multi-drug resistant
tuberculosis (MDR-TB) and the HIV/AIDS, DOTS has
been shown to prevent the emergence of MDR-TB as well
as cure tuberculosis in a HIV reactive patient.

Children have also been identified as a high-risk
group. The administration of BCG as an essential
component of the universal program of immunization
to all newborns and infants up to 9 months of age is
important. Compulsory childhood contact survey
(especially below 5 years of age) of an adult infectious
case must also be made a reality in addition to the use of
standard treatment and preventive therapy protocol.
Finally, tuberculin surveys of children below 5 years of
age must be undertaken, to observe the changing
epidemiology from time to time.
LACUNAE IN THE MANAGEMENT OF PEDIATRIC
TUBERCULOSIS IN RNTCP
Diagnosis
The emphasis being made in diagnosis as follows:
Primary health center (PHC) by a health worker, atleast
an Anganwadi worker of ICDS or auxillary nurse
midwife based on presentation of symptoms in a child
and ideally by doing the clinical evaluation of all children
at least below 6 years in a family having a sputum-
positive adult in the household.
It is very important particularly when the malnutri-
tion is still rampant in India and there is added exposure
of children to HIV and AIDS infection, which signifi-
cantly compromise the immune system of the child
leading to the danger of occurrence of severe degree of
disease with rapid progression due to limitations in the
use of available drugs.
2ND TIER
District Hospital
In the district hospital facilities should be available for
mantoux testing and chest X-ray. However, these
facilities are not freely available. It is unlikely even now
Immunization and Infectious Diseases 349
to readily procure tuberculin for readily testing of
mantoux test because Guindy Laboratory Chennai does
not have Copenhagen strain of bacillus for making
tuberculin.
In medical colleges, pediatricians in practice and other
doctors taking care of children are using 5TU of PPD
available privately. In the presence of threat of HIV-AIDS,
MDR-TB and already existing malnutrition of various
grades (particularly severe), it is quite pragmatic to use
this PPD. Seemingly there is no harm to use it in the
program, till the Ministry of Health, Government of India
is able to procure PPD for the program.
ACKNOWLEDGEMENTS
The guidelines for management of pediatric tuberculosis
under Revised National Tuberculosis Control Program,
(RNTCP) in India were developed during the national
workshop arranged at LRS Institute of Tuberculosis and
Respiratory Diseases, New Delhi on 6th and 7th Aug,
2003, which was attended by renowned pediatricians
from Indian Academy of Pediatrics (IAP), TB experts,
TB control program managers from central TB Division,
Directorate General of Health Services, Ministry of
Health and Family Welfare and representative from
WHO. The tables and figures in this chapter are
reproduced from the recommendations from the
guidelines for the management of tuberculosis in
pediatrics under RNTCP.
BIBLIOGRAPHY
1. Chauhan IS, Arora VK. Management of pediatric
tuberculosis under the revised national tuberculosis
control program (Meeting held on 6th and 7th August,
2003) Consensus Statement. Indian J Pediatr 2004;71:
341-3.
2. Seth Vimlesh, Khosla PK, Semwal OP, et al. Visual
evoked response in tuberculosis children on ethambutol
treatment. Indian Pediatric 1991;28:713-7.
350 IAP Textbook of Pediatrics
9.12 Poliomyelitis
Etiology
The poliovirus is an enterovirus. There are three sero-
types: 1, 2 and 3. All three can cause paralysis, although
type 1 causes paralysis most often, type 3 less frequently,
and type 2 rarely. Most epidemics are due to type 1. Cases
of paralysis associated with the vaccine are usually
caused by types 3 and 2. As immunization coverage levels
increase and the incidence of poliomyelitis drops, type 2
is the first serotype to disappear.
Epidemiology
The most common route of transmission is fecal-oral.
Close contacts can also be potentially infected through
pharyngeal secreations. One week after the onset, little
virus remains in the throat but continues to be excreted
in stools for up to 6 to 8 weeks. Cases are most infectious
during the first few days, before and after the onset of
symptoms.
Man is the only reservoir of infection. A long-term
carrier state is not knwon to occur. The half-life of
excreted virus in the sewage in warm climate is only 48
hours and spread of infection through sewage can occur
only during this period. However, given the large
number of inapparent infections, the wild virus can
potentially spread far and wide very quickly, if there is
high population mobility in the districs and states.
The incubation period from exposure to the virus, till
the onset of symptoms is usually 7 to 10 days (range of
4-30 days). The initial illness is followed by a few days
which are relatively free of symptoms before the onset
of paralysis. Fever is present at the time of onset.
Poliomyelitis has a marked seasonal increase from
May to September, with a peak in July-August. The
intensity of the peak has fallen and in areas of low
incidence, polio cases are seen as sporadic cases which
occur at anytime during the year. In the states which have
successfully implemented the pulse polio immunization
such a pattern of sporadic incidence could be expected.
Clinical Manifestations
Typically, a minor prodromal illness lasts several days,
with fever, sore throat, anorexia, and occasionally nausea,
Ashok K Gupta
vomiting, and diarrhea. If the later stages of the disease
do not develop, this minor illness is known as abortive
poliomyelitis, which cannot be diagnosed by clinical
criteria alone. With or without a few days of wellbeing,
there follows abrupt onset of major neurological illness.
The patient is anxious, irritable, often sweating, with
fever around 38 to 39°C headache, stiffness, and pain in
the neck, trunk, and limbs. Nuchal rigidity and a positive
Kernig’ sign are present. In about one-third of patients
that reach this stage, the condition resolves in about a
week and is then known as nonparalytic poliomyelitis
that is, aseptic meningitis due to poliovirus. The
remainder progress rapidly to paralysis, which may be
preceded by pain and fasciculations in the muscles to be
affected. Paralysis usually appears during the fever,
rarely afterward, and may be the first sign of polio-
myelitis in infants or very young children. It may evolve
rapidly or progress gradually over a week or so. The
pattern of paralysis is variable, typically asymmetrical,
and usually affects the lower limbs more seriously than
other muscles. Bulbar and encephalitic signs may appear.
The paralysis is of lower motorneurone type, flaccid with
absent tendon reflexes. It tends to be more severe,
extensive and possibly progressive, if there was
strenuous physical exercise in the incubation period.
Paralysis may be more severe or localized in a traumati-
zed area, for example, following irritating vaccine
injection, provocation poliomyelitis or recent tonsillec-
tomy, which may provoke severe bulbar paralysis.
Paralysis classically presents as follows.
Spinal Form
Muscles innervated by spinal nerves are affected by
paralysis, often preceded by diminution or loss of deep
reflexes a few hours before weakness is detectable.
Paralysis is more widespread in early stages because
many temporarily injured anterior horn cells may recover
function. Some muscle groups usually escape serious
damage and slow functional recovery can progress over
many weeks or months. Most commonly affected, in
order of frequency are:
In the lower limb
• Quadriceps

• Tibialis anterior
• Peroneal muscle
In the upper limb
• Deltoid
• Biceps
• Triceps
In the trunk
• Abdominal muscles
• Back
• Intercostals
• Diaphragm
Respiratory paralysis can cause life-threatening
impairment of ventilation, commonly associated with
involvement of shoulder muscles.
Bulbar Form
This most severe and dangerous form of poliomyelitis
results from damage in the brainstem, particularly the
medulla. Any case of poliomyelitis with usually rapid
and stormy onset and development, drowsiness or
marked apprehension, should be watched for signs of
medullary involvement, which require intensive medical
care; rarely it may progress rapidly to death despite
therapy. The main patterns are as follows:
1. Cranial nerve nuclei involved:
a. III to VII nerve nuclei, with good prognosis and
recovery usual.
b. IX to XII nerve nuclei, with difficulties in
swallowing and clearing the pharynx, where
pooled saliva and mucus can obstruct airways or
be inhaled. Airway clearance and maintenance of
ventilation are essential to preserve life.
2. Respiratory center impaired: Irregularities of rate and
rhythm of breathing may lead to respiratory failure
and sudden collapse.
3. Circulatory center impaired: Hypertension or peripheral
circulatory failure can occur, sometimes with
hyperpyrexia.
Multiple neurological signs may coincide with
hypoxia and hypercapnia from ventilatory dysfunction
and death with acute myocarditis. Encephalitic forms of
poliomyelitis are often combined with bulbar or
bulbospinal features.
In preparalytic and paralytic stages the cerebrospinal
fluid is usually clear, rarely hazy, with increased cells
(10-500/mm3), predominantly lymphocytic. The cell
count is maximal in the preparalytic stage, when
Immunization and Infectious Diseases 351
polymorphs transiently predominate. A raised protein
level persists for some time after the cell count has
reverted to normal, an example of “albumino-cytological
dissociation” to be distinguished from the Guillain-Barre
syndrome.
Clinical Management
For the abortive form, simple analgesics, sedatives, an
attractive diet, and bedrest until the child’s temperature
is normal for several days, suffice. Avoidance of exertion
for the ensuing 2 weeks is desirable, and there should be
a careful neuromusculoskeletal examination 2 months
later, to detect any minor involvement.
Treatment for the nonparalytic form is similar to that
for the abortive form, relief being indicated in particular
for the discomfort of muscle tightness and spasm of the
neck, trunk, and extremities. Analgesics are more
effective when combined with the application of hot
packs for 15-30 minutes every 2-4 hours. Hot tub baths
are sometimes useful. A firm bed is desirable and can be
improvized at home by placing table leaves or a sheet of
plywood beneath the mattress. A footboard should be
used to keep the feet at right angle with the legs. Muscular
discomfort and spasm may continue for some weeks,
even in the nonparalytic form, necessitating hot packs
and gentle physical therapy. Such patients should also
be carefully examined 2 months after apparent recovery
to detect minor residuals that might cause postural
problems in later years.
Management of paralytic poliomyelitis and other
cases of acute flaccid paralysis in the acute phase is
symptomatic. The child needs rest and care to ensure
that there is no stress on the affected muscles. Care is
also required to see that the child does not get secondary
infections. Massage and injections during this period are
contraindicated.
Uncomplicated cases of single lower limb or both
lower limbs and trunk involvement can be treated at
home. However, if poliomyelitis is suspected, such
children should be examined by a physician as early as
possible, to confirm diagnosis, rule out “high-risk”
factors, such as early respiratory involvement and for
proper advice to parents on the care of the child at home.
Treatment of the Acute Phase of Paralytic
Poliomyelitis (Table 9.12.1)
• Complete bedrest
• Correct positioning of affected limb(s)
352 IAP Textbook of Pediatrics

TABLE 9.12.1: Differential diagnosis of paralytic poliomyelitis

Signs and symptoms Polio GBS Transverse myelitis Traumatic neuritis

Progression of paralysis < 4 days, maximum 7 From hours to 20 days From hours to 4 days From hours to 4 days
Fever onset Present Absent Absent Variable
Flaccidity Acute, asymmetrical, Acute, symmetrical, Acute, lower limbs, Acute, asymmetrical,
proximal distal symmetrical one limb
Muscle tone Diminished Diminished Diminished in Diminished in limb
lower limbs
DTRs Decreased or absent Absent Absent in lower limbs Decreased or absent
Sensation Severe myalgia and Cramps, tingling, Anesthesia of lower Pain in gluteal region
backache hyperesthesia limbs
Cranial nerve Only when bulbar and Often present Absent Absent
bulbospinal
Decreased respirations Only when bulbar and In severe cases Absent Absent
bulbospinal
CSF: WBCs High WBCs < 10 WBCs Normal Normal
Protein Normal of slightly Normal or slightly Normal
increased elevated
Bladder dysfunction Transient retention Sometimes Present Absent
Conduction velocity Normal, then slightly Abnormal, demyelination Normal Abnormal in sciatic
3 weeks decreased nerve
EMG-3 weeks Abnormal Normal Normal Normal
Sequelae Severe, asymmetrical Absent or minimal Moderate atrophy Peroneal atrophy
atrophy

• Passive movements of the joints
• Warm water fomentation
• Symptomatic treatment for fever and pain
• No massage or intramuscular injections
• Report immediately, if there is progression of
paralysis.
Complete bedrest is essential during the acute phase.
There should not be any stress on the muscles involved.
The mother or other persons caring for the child should
frequently change the posture of the child in bed, every
two to three hours. The child should be placed on the
stomach for short periods each day, to avoid the risk of
pneumonia.
The limb should be placed in the optimum position
for relaxation of the paralyzed muslces. The affected
limbs can be positioned with pillows or rolled towels.
The recommended positions are: hip-slight flexion; knee-
5 degress flexion; foot-90 degress support against the sole
of the foot. Place rolled towels to prevent external
rotation. Rolled towels should also be placed under the
knee for positioning of hips and knees. Joints and
paralyzed muslces should be moved passively gently
through full range of motion of prevent contractures.
Such movements should be done for 10 minutes, two to
three times a day. The movements should involve all
joints of the affected limb. The movement should be
within the range of pain. Fomentation using hot packs
with soaked towels wrapped around the affected parts
for 10 minutes, two to three times, daily, should be started
as soon as possible, and continued up to six weeks after
onset of paralysis.
There should be no restriction on diet and normal
food may be given to the child, if she/he accepts.
Children may experience constipation during this period.
Transient urine retention may be noted which may be
relieved by alternate hot and cold compresses over the
suprapubic region. However, if constipation lasts for 3
days or if there is no urine for 24 hours, such children
should be immediately brought to a hospital.
In 2 to 20 percent of the cases, the outcome may be
fatal due to involvement of muscles affecting vital
functions, especially respiration. If the child shows any

respiratory distress; if the paralysis is progressing and
cases of upper limb involvement in the first week of
illness should preferably be hospitalized. Indications for
referral to the hospital are listed below.
Indications for Hospitalization
• Progression of paralysis
• Respiratory distress
• Bulbar involvement
• Paralysis of upper limbs of < 3 days
• Marked drowsiness
• Other complications.
As the acute phase of illness subsides and recovery
of strength begins, the emphasis shifts to active rather
than passive movements and a vigorous program of
physical therapy is initiated to regain muscle power.
Management of the recovery phase begins with a careful
assessment and recording of muscle power of the sick
muscle groups to serve as a baseline. The degree of
recovery ranges from minimal to complete. Maximum
recovery of the affected muscles takes place in the first
six months, but slow recovery continues up to two years.
Physical therapy is necessary to prevent deformities and
contractures due to muscle imbalance or improper
posture. Physical therapy under a qualified physiothera-
pist is important for regaining muscle power and
rehabilitation of the child.
Complications
Paralytic Poliomyelitis
It may result from single or multiple superficial intestinal
erosions; perforation is rare. Acute gastric dilatation may
occur abruptly during the acute or convalescent stage,
causing further embarrassment of respiration; immediate
gastric aspiration and external applications of ice bags
are indicated. Mild hypertension of a few days’ or weeks’
duration is common in the acute stage, probably related
to lesions of the vasoregulatory centers in the medulla
and especially to underventilation. In the later stages,
because of immobilization, hypertension may occur
along with hypercalcemia, nephrocalcinosis, and
vascular lesions. Dimness of vision, headache, and a
light-headed feeling in association with hypertension,
should be regarded as premonitory of a frank convulsion.
Cardiac irregularities are uncommon, but electro-
cardiographic abnormalities suggesting myocarditis are
Immunization and Infectious Diseases 353
not rare. Acute pulmonary edema occurs accasionally,
particularly in patients with arterial hyper hypertension.
Pulmonary embolism is uncommon despite the immobi-
lization and results in hypercalciuria, which in turn
predisposes to calculi, especially when urinary stasis and
infection are present. A high fluid intake is the only
effective prophylactic measure. The patient shoud be
mobilized as much and as early as possible.
Virus Isolation
Stool specimen culture for purposes of isolation of wild
poliovirus is by far the best diagnostic test. Virus usually
can be found in the faeces from 72 hours prior to onset of
paralysis and up to 6 weeks or more after infection, with
the highest probability of virus isolation during the first
2 weeks, after onset of paralysis.
Strategies for Polio Eradication
Simultaneous administration of OPV to all suspectable
infants and children interferes with the circulation of wild
polio virus in the community. It is therefore important
to ensure complete coverage with OPV during National
Immunization days so that no wild polio virus remains
in the circulation in the environment.
Polio eradication is defined as nil cases of paralytic
polio by wild polio virus in last 3 calendar years along
with absence of wild polio virus in the community, when
excellent clinical and virological surveillance exists and
the coverage of routine OPV is more than 80 percent.
Polio elimination is defined as nil cases of paralytic
poliomyelitis by wild polio virus in one calendar years
with other criteria being the same as in eradication.
• Conduct Pulse Polio Immunization days every year
for 3 to 4 years or until poliomyelitis is eradicated.
• Sustain high levels immunization coverage through
the routine delivery systems.
• Monitoring of OPV coverage at the district level.
• Improved surveillance capable of detecting all cases
of acute flaccid paralysis due to polio and nonpolio
etiology.
• Rapid case investigation, including the collection of
stool samples for virus isolation.
• Follow-up of all cases of acute flaccid paralysis, at 60
days to check for residual paralysis.
• Outbreak control for cases confirmed or suspected to
be poliomyelitis to stop transmission.
354 IAP Textbook of Pediatrics

9.12.1 DIFFERENTIAL DIAGNOSIS OF

ACUTE FLACCID PARALYSIS

AD Tewari
Acute flaccid paralysis (AFP) implies paralysis of acute
onset, i.e. less than 4 weeks and affected limb or limbs
are flaccid, i.e. floppy or limp. Tone is diminished as
evidenced by palpation or passive movement of joints.
Deep tendon reflexes are diminished or absent but
sensation is not affected.

Case Definition Figure 9.12.1.1: Virological AFB

A case of AFP is defined as any child aged less than 15
years who has acute onset of flaccid paralysis for which
no obvious cause (such as severe trauma or electrolyte
imbalances) is found, or paralytic illness in a person of
any age in which polio is suspected.
This is the definition taken for surveillance and
should be capable of detecting all cases of AFP due to
polio and non-polio etiology. All cases of AFP, regard-
less of age should be reported and investigated as
poliomyelitis. Occasionally, poliomyelitis may occur in
older children, therefore, AFP surveillance must focus
on children aged less than 15 years. A high sensitivity of
AFP reporting will ensure that all cases of paralytic Figure 9.12.1.2: Clinical AFB
poliomyelitis are detected, reported and investigated,
resulting in preventive control measures to interrupt If AFP rates reported are less than the calculated
transmission of disease. figures, then this would suggest that surveillance is not
Experience in other parts of world indicates that at sensitive to detect all cases of paralytic poliomyelitis, thus
least 1 case of AFP occurs per year for every 100,000 providing regular monitoring of the system.
population of children aged less than 15 years. This is
referred to as background rate of AFP among children and Classification of AFP—Polio vs Non-polio
is accounted for by non-polio causes of AFP, such as
Guillain-Barré syndrome, transverse myelitis, traumatic All AFP cases should be classified as polio or non-polio
neuritis, etc. regardless of whether acute poliomyelitis based on isolation of virus in the stool specimens (Fig.
exists in the community. 9.12.1.1). But for implementing AFP surveillance, a
Based on the estimated populations of children aged clinical classification as indicated below must be used so
less than 15 years, the number of expected AFP cases that true epidemiologic data are collected (Fig. 9.12.1.2).
that should be detected and reported in each state, For this purpose, main causes of AFP include
regardless of whether polio is endemic should be poliomyelitis, Guillain-Barré syndrome, transverse
calculated. myelitis, and traumatic neuritis. They are to be taken into
The goal of AFP surveillance in India is to have all account first, and then, followed by other causes of
paralysis.
states reporting AFP rates of at least 1 case per year per
100,000 population of children aged less than 15 years. Causes of AFP The main causes and differential
This would ensure adequacy of surveillance. diagnosis of AFP are depicted in Table 9.12.1.1.
 Immunization and Infectious Diseases 355

TABLE 9.12.1.1: The main causes and differential diagnosis of AFP

Polio GBS Traumatic neuritis Transverse myelitis

Etiology Polio virus type I, II Likely delayed Trauma Usually unknown;

and III and other hypersensitivity- multiple viruses
enteroviruses immunologic
Onset of 24 to 48 hours Few hours to ten Few hours to four Few hours to four
paralysis days days days
Fever at onset High. Always Not common Commonly present Rarely present
present at onset of before, during and
flaccid paralysis, after flaccid paralysis
disappears later
Flaccid paralysis Acute, asymmetrical, Generally acute, Asymmetrical, acute, Acute, symmetrical,
principally proximal symmetrical and distal and affecting only one usually involving lower
limb limbs
Muscle tone Reduced or absent in Global hypotonia Reduced or absent in Hypotonia in lower
the affected limb the affected limb limbs
Deep tendon Decreased or absent Globally absent Decreased to absent Absent in lower limbs
reflexes early, hyper-reflexia late
Sensation Severe myalgia, Cramps, tingling, Pain in gluteus, Anesthesia of lower
backache hypoesthesia of hypothermia limbs with sensory level
palms and soles
Cranial nerve Only when bulbar/ Often present, Absent Absent
involvement bulbospinal Miller-Fisher
involvement is syndrome
present
Respiratory Only when bulbar/ In severe cases Absent Absent
insufficiency bulbospinal
involvement is
present
Autonomic signs Dysautonomia Frequent blood pressure Rare Hypothermia in
and symptoms alterations, sweating, affected limb
blushing and body
temperature fluctuations
CSF: WBCs High WBCs less than 10 WBCs Normal Normal
Protein Normal or slightly High Normal Normal or slightly
elevated elevated
Bladder Absent Transient Never Present
dysfunction
Nerve conduction Anterior horn cell Abnormal demyelination Abnormal, suggestive Normal or abnormal.
values at third week disease (normal during of axonal damage No diagnostic value
the first two weeks)
EMG at three Abnormal Normal, depending Normal, depending Normal
weeks upon recovery upon recovery
Sequelae at Severe, asymmetrical Symmetrical atrophy Moderate atrophy, only Flaccid diplegia,
three months, atrophy, skeletal of distal muscles in affected lower limb atrophy after years
and up to a year deformities
developing later

Source: Adapted from Field Guide, Ministry of Health and Family Welfare, New Delhi
356 IAP Textbook of Pediatrics
Paralytic Poliomyelitis
Refer to Page 352 Ch 9.12, Table 9.12.1.
Guillain-Barré Syndrome
Refer to Page 352 Ch 9.12, Table 9.12.1.
Transverse Myelitis
Refer to Page 352 Ch 9.12, Table 9.12.1.
Traumatic Neuritis
Refer to Page 352 Ch 9.12, Table 9.12.1.
It is caused by injury to sciatic nerve by injection in
gluteal region, leading to paralysis of lower extremity.
Injection is given for the preexisting febrile illness.
Paralysis is acute and onset occurs within hour to
5 days usually accompanied by pain. Muscle tone is
reduced or absent in the affected limb. Power at hip and
knee is normal. Child walks with footdrop. Knee jerk is
present, but ankle jerk is absent or diminished. Pain
sensation in gluteal region or along with the affected leg
can be diminished. Atrophy may appear 40 to 60 days
later. CSF examination is normal. Electromyography is
abnormal after 3 weeks. Management is rehabilitation,
surgical if indicated.
Prognosis
Atrophy does not reach the same degree as seen in polio.
Differences in calf circumference usually do not exceed
0.15 to 1.5 cm. Child gradually recovers with physio-
therapy in 3 to 9 months.
Other Differential Diagnosis
Non-Polio Enteroviruses
• Non-polio enteroviruses are known to cause AFP.
They are coxsackie A virus, coxsackie B virus and
Echo virus, enteroviruses types 70 and 71, and
mumps. Complete recovery occurs in most of the
cases. In some cases, sequelae may resemble para-
lysis caused by wild poliovirus.
Hypokalemia
• History of diarrhea and vomiting for few days prior
to onset of paralysis.
• Toxic, irritable.
• Weakness affects the limbs first, followed by trunk
and respiratory muscles.
• Neckdrop is a usual feature.
• Death occurs due to respiratory muscle failure and
cardiac arrest.
• Treatment—Intravenous potassium.
Peripheral Neuropathies
They are caused by:
• Drugs
• Metabolic defects (diabetes)
• Toxins (lipid solvents and fish toxins)
• Organophosphate pesticides
• Heavy metals (lead)
• Hereditary disease (Charcot-Marie-Tooth)
• Postdiphtheritic paralysis.
Pseudoparalysis
Nonspecific toxic synovitis
• Low-grade fever for several days
• Unilateral limp
• Hip or knee joints are commonly affected
• Swelling of the joint, accompanied with painful
movements.
Scurvy
• Age group: 6 months to 2 years
• Gradual onset
• History of irritability, generalized tenderness
• Frog like position of legs, due to pain
• Spongy swelling of gums
• X-ray knee is characteristic (white line, pencil line
cortex, zone of degeneration).
Congenital Syphilitic Osteochondritis
• Found in early infancy.
• Osteochondritis is painful, causing pseudoparalysis.
• Diagnosis is by X-ray wrist, elbow, knee, ankle,
showing features of osteochondritis.
The differential diagnosis of AFP is quite extensive.
The clinical must be fully aware of other causes of AFP,
so that he neither misses the diagnosis nor he over
diagnoses polio. The importance of a 60 days follow-up
and stool for viral culture is a paramount.
SURVEILLANCE OF AFP (Fig. 9.12.1.3)
Surveillance means data collection for action. “Surveil-
lance is carried out for all cases of acute flaccid para-
lysis, not just for poliomyelitis”. The surveillance data

Figure 9.12.1.3: Sequence of action to be taken after detecting a case of AFP
collected and documented must support the principle
that, “if polio cases had occurred, they would have been
detected, reported and investigated in an expeditious
manner.” The surveillance is critical for achieving the
goal of polio eradication, which is defined as the absence
of clinical cases of poliomyelitis for at least 3 years and
the absence of detectable wild polio-viruses from
communities.
Stool Sample
Two stool specimens should be collected at an interval
of 24 to 48 hours apart and within 14 days of onset of
paralysis. However, when AFP cases are seen late (i.e.
greater than 2 weeks after paralysis onset/stool
specimen may be collected up to 60 days after onset of
paralysis).
The specimen should be placed in a clean container
such as wide mouth plastic or glass bottle with screw on
cap. It need not be autoclaved, but should be cleaned.
At least ‘one thumb sized’ 8 gm of stool is required.
Stool sample should be adequate and in good condition
accompanied by all details as required by laboratories
(the sample is to be sent to WHO accredited laboratories).
Immunization and Infectious Diseases 357
The Ministry of Health has sponsored the formation of a
network of laboratories some of which are located at:
• Sanjay Gandhi Postgraduate Institute, Lucknow
• National Institute of Communicable Diseases, New
Delhi
• ERC, Mumbai
• NIV, Bengaluru
• BJMC, Ahmedabad
• SI, Kolkata
• Enterovirus Research Institute, Kasauli
• Pasteur Institute of India, Coonoor
• King Institute of Preventive Medicine, Chennai and
others are being developed at various places.
Stool samples should be stored in the refrigerator or
any container that can maintain a temperature below 8ºC,
till they are reached to the laboratory. A vaccine carrier
with frozen ice packs is used for this purpose.
This vaccine carrier should never be used to trans-
port vaccine. Throughout transport, specimen must be
packed to maintain temperature below 8ºC.
Action
Once a case of AFP has been reported, the following
measures are to be taken:
358 IAP Textbook of Pediatrics
1. All reported cases should be investigated by District
Immunization Officer (DIO) as per the case
investigation form, within 48 hours after notification
by a reporting unit (Fig. 9.12.1.3). A reporting unit
means a center where paralytic cases are brought for
diagnosis, treatment or rehabilitation. The DIO
should send the copy to the state headquarter.
2. The District Immunization Officer should not wait
for laboratory result to conduct immunization. The
decision should be made on the spot, regardless of
whether the laboratory results are available or not.
The DIO should initiate appropriate action for
outbreak response immunization as and when
indicated.
3. The DIO must revisit every case of AFP 60 days after
the onset of paralysis, to confirm the presence or
absence of residual paralaysis. The minimum level
of residual weakness can usually be detected by the
measurements of arm or midthigh circumference as
well as by skinfolds on medial aspect of the thighs.
4. The DIO should take part in active surveillance by
regularly visiting the reporting units and private
practitioners. All health workers, Aanganwadi
workers, traditional birth attendants must be
encouraged to report AFP cases immediately to the
nearest primary health center. The medical officer
must in turn immediately inform the DIO.
5. To strengthen the surveillance system, a Surveillance
Medical Officer (SMO) has been appointed under the
National Polio Surveillance Project whose main task
is to supervise the work of polio related activities in
that district and to act in accordance with the
directions of project from time to time.
Besides medical college hospital, specialized
pediatric hospital, district hospital have been named
as reporting unit (RU). Very popular pediatrician and
quack are made informers. All health service
providers (to whom any of the AFP case have visited
in the past 2 years) are part of network.
If any deficiency is detected, the expansion of
reporting network should be important part of
monthly action plan of the surveillance medical
officer. Efforts should be made to recruit them as
quickly as possible. Active case search (ACS) will be
the most important activity in 2004. The SMO is to
ensure this action by visiting all the department/
unit/wards including medicine, pediatrics, neuro-
logy, casualty, emergency, ICU, etc. seeking and
searching all the registers at these places. The SMO is
to meet all the key doctors, including unit heads,
searching the medical record section, asking resident
doctors, nurses and paramedical staff. Telephonic
contacts with RU/informers should be maintained
to whom a visit is not planned that week by the SMO.
6. The progress made: From approximately more than 3.5
lacs cases of polio virus from 125 countries across five
contingents in 1988 to only 677 cases in 2003 (Data as
of 13 January 2004) confined to only five key hot spots
in six endemic countries representing a greater than
99 percent reduction in number of wild poliovirus—
the progress made by the eradication initiative is
indeed awesome.
i. The Milestones: 1991–Last case of polio in the
Americas (Peru), 1997–Last case of polio in
Western Pacific (Cambodia), 1998–Last case of
polio in Europe (Turkey). The Americas, Europe,
and Western Pacific regions of the World Health
Organization were certified polio-free in 1994,
2000 and 2002 respectively. More than three
billion people now live in 134 countries and
territories certified polio-free.
ii. The Current Status: Poliovirus is more geo-
graphically restricted than every before in
history. Only six countries remain polioendemic.
More than 75 percent of all polio cases
worldwide linked to just five key polio cases
worldwide linked to just five key polio hot spots
within these countries: Kano (Nigeria), Uttar
Pradesh and Bihar (India) and Sindh and North
West Frontier Province (Pakistan).
Importations of poliovirus from endemic to
polio-free areas threaten to derial efforts to
contain the virus. In the 2002-2003 period, for
the first time in history, more countries suffered
polio cases due to importations than were
themselves endemic for the disease.
In 2004, the world has a onetime opportunity to
make good on this global investment by ending
transmission of poliovirus, now and forever. This
only has become possible because of effective
surveillance.
iii. AFP-Surveillance: The country is having an
effective, widely distributed network of an
efficient surveillance system for the very first
time in its history, managed by National Polio
Surveillance Project (Government of India and
WHO). Right now, the country is having a
network of 6 Regional Coordinators (RC), 18

Subregional Coordinators (SRC), and 223
Surveillance Medical Officers (SMOs) spread
over all the nooks and corners of the country.
There are very few vacant posts lying to be filled
and the network is more concentrated in North
Indian states.
iv. Number of Reporting Units (RU) and Informers:
Number of reporting units were 9127 in 2003,
an increase of 2 percent from the last year’s
number of 8935. However, the numbers of
informers have been increased substantially this
year and their number has gone up from 6952 in
2002 to 9763 this year a 40 percent increase in
their recruitment.
v. All India Non-AFP rates: The whole country
barring few small states is maintaining a healthy
non-polio AFP rate of greater than 1 case per
100,000 population less than 15 years of age. The
exact year-wise figures are provided below:
1.74 in 2003, 1.87 in 2002, 1.76 in 2001,
1.99 in 2000, 1.83 in 1999.
Strengthening of “surveillance system” to a
level to detect all cases of AFP in children under
15 years of age, is an important element of polio
eradication strategy. The clinicians have an
important role to play in polio eradication efforts,
by detecting AFP, diagnosing the cause of para-
lysis, management of the cases and timely noti-
fication to public health authorities.
BIBLIOGRAPHY
1. Acute flaccid paralysis. IAP Journal of Practical Pediatrics
1997;221-6.
2. Conclusions and Recommendations. The Ninth Meeting
of India Expert Advisory Group for Polio Eradication,
New Delhi, India, November, 2003;18-19.
3. Polio eradications and AFP surveillance, WHO Bulletin,
1997.
4. Surveillance of Acute Flaccid Paralysis Field Guide, Pub.
By MCH division. Department of Family Welfare
Ministry of Health and Family Welfare, 2000.
9.12.2 NATIONAL IMMUNIZATION DAYS
(NIDs) AS A VITAL COMPONENT
OF ERADICATION STRATEGY
Vipin M Vashishtha, Naveen Thacker
In May 1988, the World Health Assembly committed the
member nations of the World Health Organization
Immunization and Infectious Diseases 359
(WHO) to achieving the goal of global eradication of
poliomyelitis. The polio eradication initiative (PEI) is a
global collaborative effort. WHO, UNICEF, Rotary
International, the US Centers for Disease Control and
Prevention (CDC), and a number of national govern-
ments and non-governmental organizations (NGO) are
strongly committed to the initiative. Their generous
financial and technical support has been critical in
achieving the significant progress made to date.
The “original” targets of GPEI when the initiative was
undertaken in 1988 were:
• No cases of clinical poliomyelitis associated with wild
poliovirus, and
• No WPV found world wide (including in sewage or
drinking water) despite intensive efforts to do so.
Since than various elaborative modifications were
made to final goal and the most recent published goal is
to ensure
• that poliovirus transmission is interrupted globally
through coordinated national and international
action;
• that the full humanitarian and economic benefits of
eradication are realized;
• that the lessons and infrastructure from its imple-
mentation are utilized in the strengthening of health
systems and control of other important diseases.
The new strategic plan has identified four key
objectives and milestones:
1. Interruption of WPV transmission.
2. Achieving certification of Global Polio Eradication.
3. Developing products for the Global OPV Cessation
Phase.
4. Mainstreaming the Global Polio Eradication
Initiative.
The primary strategies for achieving these goals and
objectives are:
1. Attaining high routine immunization.
2. Supplementary Immunization Activities (SIAs)
including NIDs and SNIDs.
3. Surveillance of acute flaccid paralysis (AFP).
4. “Mopping-up” immunization.
Attaining High Routine Immunization
Immunize every child aged < 1 year with at least 3 doses
of oral poliovirus vaccine (OPV). Paralytic polio can be
caused by any of 3 closely-related strains (serotypes) of
poliovirus. Trivalent OPV (OPV3) provides immunity
360 IAP Textbook of Pediatrics
against all 3 types. Three routine OPV doses should be
received by infants at ages 6, 10 and 14 weeks.
National Immunization Days (NIDs)
Conduct pulse polio immunization (PPI) program by
providing additional OPV doses to every child aged
< 5 years at intervals of 4-6 weeks.
Surveillance of Acute Flaccid Paralysis (AFP)
To identify all reservoirs of wild poliovirus transmission.
This includes AFP case investigation and laboratory
investigation of stool specimens collected from AFP
cases, which are tested for polioviruses in specialized
laboratories.
“Mopping-up” Immunization
When poliovirus transmission has been reduced to
well-defined and focal geographic areas, intensive house-
to-house, child-to-child immunization campaigns are
conducted over a period of days to break the final chains
of virus transmission.
Experience in several of the world’s WHO regions,
where polio has been eliminated, has demonstrated that
the recommended strategies are effective and that global
eradication of polio is feasible.
SUPPLEMENTARY IMMUNIZATION ACTIVITIES
(SIAS): NIDS AND SNIDS
The second part of the four-pronged strategy involves
mass immunization campaigns, known as Supple-
mentary Immunization Activities (SIAs). This includes
both National Immunization Days (NIDs) and Sub-
national Immunization Days (SNIDs). This mass activity
is also popularly known as “Pulse Polio Immunization
(PPI)”. These supplementary immunization rounds are
intended to complement - not replace - routine immuni-
zation. The aim of mass campaigns is to interrupt
circulation of poliovirus by immunizing every child
under 5 years of age with two doses of OPV, regardless
of previous immunization status.
Aims of NIDs/SNIDs
The aim of NIDs/PPI is to “flood” the community with
OPV within a very short period of time, thereby
interrupting transmission of virus throughout the
community. Intensification of the PPI programme is
accomplished by the addition of extra immunization
rounds, adding a house-to-house “search and vaccinate”
component in addition to providing vaccine at a fixed
post. The number of PPI rounds conducted during any
particular year is determined by the extent of poliovirus
transmission in the country. In recent years, several
rounds have been conducted throughout the year—
especially in the northern states of Uttar Pradesh and
Bihar, which have carried a heavier burden of poliovirus-
in an attempt to break the last chains of transmission.4
Intensification of PPI requires meticulous program
planning, intensive supervision and monitoring and
extensive social mobilization.
In 2003 for example, 415 million children under five
years were immunized during National Immunization
Days in 55 countries using over 2,2 billion doses of oral
polio vaccine (OPV).
The idea is to catch children who are either not
immunized, or only partially protected, and to boost
immunity in those who have been immunized. This way,
every child in the most susceptible age group is protected
against polio at the same time - instantly depriving the
virus of the fertile seedbed on which its survival depends.
NIDs are conducted in two rounds, one month apart.
Because OPV does not require a needle and syringe,
volunteers with minimal training can serve as vacci-
nators, increasing the number of vaccinators well beyond
the existing staff of a country’s Ministry of Health. For
example, a recent NID in India deployed two million
volunteers to immunize over 150 million children in just
a few days.
Three to five years of NIDs are usually required to
eradicate polio, but some countries require more time,
especially those where routine immunization coverage
is low. NIDs are normally conducted during the cool,
dry season because logistics are simplified, immuno-
logical response to OPV is improved and the potential
damage to heat-sensitive OPV is reduced. For last many
years, NIDs are usually conducted during months of
January and February in India.
Sub-national Immunization Days (SNIDs)
As the name implies, in this activity instead of covering
entire country, only few states/large geographical areas
are included for mass immunization. Rest all other
components remain the same. These rounds are
conducted year round contrary to cool months for NIDs,

depending upon the epidemiology of wild polio viruses.
Since, localization of wild virus in few endemic states in
India, these campaigns have now being used more
frequently and it is not unusual to have even 6 SNIDs
during a single calendar year.
“Synchronized” NIDs
As the wild poliovirus doesn’t distinguish between
borders, neighboring countries are increasingly coordi-
nating, or “synchronizing” their NIDs. This ensures
children crossing borders for any reason are identified
and immunized. Coordinated planning also allows
health teams to cross borders themselves, to immunize
children on an island which may be less accessible from
the other side, or those in pockets of territory otherwise
isolated by rivers, mountains or other impassable terrain.
This approach was first used between countries of
Eastern Europe and Central Asia, in a successful
campaign called “Operation MECACAR.” Another
massive synchronized campaign amongst 17 west and
central African countries in autumn 2000 dramatically
reduced wild poliovirus transmission by immunizing 76
million children in the same week. In Angola, Congo,
the Democratic Republic of the Congo and Gabon, 16
million children were immunized during three rounds
of synchronized NIDs in 2001. Finally, similar syn-
chronized efforts have been undertaken along the
borders of Afghanistan and Pakistan, where the
poliovirus freely circulates.
Operational Strategy
In India, the India Expert Advisory Group (IEAG),
established in May 1999 as a group of national and
international experts on polio eradication, provide
technical advice to the Ministry of Health and Family
Welfare, Government of India, on immunization and
surveillance activities for polio eradication and also
monitor the quality of immunization activities, AFP
surveillance and laboratory performance. IEAG also
issues guidelines and recommendations to Government
of India to conduct NIDs and SNIDs for the coming
months. The IEAG meets on a periodic basis, the
frequency being determined by the status of polio
eradication in India. Meetings occur more frequently
when urgent decisions must be made regarding matters
such as acceleration of supplementary immunization
Immunization and Infectious Diseases 361
activities, modifications in surveillance policies, or
changing approaches to programme communications
and social mobilization.
The NIDs/SNIDs is usually conduced over a week
now. A thorough micro-planning is done at least a
fortnight in advance and services of school children,
teachers, NGOs, paramedical personnel, health workers,
religious leaders, ‘panchayat’ and municipal board
members are usually utilized. The first day (usually
Sunday) is kept for the ‘booth activity’ where children
below 5 years of age immunized with OPV at a fixed
venue. Next 6 days are kept reserve for aggressive ‘house-
to-house’ activity to ensure 100% children are reached.
A vigorous IEC (information, education and communi-
cation) campaign is run involving all channels of
communication like print media, TV channels, cable TV,
cinema houses, meetings at public and religious places,
rallies of school children, announcements from mosques
and temples, public announcements at village fair, street
plays, distribution of pamphlets, etc to inform
community and motivate them about participating
actively in the campaigns. Mobile booths are also created
at railway stations, bus terminals and other transport
venues to catch mobile population. Oral polio vaccine is
used as the vaccine of choice by administering two drops.
The strict cold chain is maintained at +2 to 8 degree
centigrade by employing icepacks with vaccine carriers
and status is constantly monitored by ‘vaccine vial
monitor’(VVM).
The Utility and Impact of NIDs
NIDs and SNIDs have become the main source of polio
immunization in the areas where ‘routine immunization’
(RI) rates are poor. Many countries like China, Brazil,
etc, have successfully employed NIDs to rapidly wipe
off wild polio virus transmission from their environs. Its
utility as a potent tool in the armamentarium of
eradication strategies is beyond doubt. This strategy has
also got tremendous use during the ‘post-eradication era’
also where any future outbreak of wild virus will be dealt
with, mass immunization.
Since 1988, when the Global Polio Eradication
Initiative (GPEI) was launched, this program has made
tremendous progress in reducing the burden of disease
world-wide. As a result, the total number of wild polio
362 IAP Textbook of Pediatrics
virus cases has declined from an estimated 350,000 to
less than 1,500 in 2007. WHO Regions that have been
certified as polio-free are the Americas (last case in 1991,
Peru; Region certified polio-free in 1994), the Western
Pacific Region (last case in 1997, Cambodia; Region
certified 2000), and the European Region (last case in
1998, Turkey; Region certified 2001).The number of polio
endemic countries has also been reduced from 192 to only
4 in 2008. Wild polio virus type 2 has been eradicated
and last such case was seen in 1999. The remaining
reservoirs of wild polio virus are now largely confined
to sub-Saharan Africa and Indian subcontinent in south-
east Asia. India and Nigeria are now the two main
endemic countries responsible for over 90% of wild polio
virus cases world-wide in 2008.
9.13 Diphtheria
Diphtheria is an acute toxin-mediated disease caused by
Corynebacterium diphtheriae. It is one of the oldest recog-
nized infectious diseases. It used to occur in epidemics
and was associated with high mortality. Klebs identified
the organism in 1883 and Loeffler cultivated it in 1884.
The first child was treated with antitoxin on the
Christmas day in 1891. Successful immunization could
be established after Ramon produced the toxoid in 1923.
Etiology
Corynebacterium diphtheriae (Klebs-Loeffler bacillus) is an
aerobic, non-motile, non-encapsulated, non-spore
forming irregularly staining gram-positive pleomorphic
bacillus. The pathogenicity of the organism is due to
release of exotoxin. The toxin inhibits cellular protein
synthesis and is responsible for local tissue destruction
and membrane formation. The toxin is absorbed into the
bloodstream and it is responsible for the major compli-
cations like myocarditis, neuritis, proteinuria and
thrombocytopenia. Corynebacterium diphtheriae has three
biotypes – gravis, mitis and intermidius. The most severe
disease is associated with the gravis biotype.
Culture of the organism requires selective media
cystine-tellurite blood agar. If isolated, the organism must
BIBLIOGRAPHY
1. Global Polio Eradication Initiative. Available at: http://
www.polioeradication.org/Accessed on June 20, 2008.
2. Global Polio Eradication Strategy: National Immuni-
zation Days. Available at: http://www. polioeradication.
org/content/fixed/national.shtml Accessed on June 20,
2008.
3. National Polio Surveillance Project. Eradication strategy.
Available at: http://www.npspindia.org/Eradication%
20 Strategy.asp Accessed on June 20, 2008.
4. Vashishtha VM, Thacker N. Polio eradication: how near
and how far? Indian J Practical Pediatr 2006;8:220-31.
5. Wild Poliovirus Weekly Update. Available at: http://
www.polioeradication.org/content/general/
casecount.pdf Accessed on June 20, 2008.
6. World Health Organization. Global Polio Eradication
Initiative Strategic Plan 2004-2008. Weekly Epidemiol Rec
2004;79:55-7.
AP Dubey, Jaydeep Choudhury
be distinguished from diphtheroids, which normally
inhabit nasopharynx and skin.
Epidemiology
The only known reservoir of diphtheria is human being.
The patients or carriers transmit the disease through nasal
discharge or droplets by sneezing, coughing and talking.
Fomites and dust, though uncommon may also serve as
vehicle of transmission. The disease mainly affects the
unimmunized children below 15 years. The peak incidence
of the disease is during autumn and winter months. The
incubation period is 2-5 days (range 1-10 days).
Clinical Manifestations
The various sites affected are nasal mucosa, tonsils,
pharynx, larynx, trachea, conjunctiva and vagina. More
than one anatomic site may be involved. The signs and
symptoms depend upon the site of infection, immune
status of the host and the production and systemic
distribution of toxin.
Respiratory Tract
Nasal diphtheria initially resembles common cold. It
usually occurs in infants. There may be mild fever and

nasal discharge more often unilateral. The discharge is
foul smelling and serosanguineous. Careful inspection
may reveal a white membrane on the nasal septum. The
affected nostrils get obstructed and there may be
difficulty in breathing.
Tonsillar and pharyngeal diphtheria is the most
common clinical variety. Initially anorexia, malaise, low
grade fever and difficulty in swallowing are noted. Sore
throat is the universal early symptom. Within 1-2 days a
white pseudomembrane appears on the tonsils. It may
spread to cover the tonsils and pharyngeal walls or
progress down into the larynx and trachea. The pseudo-
membrane is a dense necrotic coagulum of organisms,
epithelial cells, fibrin, leukocytes and erythrocytes. It is
grey brown in colour and adherent to the base. Removal
is difficult and reveals a bleeding edematous submucosa.
Cervical lymph nodes are enlarged, accompanied by
severe edema causing swollen neck giving an appearance
of “Bull neck”. Edema is brawny with redness and
tenderness.
The typical features of the leather-like adherent
membrane, extension beyond the faucal area, relative
lack of fever and dysphagia help differentiate diphtheria
from exudative pharyngitis caused by group A strepto-
coccus and epstein-barr virus.
The course of pharyngeal diphtheria depends upon
the extent of the membrane and the amount of toxin
produced. In severe cases, respiratory obstruction and
circulatory collapse may occur. In mild cases, the
membrane sloughs off in 7-10 days and the recovery is
uneventful. Laryngeal diphtheria is usually due to
extension of the membrane from the tonsils and pharynx.
The common symptoms are noisy and difficult breathing,
barking cough, hoarseness of voice and progressive
stridor. If obstruction is not relieved (e.g. by tracheostomy),
the child may succumb to suffocation and heart failure.
Other Sites
Diphtheritic skin infection is a superficial, non-healing
ulcer with grey-brown membrane. In most cases it is a
superadded diphtheria infection over an underlying skin
lesion. Extremities are more often affected. Mucocutaneous
infections at other sites are ear, eye and genital tract.
Complications
a. Cardiac: Myocarditis is caused by the toxin of C.
diphtheriae and it occurs usually during the second
Immunization and Infectious Diseases 363
week. It occurs in approximately 10-25% of the
patients with diphtheria and is responsible for 50-
60% of deaths. There is tachypnea, dyspnea, extra-
systoles, weak pulse and muffled heart sounds. ECG
shows prolonged PR interval and ST-T changes.
Elevation of serum SGOT closely parallels the severity
of myocarditis. Recovery from myocarditis and
cardiomyopathy is usually complete.
b. Neurological: Neurological complications are multi-
phasic in onset. Palatal paralysis occurs acutely or in
the second week. Weakness of posterior pharyngeal,
laryngeal and facial nerves may follow causing a
nasal quality of voice, dysphonia and regurgitation
of fluids. Ocular palsies occur in the third week. It
involves muscles of accommodation, ciliary muscles
and lateral rectus muscle causing squint and diplopia.
Generalized symmetric polyneuropathy usually
occurs after 3-6 weeks of illness. This usually recovers
completely. In cases of palatal paralysis frequent
aspiration of secretions, feeding through nasogastric
tube and IV fluids are recommended.
c. Respiratory tract obstruction may require intubation
and mechanical ventilation. Secondary bacterial
pneumonia, nephritis and hepatitis can occur.
Diagnosis
The diagnosis is based on clinical examination and is
confirmed by isolation of bacilli. The material for culture
may be obtained from beneath or part of the membrane
itself. Other supportive investigations include raised
WBC count, raised protein and cells in CSF in cases of
neuritis. ECG may show arrhythmias in the form of block
and ST-T changes indicative of myocarditis.
Treatment
The principles of treatment are as follows:
i. Neutralization of free circulating diphtheria toxin,
ii. Eradication of bacteria by antibiotics,
iii. Supportive therapy.
Specific antitoxin is the mainstay of therapy and
should be administered early on the basis of clinical
diagnosis. Efficacy diminishes with elapsing time. For
neutralization of free circulating toxin, antidiphtheric
serum (ADS) should be given early in proper doses by
IV or IM route after skin sensitivity test. The dose of ADS
depends upon the site of infection. For nasal diphtheria
364 IAP Textbook of Pediatrics
20,000 units, for tonsillar and pharyngeal diphtheria
40,000-80,000 units and for laryngeal lesions 80,000-
120,000 units are given. Diphtheria immune globulin
(DIG) can be used in place of ADS in a dose of 0.6 ml/kg
body weight.
Antibiotics: Penicillin is the drug of choice, aqueous
crystalline penicillin G (100,000-150,000 U/kg/day).
Alternatively erythromycin (40-50mg/kg/day) can be
used. The antibiotics should be given for 14 days or until
throat culture is negative to prevent the development of
carrier state.
Patients with pharyngeal diphtheria are placed in
respiratory isolation. Supportive therapy includes bed
rest for about two weeks to reduce the risk of cardiac
complications and maintenance of proper hydration and
nutrition. In children with laryngeal obstruction,
tracheostomy is lifesaving.
Prognosis
Early diagnosis, adequate use of ADS/DIG, antibiotics
and good supportive care has reduced morbidity and
mortality. Young age, gravis type of bacteria and
laryngeal diphtheria have poor prognosis. Sudden death
may occur due to respiratory obstruction, myocarditis
and respiratory paralysis.
Prevention
Diphtheria is a notifiable disease. The patient should be
isolated until the course of antibiotics is completed or
9.14 Pertussis (Whooping Cough)
Pertussis is an acute highly communicable infection of
the respiratory tract caused by Bordetella pertussis. It may
affect any susceptible host but is more common and
serious in infancy and early childhood. It derives its name
from a latin word per—intensive and tussis— cough.
Hence, any disease which results in severe cough is often
perceived as pertussis, more so as proof of diagnosis is
difficult to obtain in routine clinical practice. Similar
illness has been known to be caused by B. parapertussis,
B. Bronchiseptica and also adenoviral infections of type
until two cultures from throat and nose are negative. The
people in close contact should ensure that they had been
immunized. If not, they should be submitted for throat
culture. If the person is culture negative, then no
treatment is required. If culture positive, then it should
be considered a carrier state and chemoprophylaxis
should be given with oral erythromycin or penicillin.
Diphtheria toxoid is available combined with tetanus
toxoid and pertussis vaccine as DTP, DT, Td and Tdap.
For primary prevention, DPT vaccine should be given at
6, 10 and 14 weeks of age two booster doses at 18 months
and 5 years of age. National EPI schedule advocates DT
instead of DPT as second booster. But over the years
immunity to diphtheria wanes despite three primary and
two booster doses of DPT vaccines. Low dose diphtheria
vaccine combined with regular dose of tetanus toxoid
(Td) is recommended as booster doses in children above
7 years and adults in subsequent immunizations in place
of tetanus toxoid (TT). This should be used in any wound
management and is also safe during pregnancy.
BIBLIOGRAPHY
1. Buescher ES. Diphtheria. In: Kliegman RM, Jenson HB,
Behrman RE, Stanton BF, editors. Nelson Textbook of
Pediatrics. 18th edn. Philadelphia: Elsevier 2007;1153-6.
2. CDC. Diphthera, tetanus and pertussis: Recommenda-
tions for vaccine use and other preventive measures.
MMWR 1991;40:1-28.
3. Epidemiology and prevention of vaccine-preventable
diseases. 10th edn. Department of Health and Human
Services CDC. 2007.
YK Amdekar
1,2,3 and 5. It should be considered with high index of
suspicion in an unimmunized child presenting with
severe spasmodic cough.
Epidemiology
In India, before the introduction of EPI, there were more
than 2.5 lacs of cases reported in 1974 and 4.5 lacs in 1978.
In 1969, Ashabai et al, reported the incidence of Pertussis
as 15/1000 < 5 years and 85/1000 < 10 years of age. In
1972-75, one hospital based study reported that pertussis

constituted 1.4 percent of total vaccine-preventable
diseases, 0.3 percent of hospital admissions, 0.3 percent
of vaccine-preventable deaths and 0.1 percent total
pediatric deaths. Mortality in pertussis was around 6
percent. Similar high incidence had been reported in ‘50s
in developed countries; but after the introduction of
vaccine, incidence of pertussis came down significantly.
In India during postvaccination era, there has been a
decline in incidence of pertussis. In 1987, Singh reported
prevalence of pertussis as 3.6 percent in children < 10
years of age as compared to 8.5 percent in 1969. Similar
observations have been made in hospital-based studies.
Risk of acquiring pertussis prior to vaccination has been
estimated 20 times more than that after vaccination.
However in recent years, isolated epidemics continue to
occur all over the world. Epidemics of pertussis are
reported every 3 to 4 years in UK. Most recent estimates
of WHO indicate that 12.9 million children die under 5
years of age, of which 4.3 million die of ARI. Pertussis
accounts for 0.26 million of them, 6.1 percent of ARI
deaths. It is thus clear, that even with decline in pertussis
after vaccination, it still continues to be a major health
hazard. Infants may be susceptible before the age at
which vaccine is immunogenic, postvaccinal immunity
is likely to wane off in older children who may suffer
from mild or modified form of disease that is unrecog-
nizable. Of course, unimmunized children in the
community continue to suffer and spread infection. In
population with higher coverage of pertussis vaccine,
there is a shift in age prevalence of disease and older
children and adults do suffer from pertussis.
Pathogenesis
Organisms spread by droplets from infected untreated
patients. Clinical manifestations depend upon the host
response to antigens associated with capsule, cellwall or
cytoplasm of the organism. Lymphocytosis promoting
factor probably plays an important role in human
infection. Both T and B lymphocytes are involved.
Endotoxin does not seem to contribute in the pathogene-
sis of the disease. Systemic and local humoral responses
are beneficial in human infection. Pathological changes
are characterized by inflammation of the mucosal lining
of the respiratory tract. Bronchopneumonia develops
with necrosis and desquamation of superficial epithe-
lium of small bronchi. Bronchiolar obstruction and ate-
lectasis result from accumulated secretions. Bronchiec-
tasis may develop and persist. Changes in brain and liver
Immunization and Infectious Diseases 365
have been noted in severe disease, especially in infants
and are considered to be due to anoxia.
Clinical Features
Unless treated early in the evolution of the disease, it
runs a lengthy course for 6 to 8 weeks, classically through
three stages—catarrhal, paroxysmal and convalescent.
The prodromal catarrhal stage lasts for 1 to 2 weeks and
is characterized by coryza, fever and mild cough, which
progresses to episodic paroxysms of increasing intensity
ending with high pitched inspiratory whoop. Whoop
may be absent in infants and partially immune older
children and adults and hence, makes the diagnosis
difficult to suspect in them. This stage lasts for a variable
period of 2 to 6 weeks or longer. Convalescent stage is
heralded by decreasing intensity and frequency of cough
over 1 to 2 weeks. It is possible to diagnose pertussis only
with high index of suspicion in a child who coughs for
more than 2 to 3 weeks without any other obvious cause.
Complications
Infants and young children are more susceptible to
complications. Respiratory complications include otitis
media, pneumonia due to B. pertussis itself or secondary
bacterial infection, atelectasis, emphysema, bronchiec-
tasis, pneumothorax and pneumomediastinum. CNS
complications result in seizures and encephalopathy and
often seen in paroxysmal stage of the disease in 0.5
percent of hospitalized patients. Severe cough leads to
marked increase in pressure in various compartments
which may result in epistaxis, retinal, subconjunctival
and intracranial hemorrhages, inguinal hernia, rectal
prolapse and rupture of diaphragm. Malnutrition is the
end result of disease in infancy and early childhood due
to protracted course of the illness interfering with
feeding. Pertussis is also known to flare up the pre-
existing silent tuberculous infection.
Differential Diagnosis
Other conditions which may present with an acute onset
of severe cough lasting for more than 2 to 3 weeks include
adenovirus infection, endobronchial tuberculosis,
inhaled foreign body or hyper-reactive airway disease.
Other chronic infections of respiratory tract may also be
considered. Recurrent episodes of cough rule out
pertussis.
366 IAP Textbook of Pediatrics
Diagnosis
It is often made on clinical features. In an unimmunized
child in contact with a patient having pertussoid cough,
it may be safe to consider the diagnosis of pertussis.
Marked lymphocytic leukocytosis is a non-specific
parameter and low ESR is often a clue. Specific
diagnosis depends on recovery of B. pertussis from
nasopharyngeal swab or cough plate cultured on Border-
Gengou medium. Cultures are often positive in catarrhal
and early paroxysmal stage. Direct fluorescent antibody
and counter-immunoelectrophoresis are other methods
for rapid diagnosis. Most of these methods are not
routinely available in clinical practice. At present, no
single test exists which is sensitive and specific enough
for the diagnosis in all the stages.
Management
Respiratory distress, CNS signs and poor intake leading
to dehydration especially in infants are strong indications
for immediate referral to a hospital.
General measures include providing adequate
nutrition and hydration and avoiding factors aggravating
cough such as excessive crying. The antibiotic of choice
is erythromycin given orally in dose of 40 to 50 mg/kg/
day in 3 to 4 divided doses. It does not shorten the course
of illness but does terminate respiratory tract carriage of
B. pertussis, thereby reducing the period of commu-
nicability. Complications are managed symptomatically.
9.15 Tetanus
Tetanus is an acute often fatal, severe exotoxin-mediated
infection caused by Clostridium tetani. Rosenbach in 1886
demonstrated for the first time these slender bacilli. The
disease is characterized by severe muscular spasm.
Epidemiology
Tetanus occurs worldwide and is an important cause of
neonatal death in developing countries. The causative
organism Clostridium tetani is part of the normal flora in
human and animal intestines and is disseminated
through the excreta. In spore form they are hard and long
Prevention
Strict respiratory isolation is desirable for 4 to 5 days after
starting antibiotic therapy. Chemoprophylaxis with
erythromycin is recommended for close family contacts
especially under 2 years of age. Under the age of 5,
children should be vaccinated as per IAP guide lines.
With availability of safer low concentration vaccine for
older children and adults, it is ideal to offer pertusis
pertusis vaccine (Tdap) to them. Pertussis vaccine is
discussed in the chapter on immunization.
BIBLIOGRAPHY
1. Ashabai PV, John TJ, Jayabal P. Infectious disease in a group
of south Indian families. Indian Pediatr 1969;6:645-50.
2. Centre for Disease Control. Pertussis surveilence. United
States 1989-1991 MMWR 1993;42.
3. Chaudhari, et al. Impact of National Immunization
schedule on vaccine preventable disease on a hospital-
based study. Indian Pediatr 1992;29:33-8.
4. Garrene M, Ronsman C, Campbell H. The magnitude of
mortality from ARI in children under 5 years in
developing countries. Wld Hth Statist Quart 1992;45:180.
5. Grenfell BT, Anderson IM. Pertussis in England and
Wales an investigation of transmission dynamics and
control by mass vaccination. Proc Royal Society London
1989;236:213-50.
6. Singh et al. Pertussis in rural children. Indian Pediatr
1987;24:553-6.
7. WHO. EPI in South-East Asia SEARO Regional Health
Papers No. 12, p. 131.
AP Dubey, Jaydeep Choudhury
lasting in soil and dust. As the spores of Clostridium tetani
are ubiquitous, wound contamination is unavoidable.
The contamination of wound, unhygienic and improper
handling of the umbilical cord in newborns, lack of
hygienic habits and aseptic care during and after delivery
in women are the main risk factors for infection. But
tetanus is a preventable disease. It is the only vaccine
preventable disease that is infectious but not contagious
from person to person.
Among the burden of vaccine preventable diseases
world over, tetanus ranks fourth with 13% disease

burden. According to WHO, published in 2008, the
reported cases of tetanus in India in 2006 were 2587, of
which 600 cases were neonatal tetanus. The incidence is
high in tropical countries with humid climate. More cases
are reported from rural than urban areas.
Etiology
The causative organism Clostridium tetani is a gram-
positive, anaerobic, spore forming organism. It forms
terminal spores resembling drumsticks. The spores are
resistant to boiling, usual antiseptics and chemical agents
like phenol. They can survive autoclaving at 121oC for
10-15 minutes.
Clostridium tetani usually enters the body through
wound. The bacilli itself is non-invasive. The spores
germinate in anaerobic conditions. They produce two
types of toxins – tetanospasmin and tetanolysin. Of these,
tetanospasin is a neurotoxin and is responsible for the
clinical signs and symptoms of the disease. Toxins are
disseminated via blood and lymphatics. Toxins act at
several sites within the nervous system.
Clinical Manifestations
The incubation period of tetanus is around 10 days (range
3-30 days). On the basis of clinical findings, three different
forms of tetanus have been described. The most common
type (80%) is generalized tetanus. Localized tetanus
produces pain and spasm of the muscles in proximity to
the site of injury. Occasionally this form of disease may
precede generalized form. Cephalic tetanus is a rare form
of the disease seen in children with otitis media.
Generalized tetanus usually presents with a
descending pattern. The first sign is trismus or lockjaw
due to spasm of masseter muscle, followed by stiffness
of the neck, difficulty in swallowing and rigidity of
abdominal muscles. The spasms can be precipitated by
bright light, noise and even touch. Difficulty in
swallowing, restlessness, irritability and headache are
early manifestations. The rigidity of facial muscles leads
to the sardonic smile of tetanus or risus sardonicus, a
typical grinning appearance. Rigidity and spasm of back
and abdominal muscles causes arching (opistho-
tonos).Laryngeal and respiratory muscle spasm can lead
to airway obstruction and asphyxia. Constipation and
retention of urine may also occur. Hyperpyrexia,
hypertension, excessive sweating, tachycardia and
cardiac arrhythmia can occur due to sympathetic nerve
involvement.
Immunization and Infectious Diseases 367
Neonatal tetanus typically occurs when the umbilical
cord is cut with an unsterile instrument and manifests
within 3-12 days of birth. It is generalized tetanus, a
serious condition and often fatal. Progressive difficulty
in feeding (sucking and swallowing) with associated
hunger and crying are generally seen. The baby becomes
stiff and spasms develop. Opisthotonos may be extreme
or sometimes absent.
Diagnosis
Diagnosis is mainly clinical. The typical setting is an
injured unimmunized patient or baby born to an
unimmunized mother presenting within 2 weeks with
trismus, rigid muscles and clear sensorium. The organism
can be isolated from wound or ear discharge.
Treatment
The aim of therapy is to neutralize all toxins, eradication
of C. tetani and wound environment conducive to
anaerobic multiplication and supportive care.
Human tetanus immunoglobulin (TIG) 3000-6000
units IM is recommended to be given immediately. TIG
has no effect on toxin which is already fixed to the neural
tissue and doesn’t penetrate the blood-CSF barrier. It can
neutralize circulating tetanospasmin. Antitetanus serum
is recommended only when TIG is not available. It can
be given in a single dose of 50,000-100,000 units, half the
dose IM and the rest intravenously after skin test.
Penicillin is the antibiotic of choice for C. tetani.
Penicillin G 200,000 units/kg body weight can be given
intravenously in 4 divided doses for 10-14 days. Local
wound, discharging ears, umbilical cord should be
cleaned and debrided.
All patients with generalized tetanus require
muscle relaxant. Diazepam is preferred as it causes
both muscle relaxation and seizure control. Initial dose
is 0.1-0.2 mg/kg every 3-6 hours given intravenously.
Midazolam, baclofen can also be used. The best
survival rates with generalized tetanus are achieved
with neuromuscular blocking agents like vecuronium
and pancuronium. These drugs produce general
flaccid paralysis which can be managed by mechanical
ventilation.
Meticulous nursing care is imperative. The patient
should be kept in a quiet, dark environment with
minimum auditory or visual stimuli. Maintenance of
nutrition, fluid and electrolyte balance, suctioning of
secretions and cardiorespiratory monitoring should be
done. Provision for tracheostomy should be kept ready.
368 IAP Textbook of Pediatrics
Prognosis
The average mortality of tetanus is 45 to 55 percent. For
neonatal tetanus the mortality is 60 to 70 percent. The
most important factor influencing outcome is supportive
care. Recovery from tetanus doesn’t confer immunity;
therefore active immunization of the patients following
recovery is imperative.
Prevention
Tetanus is an entirely preventable disease. Active
immunization is the best method to prevent tetanus. All
children should be immunized with three doses of DPT
at 6, 10 and 14 weeks followed by booster doses at 18
months and 5 years of age. Boosters should be given at
10 years and then every 10 years. Td or Tdap is the
vaccine of choice above 7 years age.
Neonatal tetanus could be prevented by immunizing
the pregnant women with two doses of tetanus toxoid
(preferably Td) between 16 and 36 weeks of pregnancy,
and with only one dose of Td in the subsequent
pregnancies.
Wound Management
All wounds should be cleaned, necrotic tissue and foreign
material should be removed. Wounds which are not
9.16 Measles
Measles is a contagious disease characterized by catarrhal
symptoms, followed by appearance of typical measly
rash. The incidence of measles has come down world
over with effective immunization. But measles is a major
cause of preventable blindness and still the leading
vaccine preventable killer in children. India contributes
27 percent of global measles deaths. WHO has started
the Measles Surveillance Project in India from 2007.
Epidemiology
Measles occurs both epidemically and endemically. The
peak incidence is during winter and spring. One attack
of measles confers lifelong immunity.
Among the burden of vaccine preventable diseases
world over, measles ranks first with 38% disease burden.
minor require human TIG except those in fully immuni-
zed patient. In patients with unknown or incomplete
immunization history, crush, puncture or projectile
wounds, wounds contaminated with soil, saliva or feces,
avulsion injuries, compound fractures, 250 U of TIG
should be given IM. In cases where the wound could not
be properly debrided or wound more than 24 hours old,
500 U TIG should be given. Tetanus toxoid may be
administered immediately depending on the immuni-
zation status of the child.
BIBLIOGRAPHY
1. Arnon SS. Tetanus. In: Kliegman RM, Jenson HB, Behrman
RE, Stanton BF, editors. Nelson Textbook of Pediatrics.
18th edn. Philadelphia: Elsevier 2007.p.1228-30.
2. CDC. Diphtheria, tetanus and pertussis: Recommenda-
tions for vaccine use and other preventive measures.
MMWR 1991;40:1-28.
3. Epidemiology and prevention of vaccine-preventable
diseases. 10th edn. Department of Health and Human
Services CDC. 2007.
4. World Health Organization. The “high risk” approach:
the WHO-recommended strategy to accelerate elimi-
nation of neonatal tetanus. Wkly Epidemiol Rec 1996;
71:33-6.
AP Dubey, Jaydeep Choudhury
The number of reported cases showed a decline from
1997 to 2005, and then there was a sharp rise in 2006.
According to WHO, published in 2008, the reported cases
of measles in India in 2006 were 60751 and in 2005 it was
52454. As per EPI fact sheet, documented measles
immunization coverage in India was 67% in 2003 in
children less than 1 year of age.
Etiology
Measles is caused by measles virus, an RNA virus, of
genus Morbillivirus, of the family Paramyxoviridae. Only
one sero-type of measles is known.
Measles is seen in early childhood in developing
countries. The disease usually occurs below 3 years age.
Infants are usually protected till the age of 4-6 months

due to immunity acquired trans-placentally from mother.
Usually these antibodies are undetectable by the age of
9 months but antibodies may persist up to 12 months of
age. The disease runs a mild course in healthy children,
whereas the disease is severe in malnourished children.
Transmission occurs either by direct contact or droplet
spray. The period of infectivity is 4 days before and 4
days after appearance of rash. It is rarely sub-clinical. It
is highly contagious and secondary attack rate is
approximately 90% in susceptible household contacts.
Pathogenesis
Measles virus enters the human body through the
respiratory epithelium of the nasopharynx. The virus
replicates initially in these cells including the epithelial
cells lining the buccal mucosa and conjunctiva. Later it
spreads to the regional lymph nodes. Further replication
of the virus leads to the primary viremia with seeding of
the cells of the reticulo-endothelial system. Infection of
these cells leads to the secondary viremia, whereby the
measles virus is disseminated through out the body,
coincident with the clinical manifestations of the disease.
Clinical Manifestations
The clinical course of measles can be divided in four
clinical stages – incubation, prodromal stage, catarrhal
stage and post-measles stage of complications.
The incubation ranges from 10-12 days. In the later
part of incubation period, the child shows prodromal
symptoms which last for 2-4 days and consist of fever,
malaise, coryza and tracheobronchitis.
At the end of prodromal phase, the child gets fever
which may be high grade. Koplik’s spots, which are
pathognomonic sign of measles, are seen on day 2-3 of
fever. These are grayish white or bluish white dots with
reddish areola occasionally they are hemorrhagic. Mostly
seen on buccal mucosa opposite lower molars but may
be seen all over the buccal mucosa. Conjunctival
congestion and photophobia is also classical of measles,
which occurs before Koplik’s spots appear. Temperature
rise abruptly as rash appears and often reaches 40°C or
higher.
Rash appears on 4th to 6th days of fever. It starts as
faint erythematous maculopapular rash on upper lateral
aspect of neck and typically behind the ears and
increasingly involve face then spreading on to trunks and
then to legs and arms over next 3 to 4 days. By the time
Immunization and Infectious Diseases 369
rash appears on feet it starts disappearing from face and
fades down in same pattern. Temperature also suddenly
normalizes once rash starts fading and child suddenly
looks well from sick look. The severity of disease is
directly related to the extent and confluence of rash. In
severe cases rash may become hemorrhagic. The rash
fades in the next 3 to 4 days. As the rash disappears it
leaves behind the brawny desquamation and brownish
discoloration characteristic of post-measles state which
disappears in 7-10 days.
Complications
Measles can affect various systems in the body resulting
in following complications.
a. Respiratory system – Postmeasles bronchopneumo-
nia, empyema, mediastinal and subcutaneous
emphysema and flaring of pulmonary tuberculosis.
b. GIT – Diarrheal episodes are quite common after
measles.
c. ENT – Otitis media.
d. Systemic – Acute malnutrition, secondary bacterial
infections like septicemia with Streptococcus, etc.
e. Cancrum oris, stomatitis nomans at different sites.
f. CNS – Measles encephalitis and encephalopathy.
g. Eye – Keratitis.
h. SSPE – Subacute sclerosing pan encephalitis (SSPE)
is a degenerative disease of the brain caused by a
persistent infection with measles virus. It can manifest
several years (usually 7 years) after measles infection.
The patient develops progressive personality
changes, developmental retardation, myoclonic
seizures and motor disability. Measles virus has been
isolated from the brain tissue of such patients. Their
sera and CSF show a high titer of measles specific
antibodies.
Prognosis
In developing countries measles has a devastating course
with a mortality of 1 to 3 percent which may go up during
epidemics to 5 to 15 percent and a high rate of compli-
cations.
Management
Management is mainly supportive. The child may be
given antipyretics, fluids and antihistaminics during
acute phase. No antiviral therapy is available. The child
may be isolated for the period of infectivity. There is
370 IAP Textbook of Pediatrics
inverse correlation between serum retinol concentration
and measles severity. A single dose of vitamin A 100,000
units orally for children 6-12 months of age and 200,000
units orally for more than 1 year of age children reduces
mortality.
Prevention
1. Isolation of the patient – From 7th day of exposure to
5 days after rash appearance.
2. Vaccine – Measles can be effectively prevented by
measles vaccine. The newborn baby is protected by
transplacentally acquired maternal antibodies. The
antibody gradually wanes and the infant becomes
susceptible to measles starting from 6 months of age.
By 9 to 12 months of age most infants become
susceptible. At this age live attenuated measles
vaccine offer good protections. The preparations of
the vaccine contains 1000 TCID dose of vaccine virus.
Unconstituted vaccine remain viable for 2 years at 2-
8°C but once reconstituted it should be used within 4
hours as vaccine does not contain any preservative
or antibiotic. Measles is a potent and effective vaccine
with a seroconversion rate of 95-98 percent. As per
national immunization programme in India and EPI
policy we give measles vaccine at 9 month of age as
0.5 ml subcutaneous injection. MMR vaccine contains
measles, mumps and rubella vaccines. The Global
recommendation now is two doses for MMR and
Varicella Vaccines – the first dose at 15 months and
9.17 Mumps: Epidemic Parotitis
Mumps is an acute, generalized, virus infection of
children and young adults. Mumps virus, is an RNA
virus of the genus Paramyovirus in the family Paramyxo-
viridae, which also includes the Parainfluenza viruses,
only one serotype is known. The virus can infect almost
any organ: the salivary glands, the pancreas, the testes
or ovary, the brain, the breast, the liver, the joints and
the heart. Parotitis is the most common illness.
Epidemiology
The mumps virus is endemic worldwide, and its only
known host is the human. In unimmunized population
the second at 4-6 years. It will be ideal to administer
the second dose at 5th year along with DTP booster
and OPV. Measles vaccine is contraindicated in
pregnancy, children with primary immunodefi-
ciency, untreated tuberculosis, cancer, organ trans-
plantation or those receiving long term immunosup-
pressive therapy or severely immunocompromised
HIV infected children.
3. Post exposure prophylaxis – (i) Less than 6 months
old child (mother usually immune in India) there is
no need for prophylaxis as child already protected. (ii)
6-12 months unimmunized then vaccinate with
measles vaccine within 72 hrs. (iii) More than 12
months unimmunized then vaccinate with measles or
MMR vaccine within 72 hrs of exposure. (iv) Immuno-
compromised give 0.5 ml/kg immunoglobulin
(maximum 15 ml) IM irrespective of immunity status.
BIBLIOGRAPHY
1. Bhargava I. Measles. Control of measles, mumps and
rubella. 1 st edn. New Delhi: BI Churchill Livingstone,
1995.
2. Epidemiology and prevention of vaccine-preventable
diseases. 10th edn. Department of Health and Human
Services CDC. 2007.
3. India EPI fact sheet, 2003, country Fact sheet WHOSE
ARO. 2004.
4. Mason WH. Measles. In: Kliegman RM, Jenson HB,
Behrman RE, Stanton BF, editors. Nelson Textbook of
Pediatrics. 18th edn. Philadelphia: Elsevier. 2007;
1331-7.
Ashok Gupta
epidemics tend to occur every 2 to 5 years, throughout
the year but often with a peak in late winter or early
spring.
Natural History
The mumps virus is transmitted via saliva, through
airborne droplets, by direct contact, fomites contamina-
ted by saliva and possibly by urine. The secondary
infection rates in susceptible populations have been as
high as 80 percent. The period of communicability
extends from several days before the onset of symptoms

to several days thereafter, but the virus has been isolated
as early as 6 days before and as late as 9 days, after the
onset of parotitis. Infection with the virus or immuni-
zation is thought to confer immunity for life.
The virus proliferates in the upper respiratory tract
epithelium and then enters circulation. It then localizes
in glandular and neural tissue.
After an incubation period of 2 to 4 weeks, average
16 to 18 days, symptoms begin acutely with fever,
malaise, and headache.
CLINICAL MANIFESTATIONS
Parotitis
Most patients develop parotitis that may appear in one
or both parotid glands. Earache, jaw tenderness with
chewing, and dry mouth are among the presenting
complaints that worsen over the next several days.
Sucking a sour stimulus produces significant worsening
of the pain. The swelling is at the angle of the jaw, and
obliterates the angle, often extending to the lower portion
of the ear, which may be displaced up and out.
Defervescence and resolution of parotid tenderness takes
about a week.
Submaxillary Mumps
Symptoms are similar to parotitic mumps. In the absence
of associated parotid swelling, differentiation from othe
submaxillary swelling is difficult. In all such situations,
examine fauces for the signs of tonsillitis that might cause
cervical adenitis, and laboratory tests are needed for
definite diagnosis.
Sublingual Mumps
The sublingual salivary glands when they swell, they
push up into the mouth below the tongue, forcing it up
against the hard palate, and also down under the chin as
a very tender swelling. It is acutely uncomfortable, often
accompanied by severe general symptoms. It usually
subsides after a few days, and is fortunately uncommon.
Orchitis
Infection can also be established in the testes and
epididymes, particularly in adolescents or adults (25%
of post pubertal males). Orchitis, unilateral in 80 to 85
percent, usually occurs 1 to 2 weeks after parotitis, but it
Immunization and Infectious Diseases 371
may occur without parotitis. Symptoms begin abruptly
with testicular swelling and tenderness and associated
nausea, vomiting, and headache. The testicle may enlarge
three or four times and become very tender. Later on,
some degree of atrophy develops in nearly half of the
affected organs.
Meningitis and Encephalitis
CNS involvement is characterized by an aseptic menin-
gitis that occurs in 1 to 10 percent of patients with parotitis.
Meningeal symptoms develop anytime between a week
before to several weeks after the parotitis. Lymphocytic
dominance with fewer than 500 cells is usual, but white
cell counts may rise to over 2000 in the spinal fluid. The
spinal fluid glucose is usually normal, and the protein is
normal or slightly elevated. These findings revert to
normal after about a week and sequelae are uncommon.
Encephalitis is rare with an estimated frequency of 3/1000
cases. It can be very serious with seizures and cortical
blindness. High fevers are common. Recovery is usually
complete, but fatalities have been reported. Occasionally
meningitis or encephalitis may occur without manifest
parotitis. Aqueductal stenosis and hydrocephalous have
been associated with mumps infection. Injecting mumps
virus into suckling hamsters has produced similar lesions.
Other Complications
Pancreatitis is another manifestation of mumps and
occurs in approximately 5 percent of the patients.
Infection with mumps virus has been implicated as a
possible cause of juvenile onset of diabetes. There has
been documentation of onset of diabetes within a few
weeks, following clinically diagnosed mumps. An
association has been found between mumps infection
and endocardial fibroelastosis (St. Geme et al. 1972).
There is no evidence of impairment of fertility in
postpubertal females patients with oophoritis reported
in about 7 percent cases. Other complications include
myocarditis, deafness unilateral or bilateral (transient or
permanent), arthiritis, dacroadenitis, optic neuritis,
thyroiditis have been reported.
Diagnosis
The clinical features of acute parotitis are diagnostic.
Laboratory findings are of little value, except that the
serum amylase is elevated in 90 percent of the patients
372 IAP Textbook of Pediatrics
with parotitis and serum lipase levels are normal,
distinguishing mumps parotitis from pancreatitis.
Serologic tests are rarely done, but it is possible to identify
infection acutely by detecting antibodies to the ‘S’ antigen
by complement fixation antibody titers which rise in first
week of illness, and V antigen by complement fixation
antibody titers that follow with a rise several weeks later,
and may persist at low levels for years. Neutralizing and
hemagglutination inhibiting antibodies appear during
convalescence.
Treatment
There is no specific treatment. Symptomatic treatment
includes simple analgesics. Immune globulin treatment
is not cost-effective and is no longer commercially
available.
Prevention
The live attenuated mumps virus vaccine induces
antibodies in 96 percent of seronegative recipients and has
97 percent protective efficacy with Jeryl Lynn strains of
mumps virus. Immunization is usually given at about 15
months of age in combination with measles and rubella
vaccination and can be given at age of 12 months if child
has not received measles vaccination at 9 months of age.
Second immunization also MMR is recommended at
any time during childhood. Children who have not
received the second dose should be immunized by 11-12
years of age. Women should avoid pregnancy for 30 days
after monovalent vaccine (3 months in case of rubella
vaccine). Neither vaccine nor immunoglobulin has been
9.18 Rubella
Rubella or German measles or third disease is a mild
disease affecting children and adults. Its importance lies
in the fact that if a woman has Rubella during pregnancy,
infection may be transmitted to the fetus across the
placental barrier, resulting in marked teratogenic effects.
Epidemiology
Humans are the only natural host of rubella virus. The
virus is transmitted by droplets via respiratory route from
shown to be effective in preventing mumps after exposure.
Mumps vaccination is contraindicated in patients with
allergy to vaccine component (anaphylaxis to neomycin),
moderate to severe acute illness with or without fever,
immuno deficiency due to immunosuppressent drugs or
disease but human io deficiency virus positive children
and symptomatic HIV infected children with CD4 count
>15 percent should be vaccinated with MMR vaccine.
BIBLIOGRAPHY
1. Annotation: Mumps embryopathy. Lancet 1966;692-3.
2. Centers for disease control and prevention: Measles,
mumps and rubella vaccine use and strategies for
elimination of measles, rubella and congenital rubella
syndrome and control of mumps. Recommendations of
the advisory committee on immunization practices
MMWR 1998;47 (RR-8):1-57.
3. Christies AB. Infectious; Epidemiology and clinical
practice, (3rd edn) Churchill Livingstone, Edinburgh
1980.
4. Feldman HA. Mumps; In Viral infections of humans
1989;471-91.
5. Gordon JE, Kilham L. Ten years in the epidemiology of
mumps. American Journal of Medicine 1949;218:338-59.
6. Hanshaw JB, Dudgeion JA. In Viral diseases of the fetus
and the newborn. Saunders, Philadelphia, 1978.
7. Kurtz JB, Tomlinson AH, Pearson J. Mumps virus
isolated from a fetus. British Medical Journal 1982;284-
471.
8. Rima BK. Mumps virus. In Webster RG, Granoff A (Eds):
Encyclopedia of Virology 1994;876-83.
9. Weibel RE. “Mumps vaccine”. In Plotkin SA, Mortimer
EA (Eds): Vaccines, Saunders, Philadelphia, 1988;223-34.
10. Wolnsky JS, Waxham MN: Mumps virus. In fields BN 9
edn. Virology 1990;989-1011.
AP Dubey, Jaydeep Choudhury
person to person and transplacentally to cause congenital
rubella syndrome. It replicates in the mucosal cells of
upper respiratory tract and spreads to the regional lymph
nodes, especially the posterior auricular and the
suboccipital group.
Secondary attack rate is 50-60% in family contacts and
almost 100% in closed populations like institution or
military barracks. Virus is shed in nasopharyngeal
secretions, blood, feces and urine during the clinical

illness. Virus can be spread 7 days prior to exanthema
and 7-8 days after its disappearance. Sub-clinical patients
are also contagious.
Etiology
The Rubella virus is a cubical, medium sized (70 nm) virus.
It is an RNA virus of the genus Rubivirus in the family
Togavirus.
Clinical Manifestations
Incubation period is 14-21 days. Initial prodromal
symptoms include malaise, headache, mild catarrhal
symptoms and low grade fever. Most characteristic
features are retro auricular, posterior cervical and post-
occipital lymphadenopathy. Discrete rose colored spots
on the soft palate (Forchheimer spots) may be seen in
approximately 20% patients before the onset of skin rash.
Skin rash is mostly discrete maculopapular but quite
variable in size and confluence. It starts on face and
spreads rapidly over trunk. Progression is so fast that by
third day it usually clears up. No significant desquama-
tion is seen in rubella. Occasionally conjunctivitis is
present. In women and young girls arthralgia and
polyarthritis may occur. Any joint can be involved but
small joints of hand are affected most frequently. It lasts
few days to few weeks and leaves no sequelae.
In pregnant women, Rubella virus can cross the
placenta and infect the developing embryo or the fetus
resulting in various congenital malformations. The exact
nature and extent of these malformations depend on the
gestational age of the affected fetus. Risk for congenital
defects is greatest with primary maternal infection.
Congenital defects occur in about 90% infants if maternal
infection occurs before 11 weeks of pregnancy and about
10-20% by the end of first trimester. This may result in
spontaneous abortion or birth of a severely malformed
baby. Maternal infection after 16th week is associated
with low risk of congenital defects.
Classically the Congenital Rubella Syndrome (CRS)
includes a triad of malformations – cataract, sensori-
neural hearing loss and congenital heart disease, most
commonly patent ductus arteriosus (PDA). CRS may also
be a disease with multisystem involvement, a wide
spectrum of clinical expression and long postnatal period
of active infection with shedding of viruses. It can also
lead to IUGR, microphthalmia, microcephaly, mental and
motor retardation.
Immunization and Infectious Diseases 373
Diagnosis
Confirmation is by serology or viral culture. IgM
antibodies are detectable in first few days of illness. Four-
fold rise in IgG in paired sera is also diagnostic.
Differential Diagnosis
It is often confused with mild variety of scarlet fever or
rubeola. Other viral illnesses like roseola infantum,
infectious mononucleosis, enteroviral infection and drug
rash closely resemble Rubella.
Prognosis
The prognosis of childhood Rubella is good, that of
congenital Rubella varies with the severity of infection
and organ involved.
Treatment
No specific antiviral therapy is available for Rubella.
Antipyretics are used for symptomatic relief.
Prevention
Rubella vaccine is a live attenuated vaccine. The vaccine
is available separately or as triple vaccine MMR that
contain measles, mumps and rubella. Principal goal of
rubella vaccination is to prevent CRS. The Global
recommendation now is two doses for MMR and
Varicella Vaccines – the first dose at 15 months and the
second at 4-6 years. It will be ideal to administer the
second dose at 5th year along with DTP booster and OPV.
Special care should be taken in reproductive females
to avoid pregnancy for 3 months after MMR vaccination.
But inadvertent vaccination during pregnancy is not an
indication for termination of pregnancy.
BIBLIOGRAPHY
1. Bhargava I. Measles. Control of measles, mumps and
rubella (1st edn). New Delhi: BI Churchill Livingstone,
1995.
2. Epidemiology and prevention of vaccine-preventable
diseases. 10th edn. Department of Health and Human
Services CDC. 2007.
3. India EPI fact sheet, 2003, country Fact sheet
WHOSEARO. 2004.
4. Mason WH. Rubella. In Kliegman RM, Jenson HB,
Behrman RE, Stanton BF (Eds). Nelson Textbook of
Pediatrics. 18th edn. Philadelphia: Elsevier 2007;
1337-41.
374 IAP Textbook of Pediatrics
9.19 Staphylococcal Infections
INTRODUCTION
Staphylococci are gram-positive cocci which grow in
clusters aerobically or as facultative anaerobes. Strains
are classified as coagulase positive, i.e. Staphylococcus
aureus responsible for most clinical problems and co-
agulase negative (e.g. S. epidermidis, S. saprophyticus, S.
hemolyticus).
Epidemiology
S. aureus are ubiquitous in healthy persons, patients,
animals and fomites. Most neonates are colonized within
the first week of life and 20 to 30 percent of normal
individuals carry S. aureus in the anterior nares at all times.
Coagulase negative Staphylococcus is also ubiquitous on
skin and mucosal surfaces. Transmission of Staphylococcus
occurs by direct contact or by spread of heavy particles
over a distance of six feet or less. Infection may follow
colonization which is favored by antibiotic therapy to
which Staphylococcus is resistant. Coagulase negative
Staphylococcus infection usually follows colonization or
direct inoculation during surgery.
Pathogenesis
Staphylococcus aureus is resistant to heat and drying. Its
pathogenicity depends on various cell wall components,
enzymes and toxins. Catalases, coagulase, hyaluronidase,
lipases and nucleases are cellular products with important
enzymatic actions. They produce a number of toxins, e.g.
exfoliative toxin A and B responsible for bullous impetigo
and scalded skin syndrome; staphylococcal enterotoxins
(Type A, B, C, C2, D, E) if ingested, result in diarrhea,
vomiting and hypotension. TSS toxin-1 is associated with
toxic shock syndrome. The development of staphylococcal
disease is related to resistance of host to infection and to
virulence of organism. Defects in mucocutaneous barrier
by trauma, surgery, foreign surfaces and burns increases
the risk of infection.
Clinical Manifestations
Staphylococcus aureus
Signs and symptoms depend on location of infection-
Skin infection—S. aureus is most common cause of loca-
AK Dutta, Anju Aggarwal
lized skin infection in the form of wound infection,
furuncles, carbuncles, folliculitis and impetigo. Impetigo
is common in children and affects exposed parts of the
body, i.e. face and legs. Children with recurrent
furunculosis should be investigated for nasal carriage,
phagocytic dysfunction and metabolic dysfunction.
Localized infection with diffuse skin rash is seen in the
form of staphylococcal scalded skin syndrome (SSSS) caused
by epidermolytic toxin produced by certain strains of
Staphylococcus aureus most often of phage group 2, type
70/71 or 51. This toxin produces superficial splitting of
skin with level of splitting high in epidermis. It starts as
macular erythema leading to flaccid bullae in 2 days.
Erosions crust and dry and heal with desquamation over
next 4 to 8 days leaving no sequelae. SSSS should be
differentiated from toxic epidermal necrolysis (TEN) in
which split is subepidermal and blisters are hemorrhagic.
TEN, scarlet fever, Kawasaki syndrome and toxic shock
syndrome are other differential diagnosis but all of them
have mucosal involvement.
Cellulits is more deep seated spreading infection of
the skin and needs systemic antibiotics for treatment.
Respiratory Infection
Staphylococcus aureus is a rare cause of otitis media and
sinusitis. It is reported to be a cause of pneumonia in 1 to
28 percent of lung aspirates and is more common cause
of pneumonia in neonates.
Septicemia and Bacteremia
They may be associated with any localized infection and
are usually seen at extremes of age and in immu-
nocompromised host organisms may subsequently
localize to any site, especially in lungs, heart, joints, bones
and kidney. This may lead to meningitis, osteomyelitis,
arthritis, pyomyositis and acute bacterial endocarditis.
Intestinal Tract
One of the following manifestations is seen:
• Staphylococcal enterocolitis follows use of broad
spectrum oral antibiotics leading to destruction of
normal bacterial flora and favoring staphylococcal
overgrowth.

• Peritonitis is seen in patients undergoing chronic
ambulatory peritoneal dialysis. Food poisoning is
caused by ingestion of enterotoxins preformed by
Staphylococcus contaminating food. Two to seven
hours after ingestion of toxin, sudden, severe
vomiting and watery diarrhea develops. Symptoms
usually subside within 12 to 24 hours.
Coagulase Negative Staphylococcus (CoNS)
CoNS causes nosocomial infection in patients with
indwelling foreign devices, (e.g. IV catheters, peritoneal
dialysis catheter, etc.) immunocompromised states, and
surgical trauma. Symptoms of bacteremia and septicemia
are seen. Infection may present as endocarditis and
urinary tract infection also.
Diagnosis
Diagnosis of Staphylococcus infection depends on isolation
of bacteria from skin lesion, abscess cavity, blood,
cerebrospinal fluid or other sites of infection. Diagnosis
of food poisoning is made on basis of normal flora,
epidemiological and clinical findings. CoNS may
contaminate blood cultures but bacteremia should be
suspected, if cultures grow rapidly (within 24-hr), when
two or more cultures are positive with same CoNS and
signs, and symptoms of CoNS are present.
Treatment
Intact skin is a powerful barrier against staphylococcal
infection. Hence, topical therapy with, bacitracin,
mupirocin or fusidic acid is enough for minor skin
infections and impetigo. Large abscesses should be
drained and systemic antibiotics should be administered.
Antibiotic therapy alone is not effective in individuals
with undrained abscesses or with infected foreign bodies.
Cellulitis should be treated with systemic antibiotics.
Since 90 percent of Staphylococcus aureus are resistant to
penicillin, therapy should be started with penicillinase
resistant antibiotics, e.g. methicillin, oxacillin, cloxacillin
or dicloxacillin. In cases resistant to these antibiotics
vancomycin or teicoplanin should be used. Linezolid,
daptomycin, quinupristin-dalfopeistin, vancomycin with
linezolid and gentamycin and vancomycin with
trimethoprim-sulphamethoxazole may be useful for
serious infections. Skin, soft tissue and minor upper
respiratory infection can be treated with oral antibiotics
dicloxacillin, oxicillin or nafcillin. Duration of therapy
Immunization and Infectious Diseases 375
depends on site and type of infection. Coagulase negative
staphylococci infection are treated with methicillin and
in cases resistant to methicillin vancomycin is used.
Toxic Shock Syndrome (TSS)
The term TSS was introduced by Todd et al, in 1978 for a
syndrome characterized by rapid onset of fever,
hypotension, erythroderma (early) and a delayed des-
quamation 1 to 2 weeks after onset, specially on palms
and soles. Diagnosis depends on clinical manifestations
as given below (Table 9.19.1). There is usually no specific
laboratory test for diagnosis. Multisystem involvement
is shown by increased creatinine, thrombocytopenia,
hypocalcemia, azotemia, hyperbilirubinemia, and leu-
kocytosis. Bacterial cultures usually reveal Staph. aureus.
Etiology and Epidemiology
It is usually seen in menstruating women between 15 to
25 years of age who use tampons or vaginal devices but
can occur in children and men with wounds, nasal
packing, sinusitis, osteomyelitis. Majority of cases are due
to Staph. aureus phage group 1 which produce number
of extracellular toxins, e.g. TSS 1 and enterotoxins
responsible for systemic manifestations.
Treatment
Patients should be treated with b lactamase resistant
antibiotics for 10 to 14 days. Intravenous vancomycin
show be started. Infected or colonized site should be
TABLE 9.19.1: Diagnostic criteria for Staphylococcal Toxic
Shock Syndrome
Major Criteria (all required)
• Acute fever (temp >38.8°C)
• Hypotension (orthostatic shock)
• Rash (erythroderma with deep desquamation)
Minor Criteria (any 3)
• Mucous membrane inflammation
• Vomiting, diarrhea
• Liver abnormalities
• Renal abnormalities
• Muscle abnormalities
• Central nervous system abnormalities
• Thrombocytopenia
Exclusionary Criteria
• Absence of another explanation
• Negative blood culture (except for S. aureus)
376 IAP Textbook of Pediatrics
drained and cleaned. Inotropic agents, and corticoste-
roids may be needed in few cases of severe hypotension.
Overall mortality is 3 percent.
Differential Diagnosis
TSS should be distinguished from Kawasaki’s disease
which usually occurs in children less than five years of
age and manifestations as myalgia, hypotension, and
diarrhea are not seen in Kawasaki’s disease. Scarlet fever,
leptospirosis and Rocky mountain spotted fever are other
differential diagnosis.
BIBLIOGRAPHY
1. Dolin R. Staphylococcal infections. In Mandell GL,
Bennett JE, Dolin R (Eds): Principles and Practice of
9.20 Pneumococcal Disease and its Prevention
INTRODUCTION
Pneumococcal disease is as old as antiquity known to
the human kind which could not be controlled effectively
despite extensive research by the medical science, nor
by the advent of newer and newer antimicrobials. This
is one of the most virulent invasive bacterial disease
under five years of age, though elderly population above
65 years of age are equally affected as well. Pneumococcal
disease is number one vaccine preventable cause of
childhood mortality worldwide.
ETIOLOGY
The causative organism ‘Streptococcus pneumoniae’ is a
gram positive lanceolate shaped encapsulated
diplococcus having a polysaccharide capsule which is
antigenic in nature and determines various serotypes of
the bacteria.
ETIOPATHOGENESIS
Person contracts the infection through respiratory
droplets and then spread occurs via nasopharyngeal
carriage. Once after gaining access the bacterium
pneumococcus has propensity to inhabitate in the
Infectious disease 4th edn. Churchill Livingstone: New
York 1995;17:54–84.
2. Hussain FM, Boyle—Vaura S, Bethal CD et al. Current
trend in community acquired methicillin resistant
Staphylococcus aureus at a tertiary care pediatric facility.
Ped Infec Dis J 2000;19:1163–66.
3. Jain A, Daum RS: Staphylococcal Infections in children:
Part I. Pediatr Rev 1999;20:183–91.
4. Miles F, Voss L, Segedin E, Anderson BJ. Review of
staphylococcus aureus injections requiring admission to
pediatric care unit. Arch Dis Child 2005;90:1274-8.
5. Todd J. Staphylococcal infections. In Behrman RE, Klieg-
man RM, Jenson HB (Eds ): Nelson Textbook of Pediatrics
(18th Edn). Saunders, Elseiver; India, 2007;1123-9.
6. Tunnessen WW Jr: Practical aspects of bacterial skin
infections in children. Pediatr Dermatol 1985;2:85.
Rohit C Agrawal
nasopharynx. From the nasopharynx the bacterium
causes the disease by oppsonising phagocytosis by two
modalities; first by direct spread in the adjoining areas
therby causing nonbacteremic pneumonia, sinusitis and
otitis media, secondly by invading the sterile fluid
compartments of the body like blood and CSF thereby
causing bacteremia, bacteremic pneumonia and
meningitis. The later conditions are known as “invasive
pneumococcal diseases (IPD)”.
CLINICAL SPECTRUM
Most vulnerable and the peak age for the invasive disease
is 6 to 18 months due to low immunity. The incidence
starts declining after 5 years only to rise again above 50
years of age. The children from day care centers, bottle
fed, malnutrited from overcrowdings and slums who are
constantly exposed to pollution and cross infections are
at risk for the disease. According to developed world
standards even an episode of otitis media in past and
the children who have received a course of antibiotics in
past one month are also at risk for this disease. The
children who have chronic lung, liver, heart and kidney
diseases, nephrotic syndrome, diabetes, CSF fistulae and
cochlear implants are at moderate risk for this disease.

Figure 9.20.1: Pleural fluid gram stain
Figure 9.20.2: Lanceolate shaped diplococci
Children with sickle cell disease, functional and
anatomical aspleenia and immunocompromised with
HIV or transplants are at very high risk for the disease.
Underlying Medical Conditions
• High risk
– Congenital or acquired immunodeficiency
– Sickle cell disease, asplenia, HIV
• Moderate risk
– Chronic pulmonary disease
– Chronic heart disease
– Chronic renal insufficiency, nephrotic syndrome
– Diabetes
Immunization and Infectious Diseases 377
– Prematurity
– Cerebrospinal fistula
– Existing or cochlear implants
• Presumed risk Age
– Child care outside – Children younger
the home than 2 years old
– Multiple courses of – Adults over 65 years
antibiotics in last of age
3 months
– Recurrent AOM
Multicentric IBIS Study done under INCLEN over
4 yrs from 1993-97 over a large no of population (5798
children) published in Lancet 1999 shows the distribution
of the invasive pneumococcal disease as follows
IBIS Study [INCLEN] [1993-97] [N-5798]
Meningitis 37.3%
Pneumonia 29.6%
Septicemia 7.6%
Peritonitis 7.3%
Others * 18.2%
[*Empyema, Arthritis, deepseated, Abscesses, etc.]
Bacteremia without focus beyond neonatal period is
the most common manifestation of the invasive disease
with a mortality rate of 40-50%. Of the survivors of
meningitis 25-50% are likely to get sequelae like MR,
seizures, hearing loss, blindness, spasticity, tube
placements, LDs, speech and language disorders and
restrictive lung diseases there by rendering the morbidity
a matter of major concern.
PNEUMOCOCCAL DISEASE BURDEN
According to a statement made by Dr. Lee Jong Wook
director general of WHO “every minute one child dies
of pneumococcal disease across the globe”. Out of
estimated 2.0 million deaths annually under 5 years of
age due to pneumonia globally, 0.9-1 million are alone
due to pneumococcal pneumonia out of which about 50%
are contributed by India and five other developing
countries. S. pneumoniae, the causative organism of
pneumococcal diseases is responsible for up to 50% of
CAP, 30-50% AOM, a significant proportion of bacterial
meningitis and bacteremia. It is number one cause of
bacteremia beyond the neonatal age. Although CFR is
only 10-22% versus 70% for pseudomonas, the total
number of deaths caused by pneumococcus exceeds
deaths caused by all other pathogens. Estimated
378 IAP Textbook of Pediatrics
incidences of this disease both invasive and noninvasive
are > 25-100 per 100000 < 5 yrs in developed world and
>250-500 per 100000 <5 yrs in developing world.
The epidemiological disease surveillance in India is
poor, the culture threshold is high and data on prevalence
of pneumococcal disease is scanty. According to IBIS
studies it is estimated that 12-35% of all IPD admissions
i.e. 6.6 million out of 22 million episodes of ARI are mostly
due to community acquired pneumococcal pneumonia
with approximately 0.2-0.4 million deaths. Younger the
age more invasive the disease with a peak between 6-18
months due to low immunity.
PREVENTION
The magnitude of pneumococcal disease burden both
invasive and noninvasive in India and developed world
as well is significant enough to warrant its prevention
on priority basis. The modalities of prevention are either
chemoprophylaxis or by effective vaccination. The
question arises why to immunize when antibiotics have
been shown to work and particularly when penicillin
resistance is been least in India (1.3-12.8%). If we glance
at the rapid emerging penicillin and multidrug bacterial
resistance the picture is as gloomy as follows
• First case of penicillin resistance in 1970 in US.
• US - 1988 - 4.1%, 1990-15%, 2000-33%.
• > 40% - Taiwan, Hong Kong, Sri Lanka.
• 10-40% - US, SA, Europe, China.
• < 10% - Pakistan, Malaysia, Australia.
• India: IBIS – 1.3%, Multicentric – 1 -4%,
ANSORP- 3.8-12.8%
Multidrug bacterial resistance in India is no rosy than
globally, which is evident from the following figures
• ANSORP Study (in 11 countries including India)
Average Resistance 35.85 %
• IBIS Study
SMX/TMP 56.3%
Erythromycin 4.2%
Chloromphenicol 16.6%
Penicillin 1.3%
Ceftriaxone 0%
Vancomycin 0%
• In Mumbai 4% in 1998 and 12% in 2000
Hence in the effective prevention and control of this
dreaded childhood bacterial disease with high mortality
and morbidity, immunization is not only “prudent” and
“must” but the “only” logical solution.
Pneumococci worldwide are developing resistance
to commonly used antimicrobials, including penicillin.
Over the past two decades there has been a rapid
emergence of antibiotic resistant pneumococci posing a
formidable threat to health in developed and developing
countries alike. Emerging antimicrobial resistance
emphasizes the need for preventing pneumococcal
infections by vaccination. Arrival of resistant pneumo-
cocci was however long overdue in India given the
inadvertent and irrational use of newer antimicrobials.
Though penicillin resistance is fortunately low and that
too intermediate, it is very likely to rise rapidly in near
future.
Nasopharyngeal carriage is an important factor in the
transmission and propagation of the disease. In a study
at a big public sector hospital in Mumbai 74% children
< 5 yrs of age were colonized with S. pneumoniae. In
ANSORP study on 227 Indian children average naso-
pharyngeal carriage rate was found to be 43.2% out of
which 12.8% isolates were PRSP. For the effective
prevention and control, a break in the chain of naso-
pharyngeal carriage is very important, which is only
possible by vaccination.
PNEUMOCOCCAL VACCINES
Historical Backgrounds
Polysaccharide vaccines were available as early as 1940s.
A 14 valent polysaccharide vaccine was used in USA in
1970 and found to be not very effective. A 23 valent non
conjugated polysaccharide vaccine was successfully
launched and licensed to use in US in 1987. However
being a polysaccharide it was “B” and not “T” cell
dependent; that is poorly immunogenic below the age
of 2 yrs, has low immune memory, does not reduce
nasopharyngeal carriage and does not provide herd
immunity. It has at best 70% efficacy against prevention
of invasive pneumococcal disease in high risk population
but no protection against non bacteremic pneumonia/
otitis media. It is quite a safe vaccine, but practically
useless < 2 yrs of age, when it is required most. In mid
2000 a conjugated polysaccharide vaccine was intro-
duced in US where the capsular antigens of S.
Pneumoniae were conjugated to a non toxic diphtheria
CRM 197 toxin as carrier protein, and thus rendering it
“T “ cell dependent there by making it potent to be used
< 2 yrs of age.

Serotypes
More than 90 serotypes and 45 serogroups have been
discovered world wide. According to IBIS study 36
serotypes were discovered in Indian subcontinent.
11-12 serotypes are the commonest, responsible for most
of the pneumococcal infections world wide, out of which
seven serotypes 4, 6B, 9V, 14, 18C, 19F and 23F are
commonest in developed countries and additionally 4
serotypes 1, 5, 7, and 3 are commonest in developing
countries. According to IBIS study most common
invasive serotypes in Indian children < 5yrs are 6, 1, 19,
14, 4, 5, 3, 29, 7, 15 and 23. Serotypes 1 and 5 together
constitute 29% of pneumococcal disease in India. The
serotype 1 which is the commonest in India is more
common in blood than CSF and also in children above 1
year of age.
The only one available 7 valent conjugated pneumo-
coccal vaccine containing serotypes 4, 6B, 9V, 14, 18C,
19F and 23F being licensed for universal immunization
since 2000 in US and 19 countries in the developed world,
meets successfully 80-90% coverage in those countries
but only 50-55% in the Indian subcontinent.
Immunogenicity- Safety - Efficacy profiles of PCV
Since this vaccine is used routinely in western and
developed countries, studies pertaining to above profiles
are available from those countries only.
Immunogenicity
PCV7 is a highly immunogenic vaccine. 100% of vac-
cinees are seroconverted after 3 doses, with protective
antibody correlates of 0.35 mcg/ml. However antibody
levels fall over a period of 1 yr, and after a booster dose
100% vaccinees are sero protected for many years due to
amenestic response on boosting with many fold rise in
GMC.
Safety
In a large study of 18000 vaccinees, barring few
insignificant local reactions like erythema and induration
and systemic reactions like fever > 38°C, rashes,
drowsiness, irritability, diarrhea and vomiting, no serious
adverse effects were seen. The side effects were similar
to HIB/MMR/DPaT, and less than DPwT.
Efficacy
Most of the studies available are from US and developed
world. NCKP (North California Kaiser Permanent) and
Immunization and Infectious Diseases 379
CDC (Center for Disease Control and Prevention)
studies showed an excellent efficacy of 97.4% in vaccine
serotypes, 89% in all serotypes and 65% in HIV positive
children. A whopping reduction in IPD to the tune of
94% was experienced within a span of 4-5 years after
the introduction of this vaccine in US for universal
immunization in the year 2000. Efficacy trials showed
30% reduction in radiologically diagnosed pneumonia,
13.3% in clinically diagnosed pneumonia and 8%
reduction in AOM. A trial in Gambia with this vaccine
showed an overall decline in childhood mortality by
16%. Apart from the direct benefits a significant decline
in pneumococcal disease in unvaccinated contacts of
the vaccinees was noticed following introduction of the
vaccine in the immunization program due to herd effect
resulting from reduced nasopharyngeal carriage
(Fig. 9.20.3).
What are the Qualities of PCV7?
• It provides efficacy both against IPD and non IPD in
children < 2yrs.
• It contains most of the invasive strains of pneumo-
cocci.
• It significantly reduces the incidence of nasopharyn-
geal carriage.
• It is efficacious against antibiotic resistant strains.
• It induces high avidity antibodies with amenestic
response on boosting.
• It is very safe and induces minimal and self-limiting
side effects.
• It is compatible with concomitant administration of
other vaccines like OPV/IPV, DTPw, DTPa, Measles,
HIB, HepB, Varicella, HepA, etc.
What are the Flip Points of PCV7?
• The burden of pneumococcal disease is the greatest
among malnourished, poor and unprivileged
children in India and thus assumes status of public
health importance and ideally should be available to
all the children. However due to its high cost it is
not. “Cost” is a big prohibitive factor.
• As of current data PCV7 covers only 52-55% of
pneumococcal serotypes in India. “ Limited serotype
coverage”
• Though a very small but there is emergence of a
challenge of “replacement of serotypes” there by
causing increase in the disease by other serotypes like
6A, 19A and 35, which are not cross protected.
380 IAP Textbook of Pediatrics

Figure 9.20.3: Efficacy against invasive pneumococcal disease (Adapted from Black S et al)

Who Should Receive it? Dose Schedule

Routine Special circum- High risk Healthy Children (PCV Vaccine)
stances (>2 yrs ) (> 2 yrs) • Dose is 0.5 ml IM
All < 2 yrs of age Children from day- Immuno compromised • Routine Vaccination: 3 doses at 6,10,14 weeks and 1
care centers/Bottle children booster at 15-18 months
fed • Catch up vaccination
All > 65 yrs of Multiple courses of Sickel cell disease, – 6-12 months: 2 doses 4-8 weeks apart and 1 booster
age (23 valent antibiotics Functional asplenia at 15 -18 months
non conjugated) and transplant – 12-23 months: 2 doses 8 weeks apart
patients – 24-59 months: single dose
Children with 1 or Ch. Lung, Heart and High Risk Children (PCV and PPV 23)
2 recent ear Liver diseases, DM
• If affordable, PCV should be given first. For
infections
children aged less than 5 years follow the schedule

mentioned above. For children older than 5 years a
single dose of PCV is recommended (Currently
available PCV 7 though licensed upto age 9 years,
has been shown to be safe and immunogenic in
children older than 9 years as well).
• In children aged 2 years or more, PPV 23 should
also be given as a single dose of 0.5 ml IM. If PCV
has been given earlier, a gap of 2 months must be
maintained between PCV and subsequent PPV 23.
• A high-risk child who has received PPV 23 in the
past but not PCV vaccine may be offered a single
dose of PCV vaccine at the time of presentation if 2
months have elapsed since receipt of PPV 23.
• Only one repeat dose of PPV 23 is recommended
only for children who have sickle cell disease, hypo-
splenia, asplenia, congenital/acquired immunodefi-
ciency, those on immunosuppressive therapy, renal
failure and nephrotic syndrome. The repeat dose of
PPV 23 may be given after 3-5 years if the child is less
than 10 years of age and after 5 years if child is aged
more than 10 years.
IAP Recommendations
IAPCOI recommends the use of the currently available
conjugate pneumococcal vaccine (PCV 7) after one to one
discussion with parents in healthy children aged less than
2 years
WHO position (2007) since Pneumococcus is a cause of
significant morbidity and mortality in less than 2yrs,
especially in the developing world, this vaccine should
be treated as one of the child survival strategy and should
be included in national immunization program in all
those countries where under 5 mortality is more than
50, despite its limited coverage.
What Holds Good for India in Future
More valent vaccines should be available. A 10 valent
vaccine by GSK with additional serotypes 1, 5, 7 and a
13 valent vaccine by Wyeth with additional 1, 5, 3, 7, 6A
and 19A are in pipeline. Advanced generation “Protein
Based” vaccines are in phase-I trials, which might cover
all the serotypes, may appear on horizon in next 5 – 10
years. For better compliance ideally these conjugated
vaccines should come in better combinations with other
Immunization and Infectious Diseases 381
vaccines. Not to emphasis, better disease surveillance and
broader epidemiological data should be available in
India.
Treatment - Antimicrobial
Penicillin is still most effective and the drug of choice in
pneumococcal disease. Penicillin resistance in India is
only 1.3-4% and that too intermediate (MIC levels
0.06-1 mcg/ml). The pneumococcus achieves the
resistance by alteration in the penicillin binding protein.
For non invasive pneumococcal diseases
i. Amoxycillin – 40 mg/kg/day in 2 to 3 divided doses
for 7 to 14 days.
ii. Ampicillin – 100 to 200 mg/kg/day in 4 divided
doses IV.
iii. Penicillin – 100000 to 200000 units/kg/ day in 4
divided doses IV.
The problem of intermediate resistance can be
overcome by doubling the dose of amoxycillin to 80 to
90 mg/kg.
For invasive pneumococcal diseases
Since the invasive diseases are dreadful and could be
fatal, the drugs of choice should be 3rd generation
injectable cephalosporins to which pneuomococci are
100% susceptible.
i. Cefotaxime 100-200 mg/kg/day in 3 to 4 divided
doses.
ii. Ceftriaxone 100 mg/kg/day in 2 divided doses.
Incase of high resistance to penicillin is suspected
(MIC level > 2 mcg / ml in CSF and 4 mcg / ml in blood)
or in case of life threatening meningitis drugs like
Vancomycin, Tiecoplanin or Rifampicin may be added.
CONCLUSION
Pneumococcal diseases are serious, common but
preventable.
BIBLIOGRAPHY
1. Black S, Shinefield H, Fireman B, et al. Efficacy, safety
and immunogenicity of hepavalent pneumococcal
conjugate vaccine in children. Pediatr Infect Dis J
2000;19:187-95
2. Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen
JR, et al. Efficacy, safety and immunogenicity of
382 IAP Textbook of Pediatrics
heptavalent pneumococcal conjugate vaccine in children.
Northern California Kaiser Permanente Vaccine Study
Center Group. Pediatr Infect Dis J. 2000;19:187-95
3. Center KJ, Prevenar Vaccination: Review of the global
data 2006. Vaccine 2007; 25:3085-9
4. Centers for Disease Control and Prevention. Direct and
indirect effects of routine vaccination of children with 7-
valent pneumococcal conjugate vaccine on incidence of
invasive pneumococcal disease – United States, 1998-
2003. Morb Mortal Wkly Rep. 2005;54 (36): 893-897.
5. Cutts FT, Zaman SM, Enwere G, Jaffar S, Levine OS,
Okoko JB et al. Efficacy of nine-valent pneumococcal
conjugate vaccine against pneumonia and invasive
pneumococcal disease in The Gambia: randomized,
double-blind, placebocontrolled trial. Lancet 2005;
365:1139-1146
6. Fishman SM, et al. Childhood and maternal under-
weight. In Ezzati, MA. Lopez A. Rodgers and C. Murray,
eds. Comparative Quantification of Health Risks: The
Global and Regional Burden of Disease Attributable to
Selected Major Risk Factors, World Health Organization,
Geneva, 2004.
7. Hausdorff WP, Bryant J, Kloek C, et al. The contribution
of specific pneumococcal serogroups to different disease
manifestations: implications for conjugate vaccine
formulation and use, part ii. Clin Infect Dis 2000;30:
122-40.
8. Hausdorff WP, Bryant J, Paradiso PR, et al. Which
pneumococcal serogroups cause the most invasive
disease: implications for conjugate vaccine formulation
and use, part 1. Clin Infect Dis 2000;30(1):100-21.
9. Invasive Bacterial Infection Surveillance (IBIS) Group.
Prospective Multicentre hospital surveillance of
Streptococcus pneumoniae disease in India. Lancet
1999;353(9160): 1216-21.
10. Jodar L, Butler J, Carlone G, Dagan R, Goldblatt D,
Kayhty H et al. Serological criteria for evaluation and
licensure of new Pneumococcal conjugate vaccine
formulation for use in infants. Vaccine 2003;23:32653272.
11. Levine O, Cherian T. Pneumococcal vaccination for
Indian children. Indian Pediatrics 2007; 44: 491-96.
Available from: URL:http://www.indianpediatrics.net/
july2007/491.pdf
12. MMWR September 16, 2005/54 36;893-97.
13. National Health and Family Welfare Survey3, Ministry
of health and Family Welfare, Government of India, 2007.
14. Poehling KA, Talbot TR, Griffin MR, Craig AS, Whitney
CG, Zell E et al. Invasive pneumococcal disease among
infants before and after introduction of pneumococcal
conjugate vaccine. JAMA.2006;29:1668-74
15. UNICEF, Pneumonia, the forgotten killer of children,
2006.
16. Whitney CG, Farley MM, Hadler J, et al. Decline in
invasive pneumococcal disease after the introduction of
protein – polysaccharide conjugate vaccine. N Engl J Med
2003;348(18):1737-46.
17. WHO, Pneumococcal conjugate vaccine for childhood
immunization—WHO position paper. Wkly Epidemiol
Rec 2007 Mar 23:82:93-104. Available from: URL:http://
www.who.int/wer/2007/wer8281.pdf

9.21 Hemophilus Influenzae b Disease
Hemophilus influenzae b (Hib) is an important etiology for
meningitis, pneumonia and other invasive infections in
children younger than five years. Serotype b is
responsible for nearly all episodes of meningitis and most
cases of severe pneumonia caused by Hemophilus
influenzae b.
Epidemiology
H. influenzae type b is a natural organism of upper
respiratory tract. Mode of transmission is person to
person mainly by inhalation if droplets. Incidence of Hib
was very high in the prevaccination era. In USA it
accounted for upto 40 percent of pneumonia and
meningitis. With introduction of Hib vaccine incidence
of invasive Hib disease decreased by 99 per cent.
Although firm figures on incidence are lacking there
is evidence for the presence of both Hib meningitis and
pneumonia in India. The invasive bacteria infections
surveillance (IBIS) group study from six-sentinel centers
across the country during 24 months period revealed:
Of the 58 isolates, 96 percent were due to H. influenzae b,
in children less than five years and 69 percent of these
were due to meningitis. The authors concluded that there
is evidence to show substantial burden of Hib disease in
India. Approximately 20 per cent of the mortality due to
lower respiratory tract infection is believed due to
invasive Hib disease.
Etiology
Hib disease is caused by Haemophilus influenzae b which
are small, nonmotile, gram-negative cocco bacilli. Six
serotypes a, b, c, d, e, and f have been defined. The strains
responsible for invasive symptoms are genetically
capsulated forms of type b, is found in 95 percent of cases.
Clinical Manifestations
In infants and young children Haemophilus influenzae b
(Hib) is a major cause of meningitis, pneumonia, sinusitis,
septic arthritis, cellulitis and empyema epiglotitis. It may
also cause purulent pericarditis, endocarditis, conjuncti-
vitis, osteomyelitis, peritonitis and epididymoorchitis.
Immunization and Infectious Diseases 383
RK Agarwal, Anju Aggarwal
In the neonate wherein nontypable H. influenzae is
more common the disease manifests as septicemia,
pneumonia, respiratory distress syndrome with shock,
conjunctivitis, scalp abscess or cellulitis, meningitis,
mastoiditis and septic arthritis.
Diagnosis
The diagnosis by immunological tests like latex aggluti-
nation, counter immunoelectrophoresis (CIE) coagu-
lation tests are confirmatory in over 90 percent of cases
of pyogenic meningitis. For respiratory infections CIE
has been shown to be better than LA (sensitivity in serum
38%; in urine 22 and 44% in concentrated urine). The
specificity is 90 percent in blood culture in children with
H. influenzae infections. Monoclonal antibody tests are
superior to LA and CIE for rapid diagnosis.
Management
Initial antibiotic therapy in meningitis caused by Hib is
cefotaxime or ceftriaxone. Combination of ampicillin and
chloramphenicol can be used but the resistance is
increasing. Duration of therapy is 10 days. Oral amoxy-
cillin should be used for otitis media and pneumonia for
5-7 days. Combination of amoxycillin and clavulanic acid
should be used if there is β lactamase producing strains.
chemoprophylaxis with rifampicin in a dose of 20
mg/kg/day for 4 days as single oral dose not exceeding
600 mg/day eradicates Hib from pharynx in approxi-
mately 90 percent of cases.
Prevention
Significant decline has been recorded in the incidence of
Hib disease worldover where Hib vaccine has been
included in the National Immunization Schedule. The
vaccine can be given in monovalent or combination
formulation. In geographical region where the burden
of Hib disease is unclear, efforts are made to evaluate
the magnitude of this problem. In view of the demon-
strated safety and efficacy of the Hib conjugate vaccines,
Hib vaccine should be included, as appropriate to
national capacities and priorities, in routine infant
384 IAP Textbook of Pediatrics
immunization program. For further details, refer Chapter
8.3 newer vaccines.
BIBLIOGRAPHY
1. American Academy of Pediatrics. H. influenzae infection.
In 2006 Rec Book: Report of Committee of Infections
Diseases, 27th edition. Elk Grove Village IL: American
Academy of Pediatrics 2006;310-8.
2. Funkhauser A, Steinhoff MC, Word J. Haemophilus
influenzae disease and immunization in developing
countries. Rev Infect Dis 1991;13:S542-54.
3. IBIS (Invasive Bacterial Infectious Surveillance Group).
Invasive Haemophilus influenzae disease in India: A
preliminary report of prospective mutihospital surveil-
lance, Pediatr Infect Dis J 1998;17:S169-71.
9.22 Typhoid Fever
Salmonella group of organisms are responsible for variety
of manifestations such as gastroenteritis, meningitis,
osteomyelitis and abscesses. Typhoid fever is one of the
most important diseases caused by Salmonella typhi. It is
an acute systemic febrile illness. It is exclusively present
in humans. It is an important public health problem in
India. Recently, it has assumed serious proportions,
especially due to increasing bacterial resistance to
multiple antibiotics.
Salmonella organisms are gram-negative bacilli,
motile and having flagella. They possess flagellar antigen
(H) and somatic antigen (O). There exists many
subgroups of these organisms. Most common pathogen
causing typhoid fever is S. typhi. Other subgroups such
as Paratyphi a and b lead to paratyphoid fever, which is
a milder form of typhoid fever. Paratyphi a infection is
prevalent in India but Paratyphi b is rare. There also occurs
other non-typhoidal Salmonella infections.
Epidemiology
S. typhi infection occurs only in humans. It is endemic in
India. It is transmitted by feco-oral route through
contaminated water or food. Acutely infected patients
excrete bacilli in their stool and urine for a variable period
of few weeks. About five percent of infected adults
become chronic carriers who continue to excrete bacilli
4. Levine OS, Schwartz B, Pierce Kane M, Development,
Evaluation and implementation of Haemophilus
influenzae type b vaccines for young children in
developing countries: Current status and priority actions,
Pediatr Infect Dis J 1998;17:S95-113.
5. Petola H. Spectrum and burden of severe Haemophilus
influenzae type b disease in Asia. Bull WHO 1999;77:878-87.
6. Wenger JD. Epidemiology of Haemophilus influenzae
type b disease and impact of Haemophilus influenzae
type b conjugate vaccines in United States and Canada.
Pediatr Infect Dis J 1998;17:S132-6.
7. WHO, Global Programme for Vaccines and Immuni-
zation: The WHO position paper on Haemophilus
influenzae type b conjugate vaccines. Wkly Epidemiol
Rev 1998;73(10):64-71.
YK Amdekar
in their excreta for a year or longer. It is the adult carrier
who serves as a reservoir of infection. Food handlers and
cooks are potent sources of infection. Most of the infected
children cease to excrete bacilli within 2 to 3 months and
are rarely chronic carriers. Epidemics occur as a result of
contaminated drinking water supply, poor sanitation and
personal hygiene, overcrowding and poverty. Typhoid
fever was on the decline in the last decade and the
estimated incidence was less than 1/1000 population.
However, in the 90s it has gone up by 15 to 20 times.
This is due to variety of adverse factors including laxity
in immunization against typhoid and emergence of
multidrug resistance. Older children and young adults
are most commonly infected though 10 percent cases
occur below five years of age and 1 to 2 percent even
below two years.
Pathogenesis
Incubation period averages to be around 10 to 14 days.
After oral ingestion, bacilli reach the intestines passing
gastric barrier and attach themselves to the mucosa and
partially penetrate the intestinal wall. They are ingested
by the phagocytic cells where they multiply and finally
enter the bloodstream via lymphatics. After transient
bacteremia, bacilli are seeded in various organs like liver,
spleen, gallbladder and bone marrow where they

multiply further. This phase heralds the onset of clinical
illness. Bile serves as a good culture medium for the
growth of organisms and gallbladder discharges large
number of organisms into the intestines. Peyer’s patches
and other lymphoid follicles take up the bacilli, get
inflamed and sloughed off to form typical typhoid ulcers,
which may lead to two most dreaded complications—
hemorrhage and perforation, especially in absence of
proper treatment.
Clinical Manifestation
The disease starts with an acute onset of fever, which
gradually rises over next 2 to 3 days. During this phase,
diagnosis of typhoid fever can hardly be suspected
clinically. Therefore, persistent high fever, toxic look,
coated tongue, gaseous distended abdomen with gurgling
in the lower part and hepatomegaly merit high index of
clinical suspicion of typhoid fever. Fever is high and
continuous, rarely touching the baseline. By the end of
first week, small soft splenomegaly appears often with
symptoms/signs of mild bronchitis. In 25 to 30 percent
of patients, liver involvement is more pronounced with
tenderness and at times mild jaundice. Right hypo-
chondrial pain and tenderness may be severe indicating
presence of acalculous cholecystitis. Signs of meningism
are at times elicited without accompanying meningitis.
Though every organ in the body may be involved in
typhoid fever, clinical manifestations of pneumonia,
myocarditis, osteomyelitis, meningitis, arthritis, etc. are
rare. In fact, characteristic bradycardia seen in adults in
typhoid fever is lacking in children.
Complications of typhoid fever are fortunately rare
in children. Intestinal hemorrhage has been reported in
one to two percent of patients and perforation in
< 0.5 percent. They occur in second week of the illness,
especially in children who remain untreated without
antibiotics. Sudden drop in fever with signs of shock,
pallor or signs of peritonitis suggests the onset of
complications. Late focal infections such as meningitis
endocarditis osteomyelitis, or pneumonia can occur.
Clinical diagnosis of typhoid fever in a previously
immunized child is not easy as disease may manifest with
atypical presentation and progress. Fever may not be
high and continuous. In fact, any pattern of fever is
possible and child may not appear toxic. Typical
abdominal signs may also be absent, which makes clinical
diagnosis very difficult. It is the persistence of fever
Immunization and Infectious Diseases 385
beyond a week without any obvious clue that should
raise the suspicion of probable diagnosis of typhoid fever.
Blood culture is the only definite diagnosis of typhoid
fever especially in immunized children as Widal’s test is
often difficult to interpret due to presence of pre-existing
antibodies.
Diagnosis of typhoid fever in a child who is already
on antibiotic therapy possesses a challenge, as blood
culture sent after an antibiotic administration is often
negative. It is important in general not to start an anti-
biotic without proper attempt at diagnosis.
Diagnosis
Isolation of organisms from blood culture in the first
week and from stool and urine samples in subsequent
weeks is the ideal confirmative test, which should be
pursued in every case of typhoid fever. Clot culture has
proved to be a useful test. Clot is lysed by streptokinase
and inoculated into culture media as for blood culture.
Serum left over from the sample is used for serological
tests.
Widal’s test measures antibodies to S. typhi, paratyphi
a and b. It is ideal to perform the test on a paired samples
of sera, one taken in an acute phase of illness at the end
of first week and another one, a week later. Rising titer
of antibodies is diagnostic. Interpretation of a test on a
single sample is unreliable, as the disease is endemic in
India and a baseline antibody titer in the community may
be high. High antibody titer against “O” antigen may
suggest recent infection. Previous immunization with TA
vaccine may account for the antibodies though oral
typhoid vaccine and VI antigen vaccine do not contribute
to the presence of these antibodies. Anamnestic reactions
are seen, especially with “H” antigens in patients with
fever of different etiologies unrelated to typhoid fever.
Antibodies rise only at the end of the first week and
Widal’s test may be negative in early stage of the disease.
It may also be negative if antibiotics are administered
too early in the course of the disease. Hence, Widal’s test
alone should not be relied upon in the diagnosis of
typhoid fever.
Hemogram shows nonspecific findings but leuko-
penia with eosinopenia in a typical clinical setting may
be highly suggestive and should be preferably followed
by blood culture prior to starting antibiotic therapy.
Appearance of eosinophils on the follow-up hemogram
heralds the beginning of recovery and is observed early
386 IAP Textbook of Pediatrics
in the course of defervescence of fever. Hepatic enzymes
(SGPT) show mild elevation in most patients and serum
bilirubin levels may be raised in few of them, generally
up to 5 mg percent. Abdominal sonography reveals
presence of acalculous cholecystitis in about 30 percent
of patients.
Management
Since the introduction of chloramphenicol in the
treatment of typhoid fever, defervescence of fever was
usually achieved within one week as compared to natural
course of illness spanning over 3-4 weeks. Mortality also
came down from 10 percent to almost 1-2 percent and
rate of complications was reduced significantly. However
in the last 5 years, with emergence of multidrug resistant
strains of S. typhi the course of illness is altered. In spite
of use of newer antibiotics, clinical course is often
prolonged to more than a week, though fortunately,
mortality has remained low.
Chloramphenicol has been the drug of choice till
recently. It is administered in dose of 50 to 100 mg/kg
body wt/day in three divided doses. It is given orally
except in very sick children in whom it may be given
intravenously. It takes about a week to control fever and
the drug must be continued for another week. Relapse
may occur in spite of proper treatment and carrier state
is not prevented by this drug. Major toxic effect of
chloramphenicol is aplastic anemia and is not dose
related. Fortunately, it is rare. Other drugs useful in the
treatment of typhoid fever are ampicillin, amoxicillin and
cotrimoxazole. Furazolidone has also been used even
though the drug is poorly absorbed from intestines and
thus has mainly a local effect and not a systemic effect.
Hence, this drug alone is not recommended for serious
infection.
Emergence of multidrug resistant typhoid fever has
necessitated use of newer antibiotics like cephalosporins
and quinolones. Oral cefuroxime or parenteral third
generation cephalosporins such as ceftriaxone or
cefotaxime are effective. Quinolones have an advantage
of convenient dosage forms but the probable toxic effect
on the growing cartilage is considered against its routine
use. However, it may be used in case no better drug is
available. Quinolones are efficacious, convenient and
cost-effective. The recent epidemic of multidrug resistant
typhoid fever has forced clinicians to use oral ciprofloxa-
cin with good results. Safety of this drug is reasonably
established if used for a short-time in otherwise normal
patients. This drug has an advantage of preventing
relapse and carrier state.
Supportive management includes bedrest, low
residue normal family diet, adequate hydration and
antipyretics for fever.
Prevention
Proper hygienic measures and consumption of clean
uncontaminated food and water ensures reasonable
prevention. Conventional TA vaccine against typhoid
and paratyphoid has an efficacy of about 70 percent.
Newer vaccines against typhoid are oral TY21 and
parenteral VI antigen vaccine. Both of them have similar
efficacy as that of TA vaccine. Thus, routine immuni-
zation with any of these vaccines is recommended after
the age of two years.
For IAP - Infectious Diseases Chapter Protocol on
Enteric Fever, refer to Chapter 36.11.2, Page No. 1528.
BIBLIOGRAPHY
1. Adam D. Use of quinolones in pediatric patients. Rev of
Infect 1989;2:1113–16.
2. Ashkenazi S, Cleary TG. Salmonella infection. Nelson
Textbook of Pediatrics (15th ed) 1996;784–90.
3. Koul PB. Multidrug resistant S. typhi infection: clinical
profile and therapy. Indian Pediatr 1991;28:357–61.
 Immunization and Infectious Diseases 387

9.23 Leprosy
Rajeshwar Dayal

Leprosy, also known as Hansen’s disease, is a chronic Direct Transmission

granulomatous disease caused by Mycobacterium leprae.
For direct transmission, a prolonged and close contact is
It particularly affects the skin and nerves besides affecting
required. An “Intrafamilial” contact with a patient is
all the organs.
more risky than an “Extrafamilial” one.
According to WHO, out of a total of 2,31,361
Untreated lepromatous patients discharge as many
registered cases of leprosy in the world in June 2007,
as 100 million bacilli from their nasal secretions everyday.
82,801 were residing in India. The global prevalence rate
These bacilli remain viable outside the human body in
is below 1/10,000 population. Only 4 countries in the
the nasal secretions for several days. Inhalation of these
world - Brazil, The Democratic Republic of Congo,
bacilli, via droplets, is now regarded as the most common
Mozambique and Nepal have yet to achieve the goal of
mode of entry of leprosy bacilli into contact person. After
eliminating leprosy as a public health program.
inhalation, these inhaled leprosy bacilli enter the
India achieved the leprosy elimination target at the
respiratory system from where they are disseminated by
end of 2005. Though the total number of registered cases
blood to skin and peripheral nerves where depending
of leprosy came down to about 82,800 in India (a
on the host immune response, the disease may manifest
prevalence rate of 0.84 cases/10,000 population ), the new
either as tuberculoid leprosy( where there is good cell
case detection rate did not reduce concomitantly. A total
mediated immune response to M.leprae) or may manifest
of 1,39,252 new cases were detected in the year 2007.
as lepromatous leprosy (where there is anergy to
Pediatric leprosy constitutes about 10% of the total
M.leprae).
disease burden. The age group most commonly affected
Other portals of entry include scratched, abraded or
in the pediatric leprosy population is 5-14 years, though
insect bitten skin which facilitates passage of organism
in very high endemic countries, prevalence in age groups
via the droplets laden with with leprosy bacilli through
0-4 years is also significant. Leprosy affects males more
the epidermis into the dermis, and ingestion of infected
than females. It is not a hereditary disease and it was
breast milk.
found that infants born to leprous parents, if separated
soon after birth and protected from the exposure, escaped Indirect Transmission
from the disease. HIV infection has not been documented
M.leprae remains viable for several days outside the
to alter the risk of leprosy in areas of high prevalence.
human body. Occasionally, leprosy may spread by
Achieving eradication of the disease from the fomites being used by a patient suffering from multi-
elimination stage is a giant task. It requires, the cases to
bacillary leprosy. Localized infection via infected
be identified at an early stage and treated promptly so
syringes and tattooing needles have been reported.
that deformity and spread of infection can be prevented.
For the diagnosis of early and suspicious cases of leprosy CLINICAL MANIFESTATIONS
newer diagnostic concepts of molecular biological
approaches like PCR, in situ PCR and in situ Hybridi- Incubation period: This varies from a few months to as
sation have evolved and are the need of the time. long as 20 years with an average between 2 and 5 years.
Onset of this disease is usually gradual but may be
SOURCE OF INFECTION AND sudden in highly susceptible people.
MODE OF TRANSMISSION Early Signs of the Disease
The only source of infection is the infected human The early signs include:
being. The capacity of multibacillary leprosy patients • A hypopigmented patch in the skin, present for a
to infect is 4-11 times that of patients with pauci- long duration, non irritating with loss of sensation
bacillary leprosy. to touch, pain and temperature.
388 IAP Textbook of Pediatrics
• Thickening of the skin, more red and shiny in
appearance than the surrounding parts; this is more
prominent on face and hands.
• Loss of sensation, numbness, feeling of “pins and
needles” or “crawling of ants”, tingling sensation in
any part of the body, especially in hands and feet.
There may be paresis in hands and feet or difficulty
in fine movements of fingers.
• Appearance of spontaneous blisters and ulcers,
especially in the fingers.
CLASSIFICATION OF THE DISEASE
According to the classification laid down by Indian
Association of Leprologists, the cases have been divided
into 5 broad groups viz, indeterminate, borderline,
tuberculoid, lepromatous and polyneuritic.The border-
line group is further subdivided into BB, BL and BT types.
Indeterminate Leprosy
This type of leprosy is seen in only 10 to 20 percent of
infected individuals and is the earliest detectable form
of leprosy.
This is characterized by presence of a single
hypopigmented macule measuring 2 to 4 cm in diameter,
with a poorly defined border without any erythema or
induration. Anaesthesia may be minimal or even absent.
Biopsy may show a granuloma but bacilli are rarely seen
in the section. In 50 to 75 percent of patients this lesion
heals spontaneously, and in the remaining cases it
gradually progresses to one of the classic forms.
Tuberculoid Leprosy
It is characterized by the presence of single or few
asymmetrical, well defined, hypopigmented, erythe-
matous or copper colored patches with sensory
impairment. The entire patch or only its margins is raised
above the level of the surrounding skin. At times, these
patches may not be raised above the level of the
surrounding skin.
Initially, a single nerve trunk related to the lesions is
affected .The nerve trunk becomes enlarged, hard, tender
and later may form a nerve abscess.
In this form of leprosy, the lepromin test is positive
and there is absence of bacilli in the skin smear. On
biopsy, foci of lymphocytes, epitheloid cells arid
Langhan’s giant cells are seen.
This form of leprosy is the most common, especially
in children and is relatively benign and stable with a good
prognosis.
Borderline Leprosy
Borderline leprosy is further classified into 3 subtypes,
on clinical and histological criteria.
Borderline Tuberculoid (BT) Leprosy
Here the lesions are greater in number but smaller in
size than in tuberculoid leprosy. There may be small
satellite lesions around older lesions and the margins of
the borderline tuberculoid lesions are less distinct and
the centre is less atrophic and anaesthetic.This form
usually involves thickening of 2 or more superficial
nerves.
Mid Borderline (BB) Leprosy
In this subtype, the lesions are more numerous and
heterogenous.The lesions may become confluent or even
plaques may be present. The borders are poorly defined
and the erythematous rim fades into the surrounding
skin. Hyperanaesthesia is more common than anesthesia.
Borderline Lepromatous (BL) Leprosy
In borderline lepromatous leprosy there are a large
number of asymmetrically distributed lesions which are
heterogenous in appearance. Macules, papules, plaques
and nodules may all co-exist. Usually, the individual
lesions are small unless confluent. Anesthesia is mild and
superficial nerve trunks are spared.
Neuritic Leprosy
This may be of primary or secondary variety. In the
former, the nerves are directly infected without any skin
lesion while in the latter infection spreads up the nerves
from leprous skin lesions. The affected nerves become
thickened and tender, producing sensory motor and
trophic changes in their areas of distribution,This
dysfunction leads to deformities, neuropathic ulcers and
lagophthalmos which may result in serious eye
complications.
Neuritic leprosy most commonly involves the ulnar,
median, lateral popliteal, tibial, great auricular and rarely
radial nerves. lt also affects the V and VII cranial nerves.
 Immunization and Infectious Diseases 389

Lepromatous Leprosy result in extreme anesthesia. The skin smear is almost

Most cases of lepromatous leprosy develop from
borderline leprosy (BB or BL). This form of leprosy is
relatively uncommon in the pediatric age group. There
are two symptoms, which may precede the classical skin
lesions by months or years, and serve to alert the
physician to a possible early diagnosis. They are: (i) nasal
symptoms and (ii) edema of legs. The nasal symptoms
chiefly constitute, stuffiness, crust formation and blood
stained discharge. Edema of legs and ankles is always
bilateral, usually prominent late in the evening and
disappears after overnight rest.
Skin lesions may take the form of macules, papules,
nodules and a combination of them. Numerous sym-
metrically distributed erythematous or coppery, shiny,
macules with ill defined margins are usually the first ones
to appear. Patients may have a leonine face due to loss
of eyebrows and eyelashes. There is no sensory
impairment in these lesions but as the disease progresses,
many peripheral nerves get symmetrically affected. Due
to enormous bacillary infiltration, nerves are initially
softer and larger than normal and are tender. In advanced
cases, nerves become thin and hard due to fibrosis and
always positive and the lepromin test is negative.
This form of leprosy (LL) is the most infectious, prone
to lepra reactions and if left untreated, the prognosis is
poor.
The features of these varieties of leprosy are
summarized in Table 9.23.1. As age advances, the disease
moves from tuberculoid end of the spectrum towards
the lepromatous end.
Reactions
Reactions are acute exacerbations due to changes in the
host parasite immune relationship. They are common
during initial years of treatment.
The following types are noted:
1. Type 1: Reversal reaction: This is seen in borderline
cases and consists of acute tenderness and swelling
at the site of lesion. Irreversible nerve injury can occur
if this reaction is not treated immediately.
2. Type 2: Erythema nodosum leprosum reactions (ENL):
This occurs in lepromatous and borderline lepro-
matous cases as a systemic inflammatory response.
There is high fever, migrating polyarthralgia, orchitis,

TABLE 9.23.1: Clinical aspects of tuberculoid, borderline and lepramatous leprosy

Observation Types of leprosy

of tests
TT BT BB BL LL

Number of Single usually Single or few Several Many Very many

lesions
Size of lesions Variable Variable Variable Variable Small
Surface of lesions Very dry, Dry Slightly shiny Shiny Shiny
sometimes scaly
Sensation of Absent Markedly Moderately Slightly diminished Not affected
lesions diminished diminished
Hair growth Absent Markedly Moderately Slightly diminished Not affected
diminished diminished
AFB in lesion Nil Nil or scanty Moderate numbers Many Very many (plus
globi)
AFB in nasal Nil Nil Nil Usually nil Very many
scrapings or in (plus globi)
nose blows
Lepromin test Strongly Weakly Negative Negative Negative
positive positive
(+++) (+ or ++)

AFB-Acid Fast Bacilli ; TT-Tuberculoid; BT- Borderline Tuberculoid; BB- Mid Borderline ; BL- Borderline Lepramatous; LL-Lepramatous
Leprosy
390 IAP Textbook of Pediatrics
iridocyclitis and lymphadenitis. Tender red papules
or nodules resembling erythema nodosum are seen
characteristically.
DIAGNOSIS
Diagnosis of leprosy is based on the presence of any one
of the following cardinal signs:
1. Characteristic skin lesion with partial or total loss of
sensation in the affected skin lesion or in the area of
the skin supplied by the peripheral nerve involved,
with or without the presence of thickened nerves.
2. Presence of acid fast bacilli in the skin smear.
Smear Examination
Sites of bacteriological examination are usually the most
affected parts of the lesion. If no definite patches or areas
of thickened skin are visible, smear should be taken from
ear lobules and buttock. Smears should be made by “slit
and scrape” method and stained by Ziehl-Neelsen
staining. Smears are positive in LL, BL and some BB and
BT cases. It is of limited help in TT and indeterminate
lesions and patients with early atypical clinical
presentation.
Histopathology
In some cases of indeterminate lesions it becomes
necessary to carry out a histological examination for the
purpose of diagnosis and classification of the lesion.
Bacillary Index
It is a semiquantitative estimation of the density of bacilli
present in the skin smears and, biopsies and is measured
on two scales, namely the Dharmendra scale and Ridley
scale. It measures the total acid fast bacilli in microscopic
field, which includes both live and dead bacilli.
Patients are labeled as having paucibacillary infection
when there are < 5 skin lesion and no bacilli on skin
smears. They are labelled as having multibacillary
infection when there are > 6 skin lesions and bacilli are
present on skin smears. The bacterial index can range
from 0 (No bacilli in 100 oil immersion field) to 6 (>1000
bacilli per field).
Immunological Methods
Test for Cell Mediated Immunity
Lepromin test: Lepromin test is not a diagnostic test for
leprosy but it has been found to be useful for
classifying the disease. This test is positive in cases of
TT and BT, negative in LL, BL and weakly positive
and variable in BB leprosy. The lepromin negative
contacts have been found to be at a much higher risk
of developing disease, than the lepromin positive
contacts. This test signifies immunity of person, i.e.
cell mediated immunity against Mycobacterium leprae
or its antigen. Two kinds of lepromin are commonly
used (a) crude antigen of Mitsuda, and (b) the refined
antigen of Dharmendra.
Serological Assays
Specific serological tests can detect subclinical infection.
The major serological assays include:
Fluorescent leprosy antibody absorption test (FLA-ABS): This
technique is highly sensitive in detecting the antibodies
against M. Leprae antigen by immune-fluorescent
technique and is useful in identifying healthy contacts
of patients who are at risk of developing disease.
Radioimmunoassay (RIA): It detects antibodies to the cell
wall antigens of M. Leprae.
Enzyme-linked immunosorbent assay (ELISA): PGL-ELISA
was found highly positive in multibacillary cases, but
positivity in paucibacillary and subclinical cases was
quite low.
Further simplified dot ELISA and dipstick ELISA
using a monoclonal antibody targeting PGL-1 have also
been studied.
Serological testing is not useful for diagnosis as it does
not detect most paucibacillary cases and it remains
positive even after treatment of multibacillary patients.
MOLECULAR BIOLOGICAL APPROACHES
Identification of organisms can be done in a more rapid
and specific way, both from culture and directly from
clinical specimen, by recombinant DNA technology.
Based on the gene sequences of M.Leprae, several probes
have been designed in recent years. Our institute has also
studied the probes developed at Agra and found them
to be of immense help for early diagnosis of the disease.
During the recent years, several gene amplification
techniques (PCR) for amplifying M. Leprae specific
sequences from variety of specimens have been pub-
lished. These have been reported to be highly sensitive
and specific.
 Immunization and Infectious Diseases 391

In Situ PCR TABLE 9.23.2: Dosage of antileprosy drugs for children

with paucibacillary leprosy (Indeterminate, TT, BT)
Our study has shown that in situ PCR, with the added
advantages of providing structural correlates and Age group Dapsone: Daily dose Rifampicin: monthly
(Yrs) Unsupervised (mg) dose supervised (mg)
permitting concomitant study of tissue pathology,
improves the diagnostic yield especially in early and 3-5 25 150-300
doubtful cases of leprosy where the histopathology is 6-14 50-100 300-450
15 100 600
non- specific.

In Situ Hybridization
Again our pioneer study has shown that in situ
hybridisation improved the diagnostic yield significantly.
In Situ PCR on Slit Skin Smears
Another latest in our series of molecular biological
approaches is the utility of in situ PCR on the slit skin
smears. It was found that with an average positivity of
72%. In situ PCR on slit skin smears was better than that
on skin biopsies (60%). In addition it has the added
advantages of being minimally invasive and less
cumbersome and can be performed even at sites from
where skin biopsy is difficult.
TREATMENT
Leprosy patients should be treated with patience,
perseverance and understanding. Besides the medical
treatment, the patients and their parents need moral
support and reassurance. Parents should be explained
hygienic measures, proper diet and importance of taking
treatment completely and regularly.
therefore, no child will require ethionamide/prothiona-
mide which are potent hepatotoxic drugs. Parents should
be advised to give rifampicin on empty stomach and
clofazimine with meals or with a glass of milk. Red stain-
ing of skin and lesions is very common with clofazimine.
Treatment of Reactions
Drugs commonly used in these conditions are anti-
malarials like chloroquine (given orally), antimonials, e.g.
potassium antimony tartratelV and fantosin IM,
clofazimine, corticosteroids and thalidomide (all the
three given orally). Symptoms like iritis and neuritis
occurring during reactions (or occurring independently)
should be properly treated in order to avoid irreversible
sequalae, i.e. deformities and neuropathic ulcers.
Duration of Therapy
The WHO study group has recommended treatment of
paucibacillary cases for only six months and of multi-
bacillary cases for twelve months.

Multidrug Therapy Prophylaxis

It is now a well known fact that, simultaneous adminis-
tration of several different antibacterial agents may
prevent the emergence of drug resistant mutants. The
dosage schedule for children as recommended by WHO,
is shown in Tables 9.23.2 and 9.23.3. In the MDT, it is
assumed that clofazimine is acceptable for children and,
Leprosy vaccine: There is no established vaccine against
leprosy as yet.
The results of 5 to 9 years follow up study conducted
on 1,20,000 randomized individuals in South Africa,
indicate that BCG booster vaccination (2 dose BCG
regimen given at 0 and 3 months) provides 50 to

TABLE 9.23.3: Dosage of antileprosy drugs for children with multibacillary leprosy (BB, BL, Polyneuritic)

Age groups Dapsone: Daily dose Rifampicin: monthly Clofazimine

(years) unsupervised (mg) dose supervised (mg)
Unsupervised dose(mg) Monthly dose (mg)

3-5 25 150-300 100 once weekly 100

6-14 50-100 300-450 150 Once weekly 150-200
15 100 600 50 daily 300
392 IAP Textbook of Pediatrics
75 percent protection against leprosy.The combined BCG
M.Leprae vaccine offered no additional benefit.
In order to accelerate the elimination of leprosy as a
public health problem in India the following activities
should receive high priority: 100 percent MDT coverage
and accessibility,, high treatment completion and cure
rates and inclusion of leprosy in the training curricula of
the general health staff off all categories.
BIBLIOGRAPHY
1. Dayal R, Agarwal M, Natrajan M, Katoch VM, Katoch
K, Singh Kalpna, et al. PCR and in-situ hybridization for
9.24 Leptospirosis in Children
Leptospirosis is an acute febrile generalized disease
whose manifestations arise from the effects of generali-
zed vasculitis.
Leptospirosis, an infectious disease that effects
humans and animals, is considered the most common
zoonosis in the world. Leptospirosis is caused by
pathogenic spiral bacteria that belong to the genus
Leptospira. The genus Leptospira was originally thought
to have two species L. interrogans which is pathogenic
and L. biflexa which is saprophytic. More recent work
has identified 7 distinct pathogenic species, which appear
as more than 250 serologic variants or serovars which
have been classified into 25 serogroups.
EPIDEMIOLOGY
The rat is the principle source of infection. Other
important reservoirs include dogs, cats, livestocks and
wild animals. The infected animals excrete spirochetes
in urine for an extended period of time. Human infection
results from exposure to leptospire contamination of
stagnant water with sewerage.
Recreational activities like swimming, out door sports
played in contaminated water are other reasons to
acquire leptospirosis.
diagnosis of leprosy. Indian Journal of Paediatrics 2007;
74:645-8.
2. Dayal R, Singh SP, Mathur PP, Katoch VM, Katoch K,
Natarajan M. Diagnostic value of in situ polymerase
chain reaction in leprosy. Indian Journal of Paediatrics
2005;72:1043-6.
3. Dwight A Powell. Hansen disease (Mycobacterium leprae).
In Kliegman, Behran, Jenson, Stanton (Eds): Nelson
Textbook of Pediatrics, 18th edn. Philadelphia, Elsevier
Saunders, 2008;1255-8.
4. Leprosy. In Park K (Ed): Textbook of Preventive and Social
Medicine, 19 edition. Bhanot Publishers 2007;264-76.
5. WHO Health Organisation: Leprosy. Global situation,
Wkly Epidemiol Rec, Nov. 25, 2007;82:225-32.
S Ramesh
PATHOPHYSIOLOGY
Human beings become infected through moist and
abraded skin and mucous membranes. The primary
lesion caused by leptospire is damage to the endothelial
lining of small blood vessels with resultant ischemic
damage to the liver, kidneys, meninges muscles, etc.
CLINICAL FEATURES OF
LEPTOSPIROSIS SYNDROME
Leptospirosis can occur as:
• Anicteric leptospirosis (common, less severe)
• Icteric leptospirosis (rare, but severe).
Anicteric Leptospirosis
Occurs as a biphasic illness.
The first phase is septicemic phase followed by the
immune phase.
Septicemic phase is associated with the multiplication
of Leptospira in the bloodstream, and immune phase
which follows is characterized by the development of
antibodies to Leptospira.
Septicemic Phase
The child may present with fever of abrupt onset,
associated with muscle pain, headache, nausea,

vomiting, abdominal pain, etc. Less common findings
include conjuctival suffusion, a transient skin and
mucosal rash, photophobia, and mild signs of menin-
gism. The septicemic phase lasts 4 to 7 days.
Immune Phase
Immune phase is characterized by circulating antibodies.
There is brief asymptomatic interlude between the
septicemic and immune phase.
The important clinical features are in the Immune
phase are:
A. Fever
B. Aseptic meningitis with abnormal CSF profile is seen
occasionally among children.
C. Hepatitis is characterized by enlargement of the liver,
elevation of bilirubin with a modest increase in liver
enzymes.
D. Renal involvement is characterized by abnormal
findings in the urine analysis (hematuria, proteinuria
and casts), azotemia with oliguria or anuria. Renal
failure is the principle cause of death of fatal cases.
Note: In clinical practice distinction between the
septicemic and immune phase may not be seen.
Icteric Leptospirosis (Weil’s Syndrome)
Weil’s syndrome is characterized by liver, kidney, and
vascular dysfunction in addition to the other symptoms
of anicteric leptospirosis. Individuals with Weil’s
syndrome will usually develop jaundice without
hepatocyte destruction and azotemia by the third to
seventh day of illness. The liver may be enlarged and
there may be right upper quadrant tenderness. With
increasing severity of jaundice, the individual is at greater
risk of developing renal failure, hemorrhage, and
cardiovascular collapse. Uremia, oliguria, and anuria
may occur with the onset of kidney failure unless dialysis
is provided. Fatalities due to icteric leptospirosis are
typically due to renal failure, cardiopulmonary failure,
and fatal hemorrhages.
Laboratory Diagnosis
The following are the tests currently available for routine
diagnosis.
1. Dark Field Microscopy (DFM)
Used to detect leptospires in blood within the first 10
days of illness and from the urine from the second week
Immunization and Infectious Diseases 393
onwards. False-positive results are common. Extrusion
of fibrillar material from RBC’s mimics leptospirosis.
Urine samples must be examined within half an hour of
collection.
2. Detection of Antibodies to Leptospirosis
i. Macroscopic slide agglutination test (MSAT): It is a
genus specific test and uses killed leptospira as
antigen.
ii IgM-ELISA and Dipstick test: These tests detect
genus specific IgM antibodies which tend to become
positive early in the disease around 4th day of
illness. The above mentioned tests are sensitive but
not specific, they do not differntiate between
pathogenic and saprophytic leptospira, the infecting
serovar cannot be identified.
iii Microscopic agglutination test (MAT): It is a serovar
specific test and is the gold standard of serological
tests to detect leptospirosis. High specificity is the
hall mark of MAT. The MAT is usually positive 10
to 12 days after symptom onset; although, antibodies
are usually present by five to seven days after
symptom onset. As it involves the use of a battery
of live leptospiral cultures to be used as antigen, it
is done in specialized labs only. The available
antisera may not identify all leptospira serotypes,
specific serotypes commonly seen in the community
are usually identified including the virulent and
serious types. Initial high titer of 1:80 or rising titers
(four fold increase) obtained 2 weeks apart are
diagnostic.
TREATMENT
Initiation of treatment early in the disease before 7th day
shortens the clinical course, penicillin is the drug of choice
and the dose is 250,000 units/kg/24 hr in 4 to 5 divided
doses for a period of 7 days. For penicillin allergic
children, erythromycin, Amoxycillin, Ofloxacin are
alternate choices for children under 8 years and
Tetracycline 10 to 20 mg/kg/day in 3 divided doses for
children beyond 8 years.
Doxycycline is the alternate drug to tetracycline given
in a dose of 100 mg twice for 5 days.
OUTCOME
• Despite the possibility of severe complications the
disease is most often self limited and non fatal.
394 IAP Textbook of Pediatrics
• Mortality is due to renal failure in anicteric
leptospirosis, and due to renal failure, cardiovascular
collapse and hemorrhagic manifestations in icteric
leptospirosis.
9.25 Chickenpox (Varicella)
Chickenpox is a highly infectious viral disease in children
and is characterized by the appearance of successive
crops of typical rash with mild constitutional symptoms.
Etiology
Chickenpox is caused by Varicella-zoster virus belonging
to the herpesvirus family. It is a DNA virus. Varicella-
zoster virus has the capacity to persist in the body after
the primary infection. It persists in the sensory nerve
ganglia. Primary infection with Varicella-zoster virus
results in chickenpox. Herpes zoster is the result of
reactivation.
Epidemiology
Man is the only known source of infection. Most children
are affected by 15 years of age, with peak incidence
between 5 and 9 years. However, the disease can occur
at any age including neonatal period. In the tropics the
age is often shifted to the right. Epidemics occur in
December to February. Spread of infection occurs either
through person to person contact or droplet infection.
Immunity is lifelong after an infection. Infection rate in
household contacts is almost 85%. Incubation period is
10-21 days. The period of infectivity is 1 to 2 days before
and up to 6 days after the onset of the rash.
Clinical Manifestations
Prodromal symptoms are fever, malaise, anorexia,
headache, which may precede the characteristic rash by
24-48 hours. The prodrome is marked in older children
compared to younger children. The rash typically begins
as crops of small, red papules which almost immediately
develop into clear, often oval “tear drop” vesicles on an
erythematous base. The vesicles are not umbilicated.
Soon they become cloudy and then dry up forming scabs
BIBLIOGRAPHY
1. Izurieta R, Galwankar SG, Clem AS. Leptospirosis: The
“Mysterious” Mimic. J Emerg Trauma Shock 2008: In
print.
AP Dubey, Jaydeep Choudhury
which fall off in the next 5 to 15 days. These lesions
usually appear in crops for 3 to 4 days and thus various
stages of the rash from macular, papular, vesicular and
crusting may be seen at the same time. Varicella lesions
are intensely pruritic. The rash has a characteristic
centripetal distribution, the lesions being more on the
trunk, back and shoulders with fewer lesions over the
scalp and the extremities. Vesicles may be seen in the
oral mucosa, pharynx, larynx, trachea, conjunctiva and
genitals. Rarely the rash becomes hemorrhagic in
association with thrombocytopenia. The condition
generally improves within 7 days.
Varicella bullosa is an uncommon variant mainly seen
in children less than two years of age. Congenital varicella
may manifest at birth or appear within a few days after
birth in infants whose mothers have an active infection.
It is associated with high mortality in newborn if they
acquire the disease from the mother when she gets
varicella 1 week before or after the delivery. The primary
infection has occurred in intrauterine life.
Congenital varicella syndrome – The risk of embryopathy
is determined by the gestational period. It is highest
during embryogenesis, during innervations of limb buds
and maturation of the eyes. Eye and brain involvement
is highest during 16-20 weeks of gestation. The disease
involves mainly the eyes, skin, brain, and lungs.
Dermatomal ‘zig zag’ scarring known as cicatrix is
diagnostic of congenital varicella syndrome. Aplasia of
brain, cataract and microcephaly may occur occasionally.
Diagnosis
The diagnosis is mainly clinical. The virus may be isolated
from vesicular lesions during the first 2 to 4 days of
eruption. Diagnosis may also be accomplished by
immunofluorescent staining of vesicular scrapings.

Serological tests for diagnosis include latex agglutination
test, indirect fluorescent antibody and enzyme immuno-
assay.
Complications
Chickenpox is usually a mild disease in children with
few complications. Complications are more common in
immune compromised children. The important compli-
cations are as follows:
i. Secondary bacterial infections of skin and mucosal
lesions. Varicella gangrene and necrotizing fascitis
are rare complications.
ii. Varicella pneumonia.
iii. Bleeding into the lesions due to thrombocytopenia
iv. Purpura fulminans due to associated consumptive
coagulopathy.
v. Reye’s syndrome.
vi. Bacterial sepsis, arthritis, osteomyelitis, hepatitis and
glomerulonephritis.
vii. Post chickenpox encephalitis is a rare complication;
cerebellar signs are common in this. Myocarditis and
pericarditis are very rare.
viii. Reactivation of latent virus after a primary infection
may result in Herpes zoster later.
Treatment
Treatment is mainly symptomatic and supportive.
Paracetamol is given to control fever. Aspirin should be
avoided as it may increase the risk of Reye’s syndrome.
Antihistaminics are advised to reduce pruritus.
Fingernails should be trimmed to prevent scratching.
Acyclovir is an antiviral drug available in tablets and
liquid form. It is safe, effective against Varicella but it is
not routinely recommended in uncomplicated infection
as Varicella is a self limiting disease, there is low risk of
complications in children, treatment has a marginal
benefit and the therapy is costly. Acyclovir is indicated
in immune compromised children. The dose for oral
therapy is 20 mg/kg/dose, maximum 800 mg/dose,
given as four doses per day for 5 days. It is more effective
when treatment is initiated within 24 hours of onset of
disease. There is dubious clinical benefit if initiation of
treatment is delayed more than 72 hours after onset of
exanthem.
Immunization and Infectious Diseases 395
Disseminated disease requires early IV acyclovir for
7 days. In severely immune compromised children rapid
IV therapy may be needed in a dose of 10 mg/kg/dose 8
hourly for 7 days.
Varicella-zoster immunoglobulin (VZIG) may be
used within 48 hours after exposure for the maximum
protection in high risk groups. These include neonates,
children with leukaemia, on steroid therapy and
pregnant women.
Prognosis
Mortality is 4 times higher in infants and adults have 25
times more chances of dying. Mortality is less in children.
The common cause of death in children is encephalitis,
pneumonia and DIC.
Prevention
Varicella transmission is difficult to prevent because the
infection is contagious 24-48 hours before the onset of
rash and until the vesicles are crusted, which is usually
3-7 days.
Varicella is a vaccine preventable disease. Live
attenuated varicella vaccine is safe and is almost 90%
effective in preventing severe diseases. Approximately
10-20% may have breakthrough varicella, a modified
manifestation of the illness in a mild form. The Global
recommendation now is two doses for MMR and
Varicella Vaccines – the first dose at 15 months and the
second at 4-6 years. It will be ideal to administer the
second dose at 5th year along with DTP booster and OPV.
IAP recommends vaccination of children after 12 months
to 13 years with a single dose of Chickenpox vaccine.
Children older than 13 years should be given 2 doses at
one month interval.
BIBLIOGRAPHY
1. Epidemiology and prevention of vaccine-preventable
diseases. 10th edn. Department of Health and Human
Services CDC, 2007.
2. India EPI fact sheet, 2003, country Fact sheet
WHOSEARO, 2004.
3. Meyers MG, Seward JF, LaRussa PS. Varicella-Zoster
Virus. In: Kliegman RM, Jenson HB, Behrman RE,
Stanton BF, editors. Nelson Textbook of Pediatrics. 18th
edn. Philadelphia: Elsevier 2007;1337-41.
396 IAP Textbook of Pediatrics
9.26 Dengue Illnesses
At the end of the previous century, the world faced the
resurgence of several infectious diseases, dengue being
one of the most significant in terms of morbidity and
mortality. The dengue virus is transmitted to humans
by the bite of a domestic mosquito, Aedes aegypti being
the prime vector although some other species such as
Aedes albopictus also are of importance. Four viruses,
dengue-1 to 4, classified in an antigenic complex of the
flavivirus genus, family Flaviviridae, are the etiological
agents of this disease. Infection with one of these
serotypes does not provide cross-protective immunity.
Thus persons living in a dengue-endemic area can have
four dengue infections during their lifespan.
ADVENT OF DHF
Over the last two hundred years dengue was known to
the physician as a self-limiting benign febrile condition;
however in the mid 1950s images of dengue illnesses
underwent a drastic change. South East Asian countries
experienced epidemics of a serious disease associated
with dengue viruses. Patients afflicted from this new
illness exhibited two potentially mortal symptoms;
bleeding diathesis and shock. Dengue hemorrhagic fever-
dengue shock syndrome (DHF-DSS) was the new name
coined for this entity. Since then the disease has spread
to large areas of the world and is posing a progressively
escalating public health problem in the tropics and
subtropics. Today 2.5 billion people live in dengue
endemic areas and disease is reported from over more
than 100 countries. Though the true incidence is not very
well-known, yearly 50 to 100 million cases of dengue
fever (DF) and few lack cases of DHF are estimated to
occur worldwide. In 1998, 1.2 million cases of DF and
DHF were reported to WHO, including 3442 deaths.
DENGUE ON RISE
Two factors directly responsible for the burgeoning
incidence of DF and DHF are–proliferation in the density
and geographic distribution of the vector, and marked
increase in the rate and geographic range of virus
transmission. Major global demographic changes such
Ashok S Kapse
as uncontrolled population growth, unplanned urbaniza-
tion resulting in substandard housing, and need for water
storage have greatly aided the vector proliferation. The
increase in air travel allows the movement of the different
serotypes, strains, and even genotypes of virus from one
region to another. Individuals in viremic phase are able
to introduce a new virus into a vulnerable population.
In general, factors that augment the contact between
vector and host favor an increase in dengue transmission.
Climatic changes also influence virus evolution. WHO
has reported that a temperature rise of 1 to 2°C could
result in an increase in the population at risk by several
hundred million, with 20, 000 to 30,000 more fatal cases
annually.
In spite of multiple dengue strain endemicity and
countrywide invasion of Aedes aegypti, till very late India
remained a silent zone [free of DHF]. However by late
eighties this scenario started changing, beginning from
Surat in 1988, and sharp outbreaks of DHF have occurred
all over the country. In the last decade many cities
including Delhi, Kolkata, Bangalore, Chennai, Jaipur and
Gwalior have suffered of DHF epidemics.
PATHOPHYSIOLOGY
For years, pathogenesis of DHF has been a matter of
controversy. Some workers argued that secondary
infection was the main factor for the severity of this
disease, whereas others thought that viral virulence was
of prime significance. Today, the majority view is that
secondary infection is the main risk factor for DHF;
however, other factors such as viral virulence and host
characteristics also have important bearings.
DHF occurs as an outcome of a very complex mecha-
nism where virus, host, and host immune responses
interact to give the severe disease in 2 to 4 percent of
individuals with secondary infection.
Taking into account the international experiences, a
basic hypothesis for the development of DHF epidemics
was published in 1987. The intersection of three groups
of factors namely host, viral, and epidemiological
determine the occurrence of a DHF epidemic. The
epidemiological and viral factors are the determinants
for an outbreak of the disease. Individual risk factors such

as sex, race, and chronic diseases are predisposing
elements which determine the occurrence in a certain
race or age group. However, the pre-existence of
antibodies is the most vital individual risk factor.
Antibody Dependent Enhancement
First infection with any of the dengue viruses in a dengue
virgin body results in self-limiting febrile illness and
recovery from this first infection is accompanied by
generation of immunological responses. Epitopes present
on E protein are capable of inducing homologous as well
heterologous neutralizing antibodies. Levels of these
antibodies have a governing role in driving dengue
infection to more or fewer infected cells.
People infected with one serotype maintain a life-long
protective immunity to infection by the homologous
virus. However protective immunity to infection with
heterologous serotypes is transitory. It has been proposed
that neutralizing antibodies down-regulate the severity
of the disease. During a secondary infection with a
different serotype, the presence of low amount of
heterotypic neutralizing antibodies could prevent severe
disease. On the other hand, when no neutralizing
antibodies are present, heterotypic antibodies form
complexes with dengue viruses, which infect mono-
nuclear phagocytes with enhanced efficiency and as a
consequence a higher number of cells are infected. This
phenomenon has been called antibody dependent
enhancement (ADE). Halstead et al in 1970 observed that
DHF occurs in situations where more than one serotype
circulates. Epidemiological and serological studies done
in Thailand and Cuba firmly established that secondary
infection is a major risk factor for DHF.
Children are at higher risk of acquiring DHF than
adults. Age-specific DHF incidence is observed to be
bimodal, with severe cases peaking at about 7 months of
age and again at 3 to 9 years of age. DHF or DSS occurred
in infants almost exclusively during primary dengue
infections. These infants were born to dengue immune
mothers and had acquired maternal dengue antibody
and subsequently experienced a dengue infection. On
the other hand, children 3 to 5 years old have DHF during
a secondary infection. Baseline microvascular perme-
ability in children is supposed to be significantly greater
than that of adults and this partly explains why DHF is
more frequently observed in children.
Immunization and Infectious Diseases 397
There seems to be no time limit to sensitization after
a primary dengue infection. The 1997 Cuban epidemic
clearly demonstrated that dengue-2 DHF could occur
even after 16 to 20 years of the primary dengue-1
infection. Besides secondary infection, chronic diseases
such as bronchial asthma and diabetes have been
suggested as risk factors for DHF. Finally, whites have
higher risk of developing DHF than blacks.
Cellular Factors and Cytokines
Neutralizing antibodies are key factors in the etio-
pathogenesis of the disease; however, the cellular
immune response is also of immense significance. Recent
observations suggest a massive T-cell activation due to
interactions with infected monocytes, and release of
pathogenetic cytokines as a consequence of this
interaction. Cytokines such as TNF [tumor necrosis
factor], interferon, interleukin-2 [IL-2], IL-6, IL-8, and IL-
10 are found to be greatly elevated in DHF. High levels
of TNF could be responsible in part for transient vascular
damage. Recently a protein of 22 to 25 kDa has been
detected in sera of DHF patients, this factor is able to
induce increased capillary permeability in mice, and is
capable of reproducing all the pathological lesions that
are seen in human beings.
Factors Responsible for Bleeding
Several factors such as vasculopathy, prothrombin -
complex deficiency, thrombocytopenia and platelet
dysfunction are thought to be responsible for hemorrhage
in DHF. However mechanisms that initiates bleeding is
yet to be established. Various reasons for instance, high
levels of platelet-activating factor inducing platelet
consumption, virus-antibody complexes on the platelet
surface and presence of cross reactive IgM antibodies,
causing platelet lysis have been thought to be responsible
for thrombocytopenia in DHF.
Genotype and Disease Severity
In spite of all the existing knowledge, it is still uncertain
what kind of host and virus-specified factors determine
why certain individuals have only mild DF while others
develop DHF. Viral strains, genotypes, mutants, and
sequence of infective strains are important contemp-
lations. Dengue 2 genotype of Southeast Asian origin, is
found to be related to most of the DHF epidemics in
398 IAP Textbook of Pediatrics

Southeast Asia and America. On the other hand, the

American genotype, is only related to DF epidemics in
the American region. Recently, some amino acid changes
on M and E proteins of dengue 2 strains have been found
to be associated with DHF epidemics. The genetic
variation between genotypes could be responsible for
differences in virus interactions with macrophages and
suggest that certain strains are more virulent than others.
Morens and Halstead reported that subtle antigenic
differences affect the degree to which strains form
immune complexes with heterotypic antibodies.

CLINICAL FEATURES
Spectrum of Presentations
Ranging from asymptomatic infection, to mild undiffe-
rentiated fever, to fatal shock, dengue illnesses have wide
spectrum of clinical presentations. WHO identifies two
types of illnesses—dengue fever (DF) and dengue
hemorrhagic fever (DHF). Dengue shock syndrome
(DSS) is a severe subset of DHF (Fig. 9.26.1).
Dengue fever again presents in two ways: classical
dengue fever and undifferentiated febrile illness.
Classical Dengue Fever
Dengue in its classical form produces a characteristic
clinical syndrome, after a short incubation period of two
to seven days. There is an abrupt onset of high grade
fever, which is associated with headache, retro-orbital
pain, photophobia, backache, myalgia and arthralgia. For
these symptoms dengue has acquired an epithet of ‘Break-
bone fever’. Besides aches and pains, other common
symptoms include extreme weakness, anorexia, constipa-
tion, altered taste sensation and colicky abdominal pain.
A transient maculopapular rash may erupt on chest and
back within first few days of fever.
Signs of skin bleeding such as positive tourniquet test,
petechiae, or ecchymosis are observed in some patients.
DF cases with bleeding complications such as epistaxis,
gingival bleeding, gastrointestinal bleeding, hematuria,
and hypermenorrhea can be observed during some
epidemics. Such phenomena tend to vary with different
strains and with age and gender. In general, bleeding
manifestations are more severe in adults. Post-convales-
cence depression and bradycardia are also common in
adults. Leucopenia and mild thrombocytopenia are two
of the usually observed hematological changes. In
Figure 9.26.1: Distribution of dengue illnesses
majority of cases fever tends to last for three to seven
days, and terminates into an uneventful convalescence;
however in few cases it tends to recur and hang about
for few more days Saddleback fever.
Undifferntiated Dengue Fever
Unfortunately classical dengue fever is an uncommon
presentation in pediatric age group. Majority of children
present with undifferentiated febrile illness, posing lots
of diagnostic problems. This undifferentiated dengue
fever may present as fever with maculopapular rash
and/or mild respiratory symptoms.
Dengue Hemorrhagic Fever
Plasma leakage is the major pathophysiological feature
observed in DHF and differentiates this from typical DF.
Initial clinical picture of DF and DHF is similar but latter
part of the disease particularly peri- and post- defer-
vescence periods, may show marked differences.
In DHF defervescence coincides with intracellular
viral killing (see pathophysiology) which in turn sets in
process of vasculopathy making capillaries leaky.
Extravasations of plasma, through these leaky capillaries
result in hemoconcentration, hypovolemia and hypo-
tension.
In majority of cases leak is transient lasting for few
hours; once it stops patient quickly stabilizes and
completely recovers. As with DF, convalescence in mild
DHF is swift and uneventful.
In a small number of cases leak is prolific and
prolonged; plasma may continue leaking for two to three
days. Fluid which drips out manifests as generalized

edema and effusions in serous cavities–untreated such
patient may develop severe shock. These cases are
designated as DSS, and carry bad prognosis; intensive
and timely IV fluid therapy can only salvage these
patients. After couple of days, when leak is over,
extravasated fluid returns to circulation. This sudden
gush of fluid into circulation may cause circulatory
congestion and sometimes even failure. Thus, course of
disease in DSS has three arbitrary phases: febrile, leaky
and congestive.
SYMPTOMATOLOGY OF MILD DHF
DHF without Shock
Typically a case of DHF has three important findings:
fever, bleeding tendency, and hepatomegaly.
The commonest bleeding manifestation is positive
tourniquet test, and bleeding at venepuncture sites, fine
purpuric rash (Fig. 9.26.2) scattered over trunk, axillae,
face and palate, are usually observed. Epistaxis, gingival
and mild gastrointestinal bleeding may occur infre-
quently, less than 10% of dengue hemorrhagic fever
patients may have clinically frank and severe bleeding
mainly from gastrointestinal tract.
Liver is usually palpable from early febrile phase,
varies in size from 2-4 cm, and is non-tender. Anorexia,
nausea, vomiting, and vague generalized abdominal pain
are common accompaniments.
Critical stage of the disease starts around deferve-
scence which is often accompanied by circulatory
disturbances as a result of plasma extravasations.
Clinically patients manifest with marked weakness,
irritability, anxiety, restlessness, oliguria and giddiness.
Majority of the patients stabilize at this point and recover
completely within couple of days of defervescence.
Figure 9.26.2: Purpuric rash in DHF
Immunization and Infectious Diseases 399
SYMPTOMATOLOGY OF SEVERE DHF (DHF/DSS)
Leaky Phase
In a small number of patients capillary leak is profuse
and continues for two to three days. These patients
progressively become oliguric and exhibit signs of
postural hypotension such as giddiness, inability to rise
from recumbent position and need to be helped or carried
for smallest movement. They have typical signs of
circulatory failure: skin becomes cool blotchy and
congested; circumoral cyanosis is commonly observed.
Untreated these patients develop fast and thready pulse,
imperceptible lower limb pulses (dorsalis pedis and
posterior tibialis), narrowed pulse pressure and in an
extreme case unrecordable blood pressure. Severe right
hypochondriac pain and progressive enlargement of liver
coincide with the development of shock. These cases
should immediately be hospitalized for intensive fluid
therapy. Uncorrected shock may head for a complicated
course and develop metabolic acidosis and DIC resulting
in severe bleeding and multiorgan failure. Poorly
managed DSS patients have a high fatality rate of 30 to
40 percent. Besides signs of circulatory failure these
patients also exhibit puffy and swollen face (Fig. 9.26.3),
generalized edema, and polyserositis.
Congestive Phase
After two to three days, leak stops and plasma which
had extravasated during the leaky phase, returns back
to circulation causing vascular congestion. Now patients
start passing copious amount of watery urine and
develop bounding pulse, wide pulse pressure and rise
Figure 9.26.3: Puffy edematous face during leaky phase of DSS
400 IAP Textbook of Pediatrics
Figure 9.26.4: Confluent petechial rash on hand
in blood pressure. Few cases may develop frank
congestive heart failure manifesting with tachycardia,
tachypnea, muffling of heart sounds and basal rales. This
phase may continue for 12-24 hours.
Convalescence
End of congestive phase heralds the recovery which,
like in DF and DHF, is rapid and complete. Bradycardia,
arrhythmias, and characteristic confluent petechial rash
are the signs seen during convalescence. Bright red
confluent petechial rash erupts along the lateral margins
of soles and palms (Fig. 9.26.4) between eighth and tenth
days of sickness. The rash shows tendency to loose
confluence as it ascends up the limbs and to fade away
above the knee and the elbow. In some cases there are
small round areas of clear skin giving it a name of
annular petechial rash.
UNUSUAL MANIFESTATIONS
Liver failure and neurological involvements are recently
described with dengue infections. Patients with
neurological manifestations are reported from India,
Indonesia, Myanmar, and Thailand. CNS expressions are
in the form of convulsion, unconsciousness, spasticity
and paresis. Till date there is no evidence for direct
neurological involvement of brain by dengue virus.
SUSPICION INDEX
Serological studies demonstrate that dengue is endemic
in our country, however excepting epidemic situations
dengue is a rarely diagnosed condition. Want of a reliable
Figure 9.26.5: Dengue Facies (Measly look)
suspicion index is the major reason for this anomaly.
Working in a dengue endemic area for two decades, the
author has observed and tested a clinical finding which
could reliably serve as a suspicion index for dengue
illnesses–this suspicion index could be termed as
erythematous flush.
ERYTHEMATOUS FLUSH
During their illness dengue patients develop a characteri-
stic erythematous flush. Flush deepens with advancing
disease and imparts peculiar facial feature to these
patients. Dengue facies could be portrayed as suffused and
swollen face, injected eyes, purplish lips and most
importantly reddened malar region and ear lobes. In
other words, patients assume a measly look (Fig. 9.26.5)
devoid of catarrhea. Around eighty percent of patients
suspected as dengue on the basis of this particular finding
were proved to be viroserologicaly positive.
LAB INVESTIGATIONS
Platelets and Hematocrit
Rise in hematocrit and drop in platelets are constant
findings in all cases of dengue hemorrhagic fever. These
parameters exhibit a unique time-bound relationship
with the disease. Changes start a little before the
defervescence (4th or 5th day of sickness) and peak
around second or third afebrile day (7th or 8th day of
sickness). Hemoconcentration and thrombocytopenia
represent the pathophysiological hallmark of the disease
viz; capillary permeability and abnormal homeostasis,

and bear a distinct correlation with the severity of the
disease.
Serous Effusions
Leaking plasma gets collected into serous cavities
resulting into development of effusions. Peritoneum is
the first and commonest site. In severe cases patients
develop polyserositis (peritoneal, pleural, and pericardial
effusions); while a mild case may present with only
ascites. Most marked on second to third post-deferve-
scence day, these effusions resolve around tenth or
eleventh day of disease and hardly ever need any
therapeutic intervention.
Turk Reaction Cells
These are transformed lymphocytes. Presence of more
than 20 percent of Turk cells in Buffy coat smear is a
frequent finding for dengue hemorrhagic fever.
A typical plan for clinical diagnosis: Patient presenting with
fever and dengue facies [non-catarrhal measly look]
during or postmonsoon season should raise the suspicion
for dengue illness. A positive tourniquet test (TT)
indicating bleeding tendency augments possibility.
Conduct CBC and platelet count serially, once during
initial period and repeat around fourth to fifth days of
fever. Patient showing rise in PCV and drop in platelets
should be categorized as DHF. Keep this patient under
close observation and monitor him for signs and
symptoms of developing shock. Patient with absence of
thrombocytopenia, and hemoconcentration should be
labeled as DF.
MANAGEMENT
Outpatient Management
Cases other than the DSS do not require hospitalization
and could be managed at outpatient level. The author
suggests following management plan for such cases:
• Keep patient under close clinical observation for
throughout the febrile period and two to three days
beyond the defervescence.
• For pain and fever use only paracetomol, avoid
aspirin and NSAID, as they interfere with platelet
functioning.
• Give parents a set goal for child’s fluid intake (100 to
150 ml/kg BW). Fluids could be water, ORS, milk,
buttermilk, fruit juices, etc.
Immunization and Infectious Diseases 401
• Instruct parents to collect childs’ urine and compare
the output against fluid intake.
• Warn parents for bad clinical signs viz giddiness,
restlessness, anxiety, severe abdominal pain and cold
extremities.
• Carefully assess every patient exhibiting above
symptoms for signs of shock e.g. poor volume pulse,
imperceptible pulses, narrowing of pulse pressure,
and fall in blood pressure. Patient with these
symptoms need immediate hospitalization for
intensive IV fluid therapy.
• Lastly one should bear in mind that DSS sets in with
the defervescence, hence any child deteriorating or
failing to improve with subsidence of fever should
be carefully assessed for signs of shock.
Management of Dengue Shock Syndrome [DSS]
How to suspect DSS and when to hospitalize patients?
A patient of dengue illness showing following signs and
symptoms in peridefervescence period is likely to
develop DSS:
i. Feeling of giddiness (postural hypotension)
ii. Cooler extremities compared to trunk and abdomen.
iii. Oliguria with dark urine
iv. Right hypochondriac pain
v. Increasing liver size.
Patients exhibiting these symptoms should be
carefully assessed for blood pressure and for pulse rate
and volume. Patient exhibiting narrowed pulse pressure,
fast and thready pulse should be considered as having
DSS and must be hospitalized for further management.
Initial Management
1. Take two intravenous lines.
2. Collect blood for blood group, Hb, PCV, and platelets.
3. Start with drip of Ringer‘s lactate in a dose of 10 ml/
kg BW/hour (e.g; for 10 kg child 100 ml/hour).
Continue Ringer‘s lactate till patient passes first urine.
Invariably patient passes small amount of dark and thick
urine only after receiving 20 to 30 ml per kg BW of IV
fluid.
Subsequent Management
Continue IV fluid at same rate; however IV fluids used
should be Ringer‘s lactate, 0.45 saline and Isolyte-P in
402 IAP Textbook of Pediatrics
sequence. IV fluids should be planned for 6 hours
quadrants.
Monitoring of the Patients in the Hospital
The most important aspect of DSS management is
frequent monitoring of these patients. Following
parameters should be monitored at hourly intervals.
• Pulse volume
• Blood pressure
• Abdominal girth
• Urine output
Pulse Volume
Pulses to be felt are radial, posterior tibialis, and dorsalis
pedis. Feel of pulse volume is very important; normal
pulse should come and touch palpating fingers without
requiring any pressure. Imperceptible or very weak
pulses indicate more fluid requirement.
Blood Pressure
Remembering blood pressure values according to age is
a difficult task in pediatrics hence it is essential that one
should keep age related blood pressure chart. If one is
unaware of age related blood pressure, then maintaining
good pulse pressure of 30 to 50 should be the manage-
ment goal.
A narrow pulse pressure less than 30mm of Hg is an
indication for stepping up IV fluid rate.
Abdominal Girth
In DSS extravasating plasma gets collected into serous
cavities. In postdefervescence period these patients
develop abdominal distension, and when they are put
on IV fluids, their abdominal girth starts further rising.
Expansion of their abdominal girth is directly propor-
tional to severity of leak.
Rapidly expanding abdominal girth is an indication
for higher fluid requirement.
Urinary Output
Urinary output must be measured every six hourly and
amount should be compared with IV fluid given over
six hours quadrant of time. Large gap between IV fluid
intake and urinary output indicates need for advancing
IV fluid therapy.
Majority of patients stabilize with aforementioned
plan of IV fluid rehabilitation, however cases with very
severe leak may require higher doses [15 ml/kg BW]
of IV fluid or even use of colloids like dextran, or
plasma for maintenance of normotension. Such cases
may need CVP monitoring. Obvious clinical bleeding,
or severe internal bleeding as indicated by marked
drop in PCV are other indications for blood or plasma
infusion.
Indication for Platelets
Main reasons for bleeding in DHF are vasculopathy and
coagulopathy; thrombocytopenia does contribute but in
a minor way, therefore patients having thrombocyto-
penia in absence of obvious clinical bleeding do not
require platelet transfusion.
Use of Vasopressors: (Dopamine and Dobutamine)
Though WHO does not recommend use of vasopressors,
author has clinical experience and scientific reasons for
their recommendation.
Dopamine During hypovolemia body’s compensatory
mechanism shunts blood from peripheral to central
circulation, effecting renal cutaneous and mesenteric
ischemia. The intense pain which DSS patients suffer at
onset of shock phase is likely owing to mesenteric
ischemia. In author’s experience DSS patients treated
with dopamine along with IV fluid suffer less of
abdominal pain and GIT bleeding.
Dobutamine
In severe cases myocardial engorgement results in a poor
cardiac contractibility. Dobutamine, a drug with strong
ionotropic effect, is a useful remedy in such situations.
Management during Congestive Phase
How to recognize its onset?
After certain time varying between 12 to 72 hours,
depending upon severity of case, DHF leak stops and
fluid which had escaped out returns back to vascular
compartment.
Following changes are likely to occur in monitoring
criteria.
• Pulse: Pulse becomes fast and bounding.

• Blood pressure: Systolic pressure would go up and
pulse pressure would become wider [>50]
• Abdominal girth starts decreasing
• Intake/output ratio: The most important signal is
narrowing gap between IV intake and urinary output.
Management of Congestive Phase
As the patient enters into congestive phase, change over
to hypotonic fluid and decrease the rate to 3 to 5 ml/kg
BW/hour, in next few hours patient would pass copious
amount of light colored urine.
In some patients regurgitant fluid may cause cardiac
overload manifesting as cough, tachypnea and tachy-
cardia. Such cases need diuretics and digitalization.
Problem is infrequent and is likely to happen in patients
treated with colloids. Congestive phase may end after
12 to 24 hours heralding recovery.
Reasons for Mortality in DHF/DSS
1. Failing to recognize that patient is in shock.
It is a usual tendency of parents and treating physician
to feel relieved when temperature subsides, however
in dengue patient may pass into shock with defer-
vescence. Instead of feeling of wellbeing, display of
anxiety, apprehension, and giddiness at defer-
vescence should immediately alert treating physician
to possibility of developing shock, failure to
appreciate this is the commonest cause of death in
DSS.
2. Hemorrhages: Though dengue is known as hemor-
rhagic fever clinical hemorrhages are uncommon, and
are rarely responsible for mortality. Shock effecting
DIC is the major cause for severe hemorrhages.
3. Failing to recognize that patient has entered congestive
phase may cause cardiac overload and consequent CHF
and death.
Though a complex disease, dengue hemorrhagic
fever exhibits a set clinical pattern and observes a
fixed time bound course of events. Awareness and
familiarity with the disease and its course greatly
facilitates diagnosis-making and initiating proper
therapy. With appropriate IV fluid management and
Immunization and Infectious Diseases 403
frequent monitoring, mortality in DSS should not
exceed more than one percent.
BIBLIOGRAPHY
1. Gamble J, Bethell D, Day NPJ, et al. Age-related changes
in microvascular permeability: a significant factor in the
susceptibility of children to shock? Clinical Science 2000;
98:211-6.
2. Gubler DJ, Kuno G, Waterman SH. Neurologic disorders
associated with dengue infection. Proceedings of the
International Conference on dengue/dengue hemor-
rhagic Fever; Kuala Lumpur, Malaysia; 1983;290-306.
3. Guzman MG, Alvarez M, Rodriguez R, et al. Fatal dengue
haemorrhagic fever in Cuba, 1997. Int J Infect Dis 1999;
3:130-5.
4. Halstead SB. Antibody, macrophages, dengue virus
infection, shock, and hemorrhage: a pathogenic cascade.
Rev Infect Dis 1989;11(suppl 4):S830-9.
5. Halstead SB. Is there an inapparent dengue explosion?
Lancet 1999;353:1100-1.
6. Kapse AS. A study of an epidemic of Dengue at Surat;
clinico-investigative analysis. In Environment and health
in developing countriess 1998;339-50.
7. Kapse AS. Dengue illnesses. IAP text book of Pediatrics.
2nd edn/2002;239-42.
8. Kliks SC, Nimmanitya S, Nisalak A, Burke DS. Evidence
that maternal dengue antibodies are important in the
development of dengue haemorrhagic fever in infants.
Am J Trop Med Hyg 1988;38:411-9.
9. Morens DM, Halstead SB. Disease severity-related anti-
genic differences in dengue 2 strains detected by dengue
4 monoclonal antibodies. J Med Virol 1987;22:169-74.
10. Nimmannitya S. Clinical spectrum and management of
dengue haemorrhagic fever. Southeast Asian J Trop Med
Pub Health 1987;20:325-30.
11. Pandey BD, Igarashi A. Severity-related molecular
differences among nineteen strains of dengue type 2
viruses. Microbiol Immunol 2000;44:179-88.
12. Rigau-Pérez JG, Clark GG, Gubler DJ, Reiter P, Saders
EJ, Vorndam AV. dengue and dengue haemorrhagic
fever. Lancet 1998;352:971-7.
13. Rush AB. An account of the bilious remitting fever, as it
appeared in Philadelphia in the summer and autumn of
the year 1780. Medical inquiries and observations.
Philadelphia: Prichard and Hall, 1789:104-17.
14. WHO. Dengue haemorrhagic fever: diagnosis, treatment,
prevention and control. Geneva: WHO, 1997.
15. Yang KD, Wang CL, Shaio MF. Production of cytokines
and platelet activating factor in secondary dengue virus
infections. J Infect Dis 1995;172:604.
404 IAP Textbook of Pediatrics
9.27 Infectious Mononucleosis
The eitological agent for infectious mononucleosis (IMN)
is the Epstein-Barr virus (EBV).
PATHOPHYSIOLOGY
EBV is predominantly transmitted by saliva (oropharyn-
geal secretions). EBV infection results in a humoral and
cellular response to the virus. The humoral immune
response directed against EBV structural proteins is the
basis for serological tests used to diagnosis EBV infectious
mononucleosis. A rapid and efficient T-cell response
results in control of the primary EBV infection and
lifelong suppression of EBV. Ineffective T-cell response
may result in excessive and uncontrolled B-cell
proliferation, resulting in B-lymphocyte malignancies,
e.g. B-cell lymphomas.
CLINICAL FINDINGS
The classic findings are fever, lymphadenopathy,
pharyngotonsillitis and splenomegaly.
Medical care is sought for the complaints of sore
throat and fever.
• Early signs include fever, lymphadenopathy,
pharyngitis, rash, or periorbital edema.
• Later physical findings include splenomegaly, uvular
edema, and rarely findings associated with splenic
rupture. Though rare, splenic rupture is a feared
complication. Rupture is commonly related to
trauma, which often may be mild.
• The pharyngitis of EBV infectious mononucleosis
may be exudative or nonexudative.
• Tonsillar enlargement is common, and massive
tonsillar enlargement may be observed leading to
airway obstruction. Palatal petechiae of the posterior
oropharynx distinguish infectious mononucleosis
from other causes of viral pharyngitis.
• Uvular edema is an uncommon finding in infectious
mononucleosis, but if present, it is a helpful sign in
distinguishing EBV infectious mononucleosis from
other causes of viral pharyngitis or from group A
streptococcal pharyngitis.
• Lymphadenopathy is predominantly cervical with
the anterior and posterior groups involved.
S Ramesh
• EBV infectious mononucleosis rarely may result in a
variety of unusual clinical manifestations including
pancreatitis, acalculous cholecystitis, myocarditis,
mesenteric adenitis, myositis, and glomerular
nephritis, autoimmune hemolytic anemia and
thrombocytopenia.
• Neurological syndromes include optic neuritis,
transverse myelitis, aseptic meningitis, encephalitis,
meningoencephalitis, cranial nerve (CN) palsies
(particularly CN VII), or Guillain-Barré syndrome.
LABORATORY EVALUATION
• Patients with infectious mononucleosis in the
differential diagnosis should have a CBC with a
differential count and an evaluation of the erythrocyte
sedimentation rate (ESR).
• Because leukocytosis is the rule in infectious
mononucleosis, the presence of a normal or decreased
WBC count should suggest an alternative diagnosis.
• Lymphocytosis accompanies infectious mono-
nucleosis, increases during the first few weeks of
illness, and then gradually returns to normal.
• Patients with fever, pharyngitis, and lymphadeno-
pathy are likely to have EBV infectious mononucleosis
if the relative atypical lymphocyte count is equal to
or greater than 20 percent.
• Atypical lymphocytes should be differentiated from
abnormal lymphocytes. Atypical lymphocytes are
each different in their morphology as observed on
the peripheral smear, whereas abnormal lymphocytes
are monotonous in their sameness, which readily
permits differentiation on the peripheral smear.
• Because of hepatic involvement elevated transami-
nases is constant finding.
SEROLOGICAL TESTING
EBV infection induces specific antibodies to EBV and a
variety of unrelated non-EBV heterophile antibodies.
These heterophile antibodies react to antigens from
animal RBCs.
• Paul Bunnell test: Sheep RBCs agglutinate in the
presence of heterophile antibodies and are the basis
for the Paul-Bunnell test.

• Monospot test: Agglutination of horse RBCs on
exposure to heterophile antibodies is the basis of the
Monospot test.
• Testing for EBV-specific antibodies is as follows:
— EBV induces a serological response to the various
parts of the Epstein-Barr viral particle. IgM and
IgG antibodies directed against the Viral Capsid
Antigen (VCA) of EBV are useful in confirming
the diagnosis of EBV and in differentiating acute
and/or recent infection from previous infection.
EBV IgM VCA titers decrease in most patients
after 3-6 months but may persist in low titer for
up to 1 year. EBV IgG VCA antibodies rise later
than the igM VCA antibodies but remain elevated
with variable titers for life.
— Elevated IgM antibody to VCA is the most
valuable and specific serologic test to confirm
acute EBV infection.
— Antibodies against Early antigen (EA) and Epstein
Barr Virus Nuclear Antigen (EBNA) are also
employed in the diagnosis of IMN.
9.28 Respiratory Syncytial Virus Infection
INTRODUCTION
RSV is a single-stranded, negative-sense RNA virus and
a member of the paramyxoviridae family. Two
subtypes, A and B, are simultaneously present in most
outbreaks, with A-subtype typically causing more
severe disease. Several distinct genotypes within these
subtypes predominate within a community; the
dominant strains shift yearly, accounting for frequent
reinfections. It causes acute respiratory tract illness in
persons of all ages. RSV causes seasonal outbreaks
throughout the world. In tropical and semitropical
climates, the seasonal outbreaks usually are associated
with the rainy season.
Transmission of RSV is primarily by inoculation of
nasopharyngeal or ocular mucous membranes after
contact with virus-containing secretions or fomites.
Direct contact is the most common route of transmission,
but large aerosol droplets also have been implicated. RSV
can survive for several hours on hands and fomites. Hand
Immunization and Infectious Diseases 405
MANAGEMENT
Rest and symptomatic treatment are the mainstay of
management. Due to the risk of splenic rupture strenuous
physical and athletic activities are not advised during
the first 3 weeks of illness.
Short course of corticosteroids (less than 2 weeks) may
be helpful for the complications of IMV namely airway
obstruction, autoimmune hemolytic anemia, seizures,
meningitis and thrombocytopenia with hemorrhage.
PROGNOSIS
The prognosis for complete recovery is excellent if no
complications ensue during the acute illness.
BIBLIOGRAPHY
1. Burke A Cunha. Infectious Mononucleosis e-medicine
updated May 2006.
A Balachandran, SO Shivbalan
washing and contact precautions are therefore important
measures to prevent nosocomial spread. The period of
viral shedding usually is three to eight days, but it may
last up to four weeks in young infants. The incubation
period ranges from two to eight days.
CLINICAL FEATURES
The clinical manifestations very depending upon the
patient’s age, health status, and whether the infection is
primary or secondary. Infants and young children with
primary infections usually present with lower respiratory
tract infection (bronchiolitis or pneumonia), whereas
older children and adults typically have upper respira-
tory tract symptoms [cough, coryza, rhinorrhea and
conjunctivitis] or tracheobronchitis but may develop
lower respiratory tract illness, particularly if they are
elderly (in institutions) or immunocompromised.
Compared with other respiratory viruses, RSV is more
likely to cause sinus and ear involvement.
406 IAP Textbook of Pediatrics
In infants, RSV can cause significant apnea via
unknown mechanisms in approximately 20 percent of
infants admitted to the hospital with RSV and has been
speculated to be associated with sudden infant death
syndrome. Apnea is more likely to occur in young
patients, those born prematurely, those with a history of
apnea of prematurity, and those with more severe
hypoxemia.
RSV causes acute respiratory tract illness in persons
of all ages. Almost all children are infected by 2 years of
age, and reinfection is common. RSV is the most common
cause of lower respiratory tract infection (LTRTI) in
children younger than 1 year. It is also a significant and
often unrecognized cause of LRTI in both elderly and
immunosuppresed. Acute respiratory disease caused by
RSV is not restricted to pediatric and high-risk adult
populations. Healthy adults are infected repeatedly
throughout their lives and typically have symptoms
restricted to the upper respiratory tract.
Though very rarely may be recovered from extrapul-
monary tissues such as liver, CSF, or pericardial fluid,
RSV is highly restricted to the respiratory epithelium,
and is shed apically into the lumen of the airways. This
leads to airway obstruction, air traping and increased
airway resistance.
Previous infection with RSV does not appear to
convey complete protection against reinfection, even
when significant specific antibody titers are present.
Individuals affected with subsequent infections of RSV
are usually milder. Transplacentally acquired antibody
against RSV does not protect infants against infection.
A correlation may exist between infection with RSV
during infancy and the later development of reactive
airways. As an example, approximately 25 percent of
infants with severe RSV infection requiring hospitali-
zation subsequently develop bronchospastic disease. RSV
pneumonia leading to respiratory failure can be a
significant cause of acute morbidity and mortality in the
immunocompromised host, with high mortality rates of
70 to 100 percent.
RISK FACTORS
Patients at risk for RSV lower respiratory tract disease
include:
a. Infants younger than 6 months of age, particularly
those who are born during the first half of the RSV
season and those attending daycare.
b. Infants and children with underlying lung disease
such as chronic lung disease (bronchopulmonary
dysplasia).
c. Infants born before 35 weeks gestation, infants and
children with congenital heart disease.
d. Immunocompromised patients (e.g. severe combined
immunodeficiency, leukemia, or bone marrow or
lung transplant).
e. Patients of any age group with significant asthma
f. Residence at altitude >2500 m.
g. Institutionalized elderly.
h. Elderly patients with chronic pulmonary diseased or
functional disability.
DIAGNOSIS
In the appropriate clinical and epidemiologic setting,
diagnosis of RSV infection can be made clinically with
reasonable accuracy. Diagnostic testing for RSV includes
culture, reverse-transcriptase polymerase chain reaction
(RT-PCR), and serology. The laboratory diagnosis of RSV
is made by analysis of respiratory secretions. In healthy
children, a nasal wash usually provides the best yield,
but a nasopharyngeal swab or throat swab may be
adequate if a nasal wash is not possible. In patients who
are intubated or are undergoing bronchoscopy, a tracheal
aspirate or bronchoalveolar lavage should be obtained.
The standard for definitive diagnosis is isolation of the
virus in HEp-2 cells. Identification of typical plaque
morphology with syncytium formation and immuno-
fluorescent staining confirms the diagnosis. Rapid assays
utilizing antigen capture technology that can be
performed in less than 30 minutes are now available. The
sensitivity and specificity of most of these tests exceed
90 percent and they are a mainstay of the diagnostics as
the identification by culture can take from four days to
two weeks.
TREATMENT
In healthy patient with mild respiratory tract infections
who are treated symptomatically as outpatients.
Supportive care for children with RSV lower respiratory
tract infection (LRTI) may include hospitalization,
supplemental oxygen, intravenous fluid and respiratory
support.
Bronchodilators may help to relieve bronchospasm in some
patients, but should not be continued in patients who

fail to demonstrate rapid improvement. Antiviral agents
are available, but their use is not indicated in most
patients. More aggressive therapy, including immuno-
therapy, or antiviral and immunotherapy with or without
corticosteroids may be warranted for immunocompro-
mised patients.
Corticosteroids may be beneficial in the management of
RSV-associated bronchospasm, particularly in those with
asthma, in whom RSV reinfection may have triggered
an exacerbation.
Ribavirin is a nucleoside with good in vitro activity
against RSV. The routine use of nebulised ribavirin in
infants and children with RSV LRTI is not recommended.
The use of ribavirin administration should be made on
the basis of:
a. Particular clinical circumstances (e.g, underlying
congenital heart disease, lung disease, immuno-
suppression or need for mechanical ventilation).
b. Clinician’ experience.
c. Unproven benefits must be weighed against the risk
of occupational exposure and cost of therapy.
In certain adults early use of inhaled ribavirin has
been shown to reduce morbidity and mortality especially
in adult bone marrow transplant recipients who develop
RSV infections. Ribavirin is contraindicated in pregnant
women, and a negative pregnancy test should precede
its use in women of child-bearing age. Ribavirin is a
known teratogen in rodent species.
Passive immunotherapy with neither intravenous
immunoglobulin with a high neutralizing activity against
RSV (RSVIG) [i.e. polyclonal hyperimmune globulin
prepared from donors with high serum titers of RSV
neutralizing antibody] nor monoclonal antibody
(Palivizumab) [i.e. humanized monoclonal antibody
against the RSV F glycoprotein], have proven beneficial
in the treatment of RSV in hospitalized infants and young
children. However ribavirin in combination with passive
immunotherapy and/or corticosteroids may be
warranted in severely ill immunocompromised patients
with RSV LRTI.
PREVENTION
General measures to decrease exposure to RSV and
decrease the risk of acquisition on exposure includes,
avoidance of exposure to tobacco smoke, restricting
participation in child care during RSV season for high-
risk infants (if possible) and hand washing in all settings.
RSV is highly contagious and can cause serious
nosocomial infections in infants with congenital heart
Immunization and Infectious Diseases 407
or lung disease, bone marrow and lung transplant
recipients, and the frail elderly with multiple underlying
conditions. Rapid diagnosis, handwashing, and appropriate
use of gloves are probably the most important infection control
measures, but contact precaution, including surgical mask
and eye protection for health care providers, should be
used when there is a chance of exposure to aerosols of
infectious respiratory secretions. Isolation of patients in
private rooms or in rooms with other RSV-infected
patients (cohorting patients), and limited transport of
patients from their rooms also is recommended. During
outbreaks, personnel caring for RSV-infected patients
should be restricted from caring for uninfected patients
as often as possible. Health care personnel and visitors
with upper respiratory tract infections should be
restricted from contact with high-risk patients as much
as is practical, especially during the peak RSV
transmission months.
PROPHYLAXIS
Infants with high titers of maternally acquired RSV-
neutralizing antibodies develop less severe RSV disease,
even though antibody does not prevent infections. This
led to the concept of immunoprophylaxis to effectively
decrease the severity of subsequent RSV infections.
Palivizumab as immunoprophylaxis is considered in:
a. Infants and children younger than two years who
have bronchopulmonary dysplasia (BPD) who
require medical therapy within six months of the
anticipated RSV season and/or hemodynamically
significant congenital heart disease.
b. Infants younger than 1 year who were born at 28
weeks of gestation.
c. Infants younger than 6 months of age who were born
between 32 and 35 week of gestation and immuno-
compromised children.
Palivizumab was preferred to RSVIG because of its
ease of administration and lack of interference with
immune response to MMR and varicella vaccines. The
dose of palivizumab is 15 mg/kg IM once per month for
a total of five doses. The first dose is administered before
the RSV season begins. Once immunoprophylaxis is
initiated, all five doses should be administered, even if
the infant becomes old enough that prophylaxis is no
longer indicated. Immunoprophylaxis also should
continue even if the infant experiences breakthrough
infection. This is because high-risk infants may be
hospitalized more than once during an RSV season and
more than one strain of RSV may cocirculate in a
community.
408 IAP Textbook of Pediatrics
9.29 Rotavirus Disease
Acute watery diarrhea resulting in moderate to severe
dehydration still continues to be an important cause of
morbidity and mortality in children. There has been no
appreciable change in the incidence of rotavirus diarrhea
worldwide in the past two decades. The incidence of
rotavirus disease has been observed to be similar in both
industrialized and developing countries, suggesting that
adequate control may not be achieved by improvements
in water supply, hygiene, and sanitation. About 600,000
children die every year from rotavirus infections, mainly
in developing countries, and this figure represents about
5% of all deaths in children younger than 5 years.
EPIDEMIOLOGY IN INDIA
In India rotavirus infection accounts for 26% of all
diarrhea-related hospitalizations. Most cases of diarrhea
(98%) occur during the first 2 years of life, peaking at 9-
11 months of age. Rotavirus-associated diarrhea occurs
year-round but is predominant in winter. If the
estimates of incidence obtained from the population
based study are applied to the total birth cohort of 25
million children in India, then 450,000 hospitalizations
for rotavirus diarrhea would be expected to occur and
will take toll of 100,000 children annually.
ROTAVIRUS
Rotaviruses are 70 nm icosahedral viruses that belong to
the family Reoviridae. Seven rotavirus groups (A to G)
are described, but only groups A, B, and C infect humans.
Group A rotaviruses are the most important from a public
health standpoint. The virus is composed of three protein
shells consisting of an outer and an inner capsid and an
internal core that encases the 11 segments of double-
stranded RNA. Rotavirus contains two structural outer
capsid proteins: VP7, the glycoprotein (G protein), and
VP4, the protrease-cleaved protein (P protein). Because
the two gene segments that encode these proteins can
segregate independently, a typing system consisting of
both P and G types has been developed.
Though there is diversity in circulating rotavirus
strains in India, analysis of data from published
Raju C Shah
epidemiological studies covering 18 Indian cities
performed during 1996-2001 showed that G1 strains had
a greater risk of developing more severe cases of
diarrhea than did children infected with other rotavirus
strains.
CLINICAL MANIFESTATIONS
Fever, nonbilious vomiting and profuse watery, non-foul
smelling diarrhea are usually the presenting symptoms.
In more than 50% cases fever is the presenting symptom.
Rhinitis, congestion of pharynx and tympanic membrane
may also be present. Irritability, lethargy or shock may
be present depending on degree of dehydration. Infection
lasts 3 to 9 days and disease is self-limiting.
DIAGNOSIS
In most places it is by ELISA and LA assays. Gold
standard of diagnosis is by demonstrating wheel like
virus which can be further subgrouped by serotyping.
MANAGEMENT
Treatment is mainly supportive and consists of manage-
ment of dehydration as per WHO standard case manage-
ment guidelines. Oral zinc in a dose of 20 mg twice daily
for ten days can help reducing stool output by 20% and
prevent further attacks of watery diarrhea in next 3
months. Antimicrobial and antisecretory agents have no
role.
PREVENTION
It is believed that diarrhea can be prevented by better
personal hygiene and use of potable drinking water but
rotavirus diarrhea cannot be prevented by such
measures. Research to develop a safe, effective rotavirus
vaccine began in the mid-1970s. The first multivalent
live oral reassortant vaccine, RRV-TV, was withdrawn
from the US market 9 months after its introduction as a
consequence of intussusceptions, a rare but potentially

dangerous adverse effect. Recently a pentavalent
human-bovine (WC3) reassortant (G1, G2, G3, G4 and
P1A [8]) live-attenuated, oral vaccine and a live,
attenuated human rotavirus G1, P1A [8], vaccine (strain
RIX 4414) have been developed (See Chapter 9.3). The
clinical efficacy of both vaccines against severe rotavirus
gastroenteritis is approximately 96 to 98%. There is no
adverse side effect like intussusceptions. Both vaccines
are part of immunization schedule in many countries
and licensed in more than 50 countries by now
Attenuated Human Rotavirus vaccine GlP [8] is licensed
and available in India also (see chapter 9.3).
9.30 Rabies
EPIZOOTIOLOGY AND EPIDEMIOLOGY
Rabies is primarily a disease of animals. All warm-
blooded animals can be infected by rabies virus. Human
rabies is endemic through the main land and canine
rabies is enzootic world over. Only a few countries and
mostly all islands are free from rabies. Rabies occurs in
all continents except Australia and Antarctica. The
countries like Guyana, Jamaica and Uruguay in Latin
America, Bahrain and Japan in Asia, Great Britain,
Scandinavian countries, Spain and Portugal in Europe,
Fiji and Papua New Guinea in Oceanea are free from
rabies. In India rabies is prevalent all over except
Andaman, Nicobar and Lakshadweep groups of islands.
Bat rabies is not reported from India but it is a major
problem in Latin American countries.
Globally 6 million take postexposure prophylaxis
(PEP); 40,000-60,000 deaths occur due to rabies. In India
more than one million take PEP. According to WHO
sponsored national multicentric rabies survey under-
taken in the year 2004 annual incidence of human rabies
deaths came to as 17,137 (14,109 to 20,165 with 95%
confidence). An addition of 20% to include paralytic/
atypical form of rabies provided an estimation of 20,565.
Frequency of human rabies deaths is 1 per 30 minutes
approximately.
Pet dog: man ratio is 1 in 36 and the estimate of pet/
owned/household dog population comes to 28 million.
Immunization and Infectious Diseases 409
BIBLIOGRAPHY
1. Kosek M, Bern C, Guerrant RL. The global burden of
diarrhoeal disease, as estimated from studies published
between 1992 and 2000. Bull World Health Organ.
2003;81:197-204.
2. Kang G, Kelkar SD, Chitambar SD, Ray P, Naik. T.
Epidemiological profile of rotaviral infection in India:
Challenges for the 21st century. J infect Dis 2005;192
Suppl 1:S120-6.
3. Parashar UD, Gibson CJ, Bresse JS, Glass RI. Rotavirus
and severe childhood diarrhea, Emerg infect Dis 2006;
2:304-6.
4. Shah M, Shah R. Rotavirus-Vaccine and magnitude.
Indian Journal of Practical Pediatrics 2007;9(4):271-9.
Tapan Kumar Ghosh, A Parthasarathy
Frequency of bite is 1 per 2 seconds, annual animal bite
incidence rate is 17.4 per 1000 population. So project
annual incidence is 17.4 million for 1 billion population.
Dogs account for 90 to 96 per cent of animal bites in India.
HISTORY
Rabies and plague are known to affect humans since
ancient times. There are mentions of this disease in
ancient literature, like Vedas. The term rabies is derived
from the Sanskrit word ‘Rabhas’ which means, “To do
violence”. Louis Pasteur had developed the first vaccine
against rabies in 1885.
ETIOLOGY AND PATHOGENESIS
Causative virus–Rabies virus is a bullet shaped, single
stranded RNA virus, and belongs to family Rhabdoviride
and genus Lyssavirus. It causes acute encephalitis in
human being. It cannot penetrate intact skin but can
penetrate intact mucosa. This virus basically infects
animals. Two cycles namely, sylvaic and urban cycles in
the animals help this disease to exist in the world. Unless
both these cycles are totally stopped, rabies will continue
to stay. Apart from dogs, which are the main culprits
other hot-blooded animals like cat, fox, jackals, etc.
transmit rabies. The domestic animals like cow, buffalo,
goat, pig, sheep can transmit rabies after they are bitten
and get infected by rabid animals. Monkey can also
transmit this disease if they are infected. Man to man
410 IAP Textbook of Pediatrics
transmission is rare except in cases of cornea transplant
from donors within diagnosed rabies.
Incubation period – 20 to 180 days; peak 30 to 60 days,
extreme 9 days and 1 year. Incubation period is shorter
if the bite is closer to brain.
Clinical types—Two types of clinical rabies are described:
furious type in 80 percent and paralytic type in 20 percent
(Dumb rabies). Both types are common for human and
canine rabies.
The virus first multiplies in striated muscles, ascends
along axons from periphery to spinal cord and eventually
to neurons in the brains. There is neuronal destruction
in the brainstem and medulla and severest changes in
pons and IV ventricles but cortex is spared.
MODES OF TRANSMISSION AND
CLINICAL FEATURES
Modes of Transmission
Common Rare
Bite and scratch from infected animals Aerosol transmission
Lick (on broken skin/intact mucus Organ transplantation
membranes)
Bites by insectivorous bats can also transmit rabies
and rabies can spread also by aerosol infection in bat
infested caves but these are not problems of India.
Clinical Features
As stated earlier furious type of rabies is the most
common (80%) but dumb type of rabies manifested by
ascending paralysis (20%) is also reported. The furious
type of rabies presents with acute neurological phase
characterized by hydrophobia, aerophobia, photo-
phobia and dysphagia. No survival is so far reported in
unvaccinated infected persons in the world literature.
The difference of the presenting features in these 2 types
is shown in Table 9.30.1.
DIAGNOSIS
Diagnosis is mainly based on clinical signs of hydro-
phobia and aerophobia in the furious type of rabies.
Confirmation of diagnosis is based on the followings:
1. Detection of Negri body in brain by Seller’s stain.
2. Detection of virus antigen by immunofluorescence.
3. Mouse pathogenicity (biological test).
TABLE 9.30.1: Clinical features of rabies
Furious type 80% paralytic type (20%)
Tingling/numbness at bite site Tingling/numbness at bite site
Nonspecific symptoms Nonspecific symptoms
(Fever, malaise, headache, (Fever, malaise, headache, etc)
etc)
Hydrophobia, aerophobia Ascending paralysis
Photophobia Coma
Death in 3-5 days Death in 7-21 days
(cardiac and respiratory (Cardiac and respiratory failure)
failure)
Detection of antibodies in CSF or serum of unimmuni-
zed persons and detection of viral nucleic acid from
infected tissue is also possible. Virus can be isolated from
saliva.
WHO Classification of Bites
Before starting the treatment of animal bite cases in
human being, classification of the exposure is most
important. Table 9.30.2 shows the WHO classification of
animal bites cases.
MANAGEMENT
Treatment following an exposure (bite, scratch or lick
on broken wounds in skin or directly on mucous
membrane, i.e. on oral cavity or on anus by suspected
rabid animal) will consist of the following stages:
1. Proper wound management.
2. Infiltration of rabies immunoglobulin (RIG) in all
category III exposure (see Table 9.30.2) rabies.
3. Antirabies vaccination with modern cell culture
rabies vaccine (CCRV).
4. Antitetanus prophylaxis.
5. Supportive treatment with antipyretic/analgesics,
local and/or systemic antibiotic as required.
For IAP - Infectious Diseases Chapter Protocol on
Management of Rabies refer to Chapter 36.11.4, Page
No. 1534.
The Steps of Management
Step I: Wound Management
In wound management, the most important steps are:
i. Through washing of wounds under running tap
water for at least 10 minutes with aim of physical
elimination/shedding of the viral loads and
application of soap/detergent for chemical treat-
ment and changing the pH of the wounds.

TABLE 9.30.2: Type of contact, exposure of recommended postexposure prophylaxis
Category Type of contact
I Touching of feeding of animals.
Licks on intact skin
II Nibbling of uncovered skin. Minor
scratches or abrasions without bleeding
III Single or multiple transdermal bites or
scratches, licks on broken skin.
Contamination of mucous membrane
with saliva (i.e. licks)
Note: After carefully assessing the category of exposure, the treating doctor should evaluate the course of action to be taken, based on
the following general considerations. He should also keep in the mind that with the presently available safe cell culture rabies vaccine
(CCRV), it is always safe to offer treatment rather than withhold in doubtful situations
ii. Application of disinfectants like providone iodine,
spirit, household antiseptics, etc. to remove the
remaining virus particles and prevention of
secondary infection.
Step II: Rabies Immunoglobulin (RIG)
Infiltration of bases of wound(s) with rabies immuno-
globulin (RIG)–Neutralization of the virus and forming
a coat around the virus thus obliterating virus entry into
the nerve ending.
Step III: Antirabies Vaccination (ARV)
A course of postexposure prophylaxis (PEP) either IM
or ID route with modern cell culture ARV (CCRV).
Step IV: Antitetanus Prophylaxis
Administration of tetanus toxoid (TT) and/or tetanus
immunoglobulin (TIG) as required.
It is to be noted that in wound management
application of irritants, cauterization and suturing, i.e.
closing of wounds are to be avoided. If suturing is needed
for the purpose of hemostasis. It can be done only after
administration of RIG.
RABIES IMMUNOGLOBULIN (RIG)
The antirabies serum (ARS)/rabies immunoglobulin
(RIG) provides passive immunity in the form of
readymade antibody to tide over the initial phase of the
infection. Antirabies serum or RIG has the property of
binding to rabies virus, thereby resulting in neutrali-
zation of the virus. Two types of RIGs are available.
Immunization and Infectious Diseases 411
Type of exposure Recommended postexposure prophylaxis
None None, if reliable case history is available
Minor Wound management +
Antirabies vaccine
Severe Wound management +
Rabies immunoglobulin +
Antirabies vaccine
1. Equine rabies immunoglobulin (ERIG): ERIG is of
heterologous origin raised by hyper-immunization
of horses. Currently manufactured ERIGs are highly
purified and enzyme refined. The dose of ERIG is 40
IU per kg body weight of patient and is given after
testing for sensitivity (Skin test), up to a maximum of
3,000 IU.
2. Human rabies immunoglobulins (HRIG): These are
prepared from the serum of people hyperimmunized
with rabies vaccines. The dose of HRIG is 20 IU per
kg body weight (maximum 1,500 IU). HRIG does not
require any prior sensitivity testing (Skin test).
RIG is to be infiltrated as much as possible into and
around all the wounds; remaining if any is to be given
intramuscularly at a site away from the site of vacci-
nation. All the wounds are to be infiltrated with RIG.
After calculation of the dose of RIG if it is seen that RIG
is insufficient by volume to infiltrate all the wounds, it is
to be diluted with normal saline to make it 2 or 3 times
of its volume.
Antirabies Vaccines
Active immunization is achieved by administration of
safe and potent CCRVs or purified duck embryo vaccines
(PDEV). In India, nerve tissue vaccine or NTV (Semple
vaccine) was used for postexposure treatment in public
sector. However, as this vaccine was reactogenic
(neuroparalyticogenic), the production was stopped in
December, 2004 in all centers. The dosage schedule of
cell culture rabies vaccine (CCRV) is same irrespective
of the body weight or age of the children.
412 IAP Textbook of Pediatrics
The Types of Antirabies Vaccine
1. Cell culture rabies vaccines (CCRV)
i. Human diploid cell vaccine (HDCV)
ii. Purified chick embryo cell vaccine (PCEC).
iii. Purified vero cell rabies vaccine (PVRV).
2. Purified duck embryo vaccine (PDEV) All CCRVs and
PDEV used for postexposure prophylaxis (PEP)
should have potency (antigen content) greater than
2.5 IU per dose.
Reconstitution and storage—The lyophilized prophilised
vaccine should be reconstituted with the diluent
provided with the vaccine immediately prior to use. In
case of unforeseen delay it should be used within 6-8
hours of reconstitution.
Presently liquid human diploid cell (HDCV) vaccine
is also available.
Intramuscular (IM) Regimen of Cell Culture
Antirabies Vaccine
The regimens for IM administration are described below.
But the Essen schedule is the only IM regimen to be
practiced in India.
1. Essen schedule: Five dose intramuscular regimen (1-1-1-
1-1) –Total five injections, single dose on days 0, 3,7,
14 and 28. Day 0 indicates date of first injection.
2. Zagreb IM Protocol (2-0-1-1)- Two doses on day 0 on
either side of deltoid or anterolateral thigh, 1 dose on
day 7 and one dose on day 21.
Site of inoculation– The anterolateral thigh region is ideal
in infants and younger children whereas of older children
can take in deltoid region safely. Gluteal region is not
recommended because the fat present in this region traps
the vaccine, retards the absorption of antigen and hence
impairs the generation of optimal immune response.
Intradermal (ID) Regimen of Cell Culture
Antirabies Vaccine
Intradermal regimens consists of administration of a
fraction of intramuscular dose of CCRVs on multiple sites
in the layers of dermis of skin. The use of intradermal
route leads to considerable savings in terms of total
amount of vaccine needed for full pre- or postexposure
vaccination, thereby reducing the cost of active
immunization. But the regimen will not make any
economic meaning when one or two doses are used in
private clinics. It is better to be used in antirabies clinics
and centers (ARCs) where a handful number of cases of
animal bites/scratches will be available.
The following vaccines have been approved by Drug
Controller General of India (DCGI) currently for use by
intradermal route: (i) Purified chick embryo cell vaccines,
(ii) Purified vero cell vaccine.
As purified duck embryo cell vaccine is a suspension,
its use is not recommended for ID administration,
similarly the liquid and adjuvanated human cell culture
vaccine is not suitable for ID use.
Potency of approved vaccine: The vaccines should have
stated potency of >2.5 IU per IM dose, irrespective of
reconstituted volume. The same vaccine is used for ID
administration as per stated schedule. 0.1 ml of vaccine,
irrespective of reconstituted volume, is administered per
ID site as per schedule below.
ID Vaccine Regimen
1. Updated Thai Red Cross (Updated TRC-ID) Schedule (2-
2-2-0-2): This is the most ideal ID schedule. This
involves injection of 0.1 ml of reconstituted vaccine
per ID site and on two such ID sites per visit (one on
each deltoid area, an inch above the insertion of
deltoid muscle) on days 0, 3, 7 and 28. The day 0 is
the day of first dose administration of IDRV and may
not be the day of rabies exposure/animal bite. No
vaccine is given on day 14.
2. Thai Red Cross (TRC-ID) schedule (2-2-2-0-1-1): Same
as the above schedule except 0.1 ml single dose is
given on day 28 and day 90, but as the chance of drop
out will increase the first regimen is preferred.
It is very important to learn the technique of giving
ID injection for the staff of antirabies clinics (ARCs).
Pre-exposure Schedule
As rabies is a cent per cent fatal disease and children
constitute a special risk for getting the infection, it may
be advisable to vaccinate children after they attain the
age of 3 years and start playing in the streets and may
come in contact with street or pet dogs. This schedule is
also practiced in persons who are engaged in rabies
research and production of rabies vaccine units, in
municipality workers, in postmen, in persons going to
forests where there are bat infested caves, veterinary
practitioners, taxidermists, etc. It has been shown in
several studies that a course of pre-exposure vaccination
will elicit a good immune response and the memory cells
generated will last for many years. In fact some studies

have also shown that protective levels of antibodies may
persist for at least a decade. If such children are exposed
to rabies by animal bites, 2 booster doses given on day 0
and on day 3 will elicit a rapid and stronger secondary
immune response which will neutralize the virus and
prevents its ascent to the CNS. There is no need for
administration of rabies immunoglobulin in patients who
had taken a complete course of pre-exposure or post-
exposure course of CCRVs in their previous exposure.
Schedule of pre-exposure vaccination:
Intramuscular: Three doses of any CCRV (1 ml or 0.5 ml
depending on the brand) administered on the antero-
lateral thigh or deltoid region on days 0, 7 and 28.
Intradermal: The dose (0.1 ml) is same for all vaccine
brands and 0.1 ml is administered intradermally over
the deltoid on days 0, 7 and 28.
ABC-AR Program
Animal birth control–anti-rabies program (ABC-AR
program) is launched in India by Blue Cross to control
stray dog population. All dogs, pet and stray, need
vaccination every year with an effective and potent anti-
rabies vaccine.
WHO Rabies Vaccine Initiative
This is formulated by WHO, vaccine manufacturers,
professional bodies and major funding agencies with the
objective to reduce cost of each effective course of
treatment making it affordable to the downtrodden in
developing countries. Only modern cell culture vaccine
is to be used in pre- and postexposure prophylaxis.
Canine Rabies
All warm-blooded animals even bats are susceptible to
rabies, the incubation period and symptoms had marked
similarities in all of them. The abnormal behavior of the
infected animals are seen commonly. Even rabies is
reported in small percentage of bites by immunized dogs
and also by puppies. The observation period of 10 days
is only true in dog and cat bites.
Dogs are the most important animals in spreading
rabies, responsible for 96% of the cases of human rabies
deaths in India. But for several reasons it is difficult to
control stray dog population in this country. The most
friendly animal to human being, the dog become restless,
move to other places of seclusion, sudden burst of
excessive affection are seen in the early stage with
Immunization and Infectious Diseases 413
persistent attempts to lick, when the dogs are infected
by rabies virus. There is behavior changes, ultimately the
dog develops irresistible tendency to scratch and bite.
The pupils dilate and salivation is increased. The furious
form which show the classical symptoms gives the
concept of mad dogs. Dumb rabies is characterized by
progressive development of paralysis.
It is to be accepted that stray dog population has to
be reduced drastically by initiative to sterilize the male
dogs in stray population and vaccination with modern
rabies vaccines by the government health departments
and NGOs combinedly are needed. Even the pet dogs
must have municipality licenses and they have to be
immunized annually with rabies vaccines. All these will
help to reduce the incidence of human deaths due to
rabies in India.
For IAP- Infectious Diseases Chapter Protocol on
Rabies, refer to Chapter 36.11.4 Page No. 1534.
BIBLIOGRAPHY
1. Association for Prevention and Control of Rabies in India.
WHO Sponsored National Multicentric Rabies Survey,
2004. Bangalore: APCRI, 2004;44-5.
2. Bompart F, Dutta AK, Wood SC, Rabies immunoglo-
bulins in WHO category III bites. Journal of Association
for Prevention and Control of Rabies in India 2001;1(2):
7-11.
3. Caplan K. Rabies: The Facts Oxford: Oxford University
Press, 1977;53-61.
4. Ghosh TK. Prevention of rabies by vaccination and
immunoglobulin therapy: Some controversies and
solutions. In: Ghosh TK, ed. Infectious Diseases in
Children and Newer Vaccines. New Delhi: Jaypee
Brothers 2007;330-5.
5. Ghosh TK. Rabies and its prevention. Pediatr Clin India
2001;36:42-51.
6. Ghosh TK. Rabies vaccine. In: Shendurnikar N, Agarwal
M, eds. Immunisation for children, 1st ed. Hyderabad,
Bangalore: Paras Publishing 2003;171-82.
7. Goswami A. Safety and tolerance of equine rabies
immunoglobulin in Indian population. Journal of
Association for Prevention and Control of Rabies in India
2000;1(2):30-4.
8. Kundu R, Ganguly N, Ghosh TK. IAP Protocols on
Infectious Diseases in Children. Kolkata: IAP infectious
Diseases Chapter 2008;57-71.
9. Madhusudana SN. Implementing intradermal vaccina-
tion: Why delay (Editorial). APCRI Newsletter 2003;3:3.
10. Meslin FX, Stohr. K. Human Rabies Vaccines. Current
situation and foreseeable Trends. Journal of Association
for Prevention and Control of Rabies in India 2000;1(2):
5-6.
11. Singh H, Bhatia R. Vaccines: Prospects and Perspectives.
New Delhi: Forward Publishing Company, 1993;282-309.
12. World Health Organisation. WHO Expert Committee on
Rabies, 89th Report. WHO Tech Rep Ser 1992;8224:
1-84.
414 IAP Textbook of Pediatrics
9.31 Pediatric HIV Disease
Acquired Immune Deficiency Syndrome (AIDS) is
caused by human immunodeficiency virus types 1 and
2 (HIV). It is a worldwide problem, but more so in
developing countries like sub-Saharan Africa,
Thailand, India and the rest of the Asia. Ever since the
report of the first pediatric case in 1983, there has been
an alarming increase in the rate of disease. It is
estimated that currently 38.6 million people live with
HIV infection world over of which 2-3 million, i.e.
5-9% are children <15 yrs of age. HIV transmission
occurs by contact with infected cells in blood and body
fluids.
The predominant cells infected are CD4+T lympho-
cytes, depletion of which causes immunodeficiency.
EPIDEMIOLOGY
The estimated number of children living with HIV/AIDS
in India is 0.17 million (UNAIDS 2004 report), which
means they form about 3.5-5% of people living with HIV
in the country. The pediatric population at risk of HIV-1
infection are infants born to infected mothers, children
given HIV-1 contaminated blood or blood products and
adolescents who acquire infection sexually or by use of
intravenous drugs. Unlike in adults where > 90% of the
time HIV infection occurs through sexual route, in the
developing countries 95% of cases in children occur due
to vertical transmission from their infected parents.
In vertical transmission, HIV can be transmitted
during pregnancy, during childbirth, or breastfeeding.
Without intervention, the risk of transmission from
an infected mother to her child ranges from 15-20% in
developed countries and from 25-45% in developing
countries (Table 9.31.1).
TABLE 9.31.1: Estimated risk and timing of Mother To
child Transmission (MTCT) in the absence of interventions
– During pregnancy 5-10%
– During labor and delivery 10-15%
– During breastfeeding 5-20%
– Overall without breastfeeding 15-25%
– Overall without breastfeeding upto 6 months 20-35%
– Overall without breastfeeding upto 18-24 months 30-45%
Meena Malkani
VERTICAL TRANSMISSION OF HIV-1
It is an important and unique aspect of pediatric AIDS.
Potential routes of infection include admixture of
maternal fetal blood, or infection across the placenta
antenatally or extensive mucocutaneous exposure to
maternal blood and vaginal secretions intranatally.
Factors which may increase rate of vertical trans-
mission of HIV-1 are:
• High viral load in the maternal circulation
• Maternal seroconversion just before delivery
• Vitamin A deficiency in mother
• > 4-hr duration of rupture of membrane
• Vaginal delivery
• STD in mother
• Delivery before 34 weeks
• Birth weight < 2.5 kg
• Detectable p24 antigen in maternal serum
• Absence of neutralizing antibodies in maternal serum
• Maternal CD4+ count less than 700/cumm or CD4+/
CD8+ ratio less than 0.6.
BREAST MILK ACQUIRED HIV-I INFECTION
Transmission through breastfeeding seems to be related
to the virus load in the breast milk as well as to length of
time the child is fed. HIV-1 has been detected by culture
and by the PCR method in cellular and acellular
components of breast milk. The colostral viral load
appears to be particularly with HIV-1, such a route is
facilitated by the absence of an acid environment in the
newborn baby’s stomach that allow HIV-1 to retain its
infectivity.
TRANSFUSION ACQUIRED HIV-1 INFECTION
The risk of transmission to a recipient of HIV-1 infected
blood is at least 95 percent (Table 9.31.2).
TABLE 9.31.2: Differences between perinatal and
transfusion acquired HIV-1 infection
Perinatal Transfusion acquired
1. Shorter incubation period 1. Longer incubation period
2. LIP common 2. LIP rare
3. Acute HIV syndrome 3. Acute HIV syndrome seen
almost never identifiable 4-6 weeks after transfusion

Figure 9.31.1: The genome of HIV
ADOLESCENT AND HIV
Worldwide data demonstrate that the AIDS pandemic
remains dynamic among adolescents, most of which is
transmitted heterosexually. However homosexual
behavior and sexual abuse is also a major route of
transmission in adolescent population. These are
generally in early stage of HIV infection. Intravenous
drug use and receipt of infected blood products account
for a smaller percentage of transmission while youth who
acquire HIV perinatally account for a small but growing
number of adolescents living with HIV or AIDS. This
group forms advanced stage of the disease.
ETIOPATHOGENESIS
HIV genome is single stranded RNA, 9.8 Kb in size. Both
the ends have identical regions that contain regulation
and expression genes of HIV (Fig. 9.31.1). The remainder
of genome includes three major sections.
The pol region: Produces viral enzymes–reverse
transcriptase, protease, and integrase.
The env region: Encodes the viral envelope proteins.
Immunization and Infectious Diseases 415
HIV selectively binds to cells expressing CD4
molecule on their surface–primarily T4 lymphocytes
(CD4+ cells), cells of monocyte-macrophage lineage,
microglia, astrocytes, oligodendrogila and placental
tissue containing villous Hafbauer cells may be infected
by HIV.
The gp120, which has a knob-like structure, interacts
with protruding loop on CD4 protein forming CD4+-gp
120 complex. RNA is released from viral particle. RNA
produces DNA, using reverse transcriptase. The cell’s
own DNA is broken and the viral DNA, now called
provirus, is inserted. DNA is switched on and copies of
the virus are made, which leave the cell and infect other
cells. With HIV replication, host cell is killed or survives,
but is permanently infected. Monocytes and macro-
phages are relatively refractory to cell killing and syncytia
formation, and serve as a reservoir of persisting infection.
Since CD4+ lymphocytes are responsible for orchestra-
tion of many important immune responses, its inacti-
vation by HIV leads to many defects of monocytes,
macrophages, cytotoxic T-cells, natural killer cells (K) and
B cells. After HIV enters the circulation intense viremia
ensues, resulting in widespread seeding of virus to
various organs, including brain and lymphoid tissue.
CD4+ lymphocytes migrate to lymph nodes where they
become activated and proliferate, causing generalized
lymphadenopathy (acute retroviral syndrome).
Following cellular and humoral response within one
week to three months the level of culturable virus
declines and patient enters a phase of clinical latency,
with lack of symptoms and return of CD4+ cells to only
a moderately decreased level. During clinical latency,
patients undergo gradual deterioration of immune
system with depletion of architecture and degeneration
of the follicular dendritic cell network with loss of ability
to trap HIV particles. This frees the virus to recirculate,
producing high levels of viremia seen during the later
stages of disease. Perinatally infected infants generally
demonstrate a relatively shorter period of clinical latency.
This may be so, if intrauterine infection coincides with
the period of rapid expansion of CD4+ cells in fetus; it
could effectively infect the majority of the body’s
immunocompetent cells causing more severe impair-
ment of immunity than HIV infection in adults.
Protection from Infection
A strong immune response might reduce virus load or
even clear the virus. The frequency of clearance has been
416 IAP Textbook of Pediatrics

reported to range from 2.7 to 6.4 percent. Detection of TABLE 9.31.3: Revised WHO clinical staging of HIV/AIDS
HIV-1 envelope specific T-cell response in cord blood of
Clinical stage 1 (asymptomatic):
uninfected newborn of seropositive mother indicates that • Asymptomatic
clearance may already have occurred in utero. HIV-1 • Persistent generalized lymphadenopathy
specific cytotoxic lymphocytes and in vitro antibody
Clinical stage 2 (mild):
production to viral gag and env proteins in apparently • Unexplained persistent hepatomegaly
uninfected infants has also been reported. • Papular pruritic eruptions
• Extensive wart virus infections
CLINICAL FEATURES • Molluscum contagiosum
• Fungal nail infections
Pattern of disease expression and progression is quite
• Recurrent oral ulcerations
variable in HIV-1 infected children. 20 to 30 percent
• Unexplained parotid enlargement
develop profound immunodeficiency and AIDS defining
• Herpes zoster
illnesses before the first year of life and two-thirds have • Recurrent upper respiratory tract infections (otorrhea, sinusitis)
more slowly progressive course from 5 to 10 years. Age
Clinical stage 3 (advanced):
of onset of any sign of HIV-1 infection predicts length of
• Unexplained malnutrition not responding to standard therapy
survival. • Unexplained persistent diarrhea
• Unexplained persistent fever
Revised WHO Clinical Classification 2006 • Persistent oral candidiasis
WHO has recently revised the earlier CDC classification • Oral hairy leukoplakia
• Lymph node TB
and given the clinical classification (Table 9.31.3, based
• Pulmonary TB
on sign and symptoms) and immunological classification
• Severe recurrent bacterial pneumonia
(Table 9.31.4, based on CD4+ counts.) • Lymphoid interstitial pneumonia
• Unexplained anemia, neutropenia or chronic thrombo-
OPPORTUNISTIC INFECTIONS (OI) cytopenia

OI occur as CD4+ count declines. Pneumocystic carinii Clinical stage 4 (severe):

(PCP) is the most common and lethal opportunistic • Unexplained severe wasting
• Pneumocystis carinii pneumonia
infection in pediatric population. Clinically, there is
• Recurrent severe bacterial infections
respiratory distress with cough and hypoxemia. Chest
• Chronic Herpes simplex infection
X-ray radiograph reveals interstitial infiltrates or diffuse • Extrapulmonary TB
alveolar disease. Diagnosis is made by demonstration of • Kaposi sarcoma
P. carinii in bronchoalveolar fluid or lung biopsy. • Esophageal candidiasis
Oral candidiasis is the most common fungal infection. • CNS toxoplasmosis
It may involve the esophagus resulting in vomiting, fever, • HIV Encephalopathy
dysphagia and anorexia. Intestinal cryptosporidiosis may • Cytoegalovirus infections
result in severe chronic diarrhea and malnutrition. • Cryptococcosis, cryptosporidiosis, isosporiasis
Atypical mycobacterial infection with Mycobacterium • Progressive multifocal leucoencephalopathy
• Cerebral or B cell non-Hodgkin lymphoma
avium intracellular complex (MAC) has been recognized
• HIV-associated nephropathy/cardiomyopathy
increasingly. It presents with fever, weight loss, diarrhea,

TABLE 9.31.4: Revised classification of immune suppression in children based on CD 4+ levels

Classification of HIV <11 months 12-35 months 36-39 months >5 years
associated immune (% CD4) (% CD4) (% CD4) (cells/mm3)
deficiency
Not significant >35 >30 >25 >500
Mild 30-35 25-30 20-25 350-499
Advanced 25-30 20-25 15-20 200-349
Severe <25 <20 <15 <200
 Immunization and Infectious Diseases 417

anemia, granulocytopenia and diagnosed by isolation of Other Markers of HIV-1 Infection Include
MAC from blood or bone marrow. Other opportunistic
Decreased CD4+ count, increased CD8+ count, depressed
pathogens include Toxoplasma gondii, Mycobacterium
lymphocyte proliferative response to mitogens and
tuberculosis and malarial parasites. Viral infection with
marked hypergammaglobulinemia.
Herpes simplex, Varicella zoster, cytomegalovirus and measles
virus are often seen. MANAGEMENT
Other common clinical presentation of pediatric AIDS
is lymphocytic interstitial pneumonia (LIP)–it is a chronic A multidisciplinary team approach is essential for
lower respiratory tract abnormality. It causes reticulo- successful management of pediatric HIV-1 infection.
nodular pulmonary infiltrate with or without hilar
lymphadenopathy. The infiltrate is composed of CD8+ Specific Therapy
lymphocytes. Children with LIP having clubbing, Specific antiretroviral therapy (Table 9.31.5) is believed
persistent cough with exertional dyspnea require chronic to result in extended survival and reduction in
oxygen therapy. It may resolve with oral corticosteroids. opportunistic infections with improvement in weight
Neoplasms are relatively uncommon in pediatric gain and general wellbeing.
HIV-1 infection. Non-Hodgkin’s lymphoma and primary
CNS lymphoma are the most commonly reported Monotherapy
malignant disease.
Early trials with ZDV monotherapy were encouraging,
Recently, multiple soft tissue tumors have been
reported. especially regarding improvement in or prevention of
CNS abnormalities. However lack of resistance reduced
DIAGNOSIS OF HIV INFECTION the importance of monotherapy. Subsequent studies
documented the benefit of combination NRTI regimens
Detection of HIV-1 antibody (IgG) by ELISA is over monotherapy.
extremely sensitive and very specific. It is simple and
inexpensive. However, maternal transplacental IgG in
TABLE 9.31.5: Antiretroviral agents
the infant obscures the usefulness of antibody screening
for diagnosis, except in older children and adolescents. Nucleoside reverse transcriptase inhibitor (NRTI)
It may be necessary to wait until 15 to 18 months to 1. Zidovudine (ZDV, AZT) 90-180 mg/m2 every 6-8 hrly
identify an HIV-1 exposed infant by ELISA test. Western 2. Didanosine (ddl) 90-150 mg/m2 every 12 hrly
blot analysis measures antibody to specific viral 3. Lamivudine (3TC) 4 mg/kg bid
polypeptides and can be used as a confirmatory test 4. Stavudine (d4T) 1 mg/kg q 12 hrly (to 30 kg)
5. Abacavir (ABC) 8 mg/kg q12 hrly
after six months of age. The presence of IgM or IgA anti-
6. Zalcitabine (ddc) 0.005-0.01 mg/kg q 8 hrly
HIV in the infant’s circulation can indicate HIV *7. Adefovir (ADV) Pediatric dose not established
infections, as these immunoglobulin classes do not cross
the placenta. However, detectable quantities of IgA anti- Non-nucleoside RTI (NNRTI)
HIV are not generally produced until 3 to 6 months of 1. Nevirapine (NVP) 120-200 mg/32 every 12 hrly
age and IgM anti-HIV are insensitive and nonspecific. 2. Efavirenz (EFV) 200-600 mg/qd (by wt)
Tests identifying viral presence as HIV-1 culture and 3. Delavirdine (DLV) Adolescent/adult 400 mg tid
HIV-1 DNA and RNA polymerase chain reaction (PCR)
Protease inhibitor (PI)
are more valuable but are very costly. Two types of PCR
are available: 1. Ritonavir (RTV) 400-450 mg/m2 every 12 hrly
2. Nelfinavir (NFV) 30 mg/kg every 8 hrly
1. HIV DNA PCR: This is a qualitative test that detects
*3. Indinavir (IDV) 500 mg/m2 every 8 hrly
the proviral DNA integrated with the host cell. *4. Saquinavir (SQV) 50 mg/kg tid (under study)
2. HIV RNA PCR: This is a quantitative test using 5. Amprenavir 20 mg/kg bid
reverse transriptase and thus determines the viral
*WHO directive-pediatric dose not approved
load.
418 IAP Textbook of Pediatrics
• In the 2006 WHO guidelines for treatment of infants
and children with HIV, the drugs recommended for
use are:
• NRTI (AZT, d4T, 3TC, ABC).
• NNRTI (NVP, EFV).
• PI (LPV, NFV, SQV).
The recommended first line ARV regimen for infants
and children is:
→ Regimen of 2 NRTI+1 NNRTI, i.e.
1. AZT + 3TC + NVP/EFV
2. D4T + 3 TC+ NVP/EFV
• Under the National AIDS Control Program, specific
fixed dose combination (FDCs) of ARV drugs in
pediatric dosages have been made available at
selected ART countries.
• Protease inhibitors are used as second line treatment
in case of treatment failure with first line drugs or
severe adverse reactions to first line drugs.
REDUCTION OF VERTICAL TRANSMISSION
The recommended methods to reduce vertical trans-
mission are:
1. Elective cesarian section
2. Antiretroviral therapy
3. Avoidance of breastfeeding.
However WHO advocates breastfeeding by infected
mothers in developing countries in view of high mortality
related to diarrhea, malnutrition and respiratory disease
in non-breastfed children. Hence, breastfeeding needs
to be decided on individual merit depending on hygiene
and socio-economic factors. Invasive procedures such as
amniocentesis or fetal blood sampling should be avoided
and any sexually transmitted disease in mother should
be adequately treated. AZT is to be included in all
perinatal regimen.
When a pregnant women presents during pregnancy,
she should be given ART as follows (to prevent MTCT):
1. Antepartum: Oral AZT 300 mg BD from 28 weeks
gestation or as soon as feasible.
2. Intrapartum: AZT continued as 300 mg at onset of
labor and 300 mg every 3 hrly till labor.
Also 3TC 150 mg every 12 hrly till labor
Also single dose NVP 200 mg at onset of labor
3. Postpartum: Oral AZT 300 mg BD and 3TC 150 mg
BD for 7 days.
For the baby: NVP single dose 2 mg/kg within 72 hours
of birth and oral AZT 2 mg/kg 4 times a day for 7 days.
PREVENTION OF PCP
PCP prevention is one of the most important goals of
HIV-1 infection management. All infants from 4-6 weeks
of age, either born to HIV-1 infected mothers or proved
to be HIV-1 infected should receive prophylaxis for PCP.
The drug of choice is co-trimoxazole in the dose of 5 mg/
kg/day single daily dose.
Alternatively dapsone 2 mg/kg orally, once a day or
pentamidine or atovaquon may be given.
NUTRITION
Malnutrition is a serious problem, especially if diarrhea
is associated with HIV-1 infection. Dietary supervision
may help to prevent weight loss with adequate calorie
and protein intake.
OTHER INFECTIONS
Prompt treatment of associated bacterial and opportu-
nistic infections with appropriate antiobiotics and drugs
is very necessary.
IMMUNIZATION
All HIV infected children should receive standard
pediatric immunization. However, OPV and BCG in
symptomatic children need to be withheld.
COUNSELING AND SUPPORT
Coping with the complex psychological and social needs
of the family is one of the most important and challenging
aspects of pediatric HIV management.
The child may be the first family member to be
diagnosed and the mother feels an enormous sense of
guilt of having infected her own child. Due to the stigma
attached to diagnosis of HIV, families often feel socially
and culturally isolated. Illness and unemployment can
create financial problems. It is important to establish links
with support agencies in the community, while respect-
ing the family’s need for confidentiality. A multidiscip-
linary team of health professionals who can deliver
coordinated care in a family oriented and child centered
manner, is necessary for the support of the family
afflicted with AIDS. Helping HIV infected children and
their families lead healthier and happier lives must be
one of the biggest and most rewarding challenges of
pediatrics.

FUTURE PROSPECTS
Gene Therapy
Employing inhibitor molecules targeted against CD4+
T-cells indicated that anti-reverse transcriptase antibody
inhibits HIV-1 replication. Gene therapy is defined as
introduction of new genetic material into cells of an
individual with resulting therapeutic benefit. Because
HIV-1 integrates itself into host’s genome, AIDS can be
considered as an ‘acquired genetic disease’. This therapy
requires the introduction of anti-HIV-1 genes into cells,
to prevent or inhibit HIV-1 viral gene expression of
function and consequently to limit HIV-1 replication and
AIDS pathogenesis. Gene therapy also down-regulates
HIV-1 gene expression in contrast to conventional drug
therapies.
HIV Vaccine
The development of an efficacious vaccine against HIV
would be the best strategy for controlling the HIV
epidemic. The goal for a preventive HIV vaccine is to
generate both humoral and cellular immunity against
HIV in the host before exposure to the virus. However,
there are many hindrances to the development of an
effective HIV vaccine which includes factors like
antigenic diversity and hypervariability of the virus,
integration of the viral genome into the host cell
chromosome, transmission of disease by mucosal route,
progressive destruction of the immune system of the host,
etc. Several different vaccine concepts have been used to
9.32 Chikungunya Fever
Chikungunya is a viral fever caused by an alphavirus
and spread by bite of an infected Aedes aegypti mosquito.
The disease was first discovered by Marion Robinson and
WHR Lumsden in 1955 following an outbreak on the
Makonde plateau. The name derives from a Kimakonde
root verb, kungunyala, meaning ‘to dry up or become
contorted’, specifically modified in early times to describe
the bent posture of patients. Although primarily African
and zoonotic, it is known chiefly for its non-African large
Immunization and Infectious Diseases 419
elicit HIV specific immune responses. The first phase 1
trail of an HIV candidate vaccine was conducted in the
USA in 1987, using gp 160 candidate vaccine.
Subsequently more than 30 candidate vaccines have
been tested in 60 phase 1 or phase 2 trials, involving more
than 10,000 healthy volunteers. But none of the vaccines
have been proved to be effective in preventing HIV
disease in humans so far.
BIBLIOGRAPHY
1. Americal Academy of Pediatrics Committee on Pediatric
AIDS, evaluation and medical treatment of the HIV
exposed infant. Pediatrics, 1997;99.
2. ARV drugs for treating pregnant women and preventing
HIV infection in resource limited settings; towards
universal access. Recommendations for a public health
approach 2006 version.
3. Chadwick EC, Yogev R: Pediatric HIV/AIDS, PCNA
1995; 42(4):969-90.
4. Luzuriaga K, Sullivan JL. Transmission of the HIV from
mother to fetus and infants. AIDS: etiology, diagnosis,
treatment and prevention (4th edition), 1997;167-72.
5. Nelson Textbook of Pediatrics, 17th edition, Ram Yogev
and Ellen Chadwick 2004;1109-21.
6. Scarlatti G. Pediatric HIV infection. The Lancet
1996:348:863-8.
7. Singh S. HIV infection. Frontiers in pediatrics 1996;102-
15.
8. The Indian Journal of Pediatrics, Prevention of Mother
to Child Transmission of HIV, March 2004.
9. The PCNA HIV/AIDS in infants, children and adoles-
cents; Martha A Rogers, February, 2000.
10. WHO 2006 guidelines on ART in infants and children in
resource limited settings: towards universal access,
recommendations for a public health approach.
Utpal Kant Singh, Rajniti Prasad
urban outbreaks, which is transmitted by the same
vectors as those of Dengue viruses. Since 1953, virus
(CHIKV) has caused numerous outbreaks and epidemics
in both Africa and South East Asia, involving hundreds
and thousands of children.
EPIDEMIOLOGY
CHIKV was probably an infection of primates in forests
of Savannahs of Africa maintained by sylvatic Aedes
420 IAP Textbook of Pediatrics
mosquitoes. However, today, CHIKV is also responsible
for extensive A. aegypti transmitted urban disease in the
cities of Africa and major epidemics in Asia. In Africa,
CHIKV is transmitted in the savannahs and forests of
tropical Africa by Aedes mosquito. The vertebrate
portion of the cycle is provided by non-human primates
such as Cercopithecus, monkeys or baboons, which
amplify and maintain virus circulation. It is thought that
endemic circulation and epidemics in troops of primates
are responsible for survival of the virus and local spill
over into human population.
In India, after quiescence of about three decades, an
outbreak of CHIKV is being reported from different parts
of India .The current outbreak in India started in the end
of 2005, when cases of suspected fever were reported
from coastal parts of Andhra Pradesh and Karnataka.
The number of suspected cases reported have varied
from different sources ranging up to a million. The
current outbreak has an attack rate of 4-45%. The
confirmed cases of chikungunya fever have been
reported from all over of country but more so from
Andhra Pradesh, Karnataka, Maharashtra, Tamil Nadu,
Madhya Pradesh and Gujarat states.
CHIKV is commonly transmitted to humans through
the bite of infected mosquitoes of the Aedes genus, which
usually bite during daylight hours. Mother to child
transmission, occupational exposure and occurrence in
a health worker from careless handling a patient’s blood
has also been reported. In Africa, CHIK virus appears to
be maintained in sylvatic cycle involving wild primates
and forest dwelling Aedes spp. Monkeys and possibly
other wild animals may also serve as reservoirs of the
virus.
A. aegypti, Ae. albopictus and Ae. polynesiensis are
commonly involved in the transmission of virus,
although Culex has also been reported for the transmis-
sion in some cases. A. aegypti is the principal vector of
CHIKV in India. This vector species is anthropophilic,
endophagic and bites during the day time. It mainly
breeds in man made containers such as rain water barrels,
cisterns, wells, water storage drums, pots, discarded
bottles, tin cans, motor vehicle tyres, etc. A recent
epidemic in the Indian Ocean islands suggested that
Asian tiger mosquito, A. albopictus was responsible for
spread. A mutation in the envelope protein gene (E1-
A226V) was found in some strains of CHIKV causing
epidemics on islands in the Indian Ocean. This mutation
is directly responsible for CHIKV adaptation to the Asian
tiger mosquito. Both A. aegypti and Ae. albopictus are
present in the US and the Asian tiger mosquito in Europe.
With the global climate warming, CHIKV could expand
to new geographic locations.
Chikungunya Virus
CHIKV, a positive strand, enveloped RNA virus, is a
member of the Alphavirus genus and belongs to the
Togaviridae family. It is endemic in large parts of Africa,
the Middle East, India, and South-East Asia and is closely
related to O’nyong-nyong viruses. Genetic analysis based
on partial E1 envelope glycoprotein gene sequences
showed the presence of three distinct phylogroups. The
first contained all isolates from West Africa; the second
comprised all Central, Southern and Eastern African
strains (CSEA); and the third contained isolates from
Asia. Phylogenetic studies have suggested that the West
African CHIKV cluster was ancestral, the CSEA cluster
diverged from West African ancestors, and the Asian and
Indian Ocean clusters of genotypes had lately and
independently evolved from CSEA variants.
Complete genomic sequence of CHIKV has been
determined and found to have 11,805 nucleotides in
length. Coding sequences consisting of two large open
reading frames of 7,422 nucleotide and 3,744 nucleotide
encoding the non-structural polyprotein (2,474 amino
acids) and the structural polyprotein (1,248 amino acids),
respectively. The non-structural polyprotein is the
precursor of proteins nsP1 (535 amino acids), nsP2 (798
amino acids), nsP3 (530 amino acids) and nsP4 (611
amino acids) and the structural polyprotein is the
precursor of protein C (261 amino acids), E3 (64 amino
acids), E2 (423 amino acids), 6K (61 amino acids) and E1
(439 amino acids).
PATHOGENESIS
CHIKV replicates in various human cells, including
epithelial and endothelial cells, but primarily in
fibroblasts and macrophages. T and B lymphocytes and
monocyte-derived dendritic cells are not susceptible.
Viral entry occurs through a pH-dependent, endocytic
pathway. CHIKV is highly cytopathic for mammalian
cells, inducing apoptosis of infected cells. CHIKV
replication is significantly inhibited by type I and II IFNs.
In humans, CHIKV produces disease about 48 hours after
mosquito bite. Patients have high viremia during the first
2 days of illness. Viremia declines around day 3 or 4 and
 Immunization and Infectious Diseases 421

usually disappears by day 5. Hemagglutination inhibi-

tion and neutralizing antibodies can usually be detected
after day 5 with fading viremia. “Silent” CHIKV
infections do occur, but how commonly this happens is
not yet known. CHIKV infection (whether clinical or
silent) is thought to confer lifelong immunity. A recent
study has suggested CHIKV tropism for muscular
satellite cells, which can act as small reservoirs for virus
or virus-encoded components or both for longer-than-
expected periods.

CLINICAL MANIFESTATIONS
Chikungunya is an acute infection characterized by
abrupt onset fever and severe arthralgia, followed by
other constitutional symptoms and rash lasting for a
period of 1-7 days (triad: fever, rashes and arthralgia).
The incubation period is usually 2-3 days, with a range
of 1-12 days. All age groups are affected, including
newborns. Fever rises abruptly, often reaching 39-40°C
accompanied by intermittent shaking chills. This acute
phase lasts 2-3 days. The temperature may remit for 1-2
days, after a gap of 4-10 days, resulting in a “saddle back”
Figure 9.32.1: Frequency of pain by location during acute
fever curve. stage of chikungunya infection
The arthralgias are polyarticular, migratory and
predominantly affect the small joints of hands, wrists,
Iridocyclitis and retinitis are the most common ocular
ankles and feet with lesser involvement of larger joints
(Fig. 9.32.1). In acute stage, patients complain bitterly of manifestations associated with chikungunya, with a
typically benign clinical course. Less frequent ocular
pain when asked to move and assume an attitude of
lesions include episcleritis. Other manifestations include
flexion. Pain on movement is worse in the morning,
improved by mild exercise and exacerbated by strenuous meningoencephalitis (1%), fulminant hepatitis (2%) and
mild hemorrhagic manifestations in 3%.
exercise. Swelling may occur but fluid accumulation is
Most symptomatic patients (93.7%) complained of a
uncommon. Patients with milder articular manifestation
are usually symptom-free within a few weeks, but more chronic stage of the disease, which is characterised by
pains in joints and/or bones or both. This persisting pain
severe cases require months to resolve entirely.
was continuous (41.3%) or discontinuous with alter-
Cutaneous manifestations include flushing of the face
and trunk. This is usually followed by maculopapular nation of clinical remission and relapses (58.7%). Some
infected individuals (11.7%) also mentioned fever at this
rash. The trunks and limbs are commonly involved, but
stage.
face, palms and soles may also show lesions. The rash
may simply fade or desquamate. Petechiae may occur
Laboratory Diagnosis
alone or in association with rash. They are observed
during the acute stage of the illness, and others during Laboratory investigation is critical to establish diagnosis
convalescence or thereafter. Pigmentary changes have and initiate specific public health response. Three main
been reported to be the most common cutaneous finding laboratory tests are used for diagnosing Chikungunya
(42%), followed by maculopapular eruption (33%) and fevers: virus isolation, serological tests and molecular
intertriginous aphthous-like ulcers (21.37%). Exacerba- technique of Polymerase Chain Reaction (PCR). Virus
tion of existing dermatoses, such as psoriasis, and isolation is the most definitive tests. 2-5 ml of whole blood
unmasking of undiagnosed Hansen’s disease were also is collected during the first week of illness in heparinzed
observed. tube and transported on ice to the laboratory. The CHIK
422 IAP Textbook of Pediatrics
virus produces cytopathic effects in a variety of cell lines
including BHK-21, HeLa and Vero cells. The cytopathic
effects must be confirmed by CHIK specific antiserum
and the results can take between 1-2 weeks. Virus
isolation must only be carried in BSL-3 laboratories to
reduce the risk of viral transmission.
Recently, a reverse transcriptase, RT- PCR technique
for diagnosis has been developed using nested primer
pairs amplifying specific components of three structural
gene regions, Capsid (C), Envelope E-2 and part of
Envelope E1. PCR results can be available within 1-2 days.
For serological diagnosis, an acute phase serum must
be collected immediately after clinical onset and a
convalescent phase, 10-14 days after the disease onset.
The blood specimen is transported at 4°C and should
not be frozen to the laboratory immediately. If testing
cannot be done immediately, the blood specimen is
separated into sera that should be stored and shipped
frozen. Serologic diagnosis can be made by demons-
tration of fourfold increase in antibody in acute and
convalescent sera or demonstrating IgM antibodies
specific for CHIKV. A commonly used test is the
immunoglobulin M antibody (IgM) capture enzyme-
linked immunosorbent assay (MAC-ELISA). Results of
MAC-ELISA can be available within 2-3 days. Cross-
reaction with other flavirus antibodies such as O’nyong-
nyong and Semliki forest may occur in the MAC-ELISA;
however, the latter viruses are relatively rare in South
East Asia but if further confirmation is required, it can
be done by neutralization tests and hemagglutination
inhibition assay (HIA). A positive virus culture
supplemented with neutralization is taken as definitive
proof for the presence of Chikungunya virus. PCR results
for E1 and C genome either singly or together constitute
a positive result for Chikungunya virus.
Management
There is no specific treatment for Chikungunya fever.
The illness is usually self-limiting and resolves with time.
Supportive care with rest is indicated during the acute
joint symptoms. Movement and mild exercise tend to
improve stiffness and morning arthralgia, but heavy
exercise may exacerbate rheumatic symptoms. Non-
aspirin and non-steroidal anti-inflammatory drugs
(NSAID) are recommended. In unresolved arthritis
refractory to NSAID, chloroquine (10 mg/kg/day) has
proved to be useful. Chloroquine inhibits viral replication
by blocking the pH dependent endocytosis of CHIKV
into host cells. Although chloroquine blocks CHIKV
replication, the therapeutic (antiviral) index of chloro-
quine in cell cultures is rather narrow thus, one should
be cautious when planning the use of chloroquine as an
antiviral treatment in infected individuals.
Self-resolution occurs with cutaneous lesions. Patients
with hyperpigmentation may be treated with sunscreens
and topical steroids. All patients with only centrofacial
involvement showed complete clearance during follow-
up at 3 weeks. Patients with more diffuse involvement
showed a slower resolution. Aphthous ulcers usually
heal over 7-10 days with local cleaning and topical
antimicrobials to prevent secondary infection. Iridocyc-
litis and retinitis have a typically benign clinical course.
All the patients respond well to the treatment with
preservation of good vision.
Infected persons should be protected from further
mosquito exposure (staying indoors and/or under
mosquito net during the first few days of illness) so that
they cannot contribute to the transmission cycle.
Prevention and Control
Prevention is entirely dependent upon taking steps to
avoid mosquito bites and elimination of mosquito
breeding sites and include the following.
1. Wear full sleeve clothes and long dresses to cover the
limbs.
2. Use mosquito coils, repellents and electric vapor mats
during the daytime.
3. Use mosquito nets to protect babies, old people and
others, who may rest during the day. The effective-
ness of such nets can be improved by treating them
with permethrin. Curtains can also be treated with
insecticide and hung at windows or doorways, to
repel or kill mosquitoes.
4. Drain water from coolers, tanks, barrels, drums and
buckets, etc.
5. Emptying coolers when not in use.
6. Remove from the house all objects, e.g. plant saucers,
etc. which have water collected in them.
7. Cooperating with the public health authorities in anti-
mosquito measures.
Vaccine
The widespread geographic distribution, recurrent
epidemics and infection of military personnel, travellers,
and laboratory staff working with CHIKV have indicated
the need for a safe and efficacious vaccine.

In Thailand, CHIK strain 15561, was used to develop
a small lot of vaccine The vaccine produced no untoward
reactions and was highly immunogenic. The current live
vaccine (Lot 1-85, TSI-GSD-218) was developed in United
States in USAMRIID and was produced at the Salk
Institute, from GMK strain 15561 by serial passage in
MRC-5 cells. The results of phase I and phase II trials
strongly suggest that the live vaccine is safe and well-
tolerated and produces no severe or frequent symptoms
than found in placebo recipients.
Surveillance
Epidemiological and entomological surveillance should
be intensified. Reporting of fever cases should be
monitored closely. Active surveillance by health workers
using the case definitions for cases presenting with acute
fever associated with arthralgia/arthritis (painful and
stiff joints) to detect new cases early for treatment should
be undertaken. This will help in identifying the affected
areas, so that control measures may be initiated. Vector
surveillance should also be done and will help in
identifying the areas for initiating control measures and
assess the impact of the measures taken. People need to
be educated about the disease, mode of transmission,
availability of treatment and adoption of control
measures. The activities have to be identified particularly
to effect changes in the practice of storage of water and
personal protection.
BIBLIOGRAPHY
1. Queyriaux B, Simon F, Grandadam M, Michel R, Tolou
R, Boutin J. Clinical burden of chikungunya virus
infection. Lancet Infect Dis 2008;1:2-3.
9.33 Malaria in Children
Malaria a, paroxysmal febrile illness is caused by
protozoan microorganisms commonly called as malarial
parasites. Belonging to family plasmodidae malaria
parasites have more than 120 species however only four
of them: P.vivax, P.falciparum, P.ovale and P.malariae are
capable of infecting human beings. P.vivax, and
Immunization and Infectious Diseases 423
2. Chhabra M, Mittal V, Bhattacharya D, Rana U, Lal S.
Chikungunya fever: A re-emerging viral infection. Indian
J Med Microbiol 2008;26:5-12.
3. Chikungunya Fever Fact Sheet - CDC Division of Vector
Borne Infectious Diseases. Available from: http://
www.cdc.gov/ncidod/chikungunya/chickfact.
htm.2006.
4. Edelman R, Tacket CO, Wasserman SS, Bodison SA,
Perry JG, Mangiafico JA. Phase II safety and immuno-
genecity study of live chikungunya virus vaccine TSI-
GSD-218. Am J Trop Med Hyg 2000;62(6):681-5.
5. Inamadar AC, Palit A, Sampagavi VV, Raghunath S,
Deshmukh NS. Cutaneous manifestations of chikun-
gunya fever: Observations made during a recent outbreak
in south India. Intern J Dermatol 2008;47:154-9.
6. Khan AH, Morita K, Parquet MC, Hasebe F, Mathenge
EG, Igarashi A. Complete nucleotide sequence of
chikungunya virus and evidence for an internal
polyadenylation site. J Gen Virol 2002;83:3075-84.
7. Lahariya C, Pradhan SK. Emergence of chikungunya
virus in Indian subcontinent after 32 years: A review. J
Vect Borne Dis 2006;43:151-60
8. Mahendradas P, Ranganna SK, Shetty R, Balu R,
Narayana KM, Babu RB, et al. Ocular Manifestations
Associated with Chikungunya. Ophthalmology 2008;
115(2):287-91.
9. Mohan A. Chikungunya fever: Clinical manifestations
and management. Indian J Med Res 2006;124:471-4.
10. Powers AM, Brault AC, Tesh RB, et al. Re-emergence of
Chikungunya and O ’ nyong-nyong viruses: Evidence
for distinct geographical lineages and distant evolu-
tionary relationships. J Gen Virol 2000;81:471-9.
11. Parola P, Lamballerie X, Jourdan J, et al. Novel
chikungunya virus variant in travelers returning
from Indian Ocean Islands.Emerg Infect Dis
2006;12:1493-9.
12. Pialoux G, Gauzere BA, Strobel M. Chikungunya virus
infection: Review through an epidemic. Med Mal Infect
2006;36:253-63.
13. WHO. Disease outbreak news. Chikungunya and dengue
in the southwest Indian Ocean, Geneva 17 March 2006.
Ashok S Kapse
P.falciparum (P.F.) are commonly prevalent species in our
country. Within the species these parasites tend to differ
in their morphological and clinical characteristics; termed
as strains or isolates these parasitic populations display
distinct biological and antigenic variations.
424 IAP Textbook of Pediatrics
LIFECYCLE OF MALARIAL PARASITES
Spread over two hosts, man and mosquito, malarial
parasites complete their life cycle in two phases–namely
sporogony and schizogony; sporozoites and merozoites
being the respective end products of these phases
(Fig. 9.33.1).
SCHIZOGONY
While taking blood meal female anopheles mosquito
injects sporozoites in human beings, whereas majority
of these parasites are phagocytosed and destroyed, some
of them succeed in reaching into human liver.
Sporozoites asexually proliferate and multiply into
hepatic parenchymatous cells, after some time hepatic
cells burst and thousands of merozoites are liberated
in to the circulation. These merozoites invade RBCs; using
hemoglobin for their growth merozoites proliferates and
divides into daughter merozoites. Disintegration of
invaded RBC sets merozoites free to attack further RBCs;
this cycle may perpetually carry on, until interrupted by
drugs or immunity.
Sporogony
After few erythrocytic cycles some of the merozoites shift
the line of development and change into the sexual forms;
the male and female gametocytes. Picked up by female
anopheles mosquito during blood meal, these gametocytes
meet and form zygotes inside the mosquito. Going
through various developmental processes termed as
Figure 9.33.1: Lifecycle of malaria parasite
sporogony, zygotes end into formation of sporozoites;
the forms capable of infecting human beings.
Hypnozoites
Some of the p.vivax sporozoites exhibit a different
behavior; after entering hepatic cells instead of entering
into immediate schizogony, they opt to remain dormant
for a long duration of time. Christened as hypnozoites
these parasites awaken at a predestined time and liberate
merozoites in the blood, causing relapse.
MAGNITUDE OF PROBLEM
Discovery of spraying insecticide in 1940 raised vision
for malarial abolition. In 1957, WHO launched a global
campaign for malaria eradication. Program initially
had good progress, but eventually due to technical and
often imponderable factors dithered in late seventies;
paving way for a huge malarial resurgence.
Today malaria is one of the biggest medical
problems with some 1600 million people exposed to
the risk of disease and more than one hundred million
cases occurring annually. The estimated deaths are
between one to two millions per year and majority of
them being children under five years. Barring very few
cases deaths are exclusively attributable to P.
falciparum.
With a striking increase in P. falciparum strain, India
is one of the worst affected countries of this malaria
resurgence. Invasion of new areas and development of
drug resistance are particularly troublesome features of
this resurgence.
MALARIA: A HETEROGENEOUS DISEASE
Malaria presents with marked clinical heterogeneity.
Presentation may vary from severe and fatal illness, to
asymptomatic parasitic circulation in the blood.
Parasitic variations and host immunity are two major
determinants of clinical malarial presentations.
IMMUNITY IN MALARIA
Immunity in malaria could be innate and acquired and
both depend on genetic constitution of the host.
Innate Immunity
Innate immunity is the inherent property of the host,
which being detrimental to the growth and proliferation

of malarial parasites makes a person invulnerable to
malarial infection. This immunity could be absolute or
relative. Following are the examples of this kind of
immunity.
A. Nonexistence of vivax malaria in west Africa due to
absence of Duffy blood group from indigenous
population. (Duffy blood group antigen acts as a
receptor between vivax merozoites and RBCs).
B. Partial protection afforded by certain hemoglobino-
pathies, e.g. Hb-S, Hb-F, Hb-C and enzymopathies
like G6PD deficiency.
Acquired Immunity
Immunity acquisition in malaria is a slow process
spanning over the years. Biologically malaria parasites
are pleotropic in nature hence only after exposure to
multiple parasitic strains one develops sufficient clinical
invulnerability. Furthermore immunity is invariably
incomplete and needs constant antigenic stimulation for
its sustenance. Presences of antigenicaly variable
plasmodial strains, smokescreen, and down-regulation
of host immune system are some of the postulated
explanations for the slow and incomplete acquisition of
acquired immunity.
Antigenic Variability
In a given locality plasmodium species consist of
antigenicaly distinct races or strains. These races or
strains afford partial cross protection among them. It is
only after a prolonged stay in endemic area that a person
encounters and overcomes each of the plasmodial races
and strains present in his locality and for this very reason
immunity acquisition is a sluggish and a partial process
in malaria.
Smoke Screen Theory
Asexual erythrocytic parasites are the key source of
antigens which provoke nonspecific defense mechanism
as well as induce both species and stage specific,
protective immunity. The effective parasiticidal
immunity is mainly directed against mature schizont or
extracellular merozoites. The parasite material released
during the schizont rupture comprises of loads of
antigens; these antigens come both from the plasmodial
cytoplasm, as well as modified host cell material. A very
small part of this huge antigenic material is protective
merozoite antigen. This inappropriate antigenic material
creates a smoke screen which swamps and blinds the
immune defense system. Consequently a major part of
the immune response is directed towards non-protective
Immunization and Infectious Diseases 425
antigen, there by negatively influencing the acquirement
of specific protective immunity.
Immunosuppression
Malaria cause significant immune repression. Apoptosis
of mononuclear cells, disturbances into macrophagic
functions and interference with functioning of the
dendritic cells, are some of the important reasons for
malarial immune suppression.
Community Immunity
Like in an individual, malaria varies greatly in its
community presentation. In 1957, Macdonald drew
attention to, two extreme forms of community malarial
presentations–he termed them as stable and unstable
malaria.
High malarial endemicity is categorized into two
forms:
i. Holo-endemicity, and
ii. Hyper-endemicity.
Holo-endemicity and Stable Malaria
In holo-endemic area intense malarial transmission
continues round the year, as a result entomological
inoculation rate (EIR, parasitic bites in a year) is as high
as 100-1,000 bites per annum. Consequentially, infection
rate and fatality rate are high in infancy and early
childhood, but by late childhood due to persistent
antigenic stimulation majority of the children develop
good immunity and are protected from severe and
complicated malaria. Adult population does get
frequent malarial infection, possess circulating
parasitemia, and yet hardly ever suffer from malaria.
This state of clinical immunity in the presence of
parasitemia is called as premunition and this form of
community presentation is termed as stable malaria
(Fig. 9.33.2).
Figure 9.33.2: High EIR = stable malaria
426 IAP Textbook of Pediatrics
Majority of African countries have year long rain
pattern which facilitate high entomological inoculation
rate (EIR) and consequential stable malaria.
Hyper-endemicity and Unstable Malaria
Unstable malaria exists in the area where malarial
transmission has marked seasonal swings; in such areas
entomological inoculation, and consequent high
transmission occurs only in certain parts of the year while
rest of the times transmission is low. In such areas malaria
comes in the form of epidemics and takes a heavy toll in
terms of morbidity and mortality. Community immunity
premunition in this kind of malaria is poor and as a result
all the ages including adults are prone to severe and
complicated malaria. Barring parts of Assam, malaria is
unstable all over our country.
CLINICAL PRESENTATIONS
Malaria poses wide variability in the clinical presenta-
tions creating great difficulties in clinical diagnosis and
management.
For clinico-therapeutic purposes malaria could be
divided into uncomplicated and severe-complicated
malaria. Severe-complicated malaria is defined as clinical
situation where malaria has involved body’s vital organ
systems and disturbed its functioning and/or signi-
ficantly deranged some vital metabolic function.
Excepting stray reports of involvement of P. vivax,
for all practical purposes severe and complicated malaria
is caused by P. falciparum species.
P. FLACIPARUM MALARIA —A MICROVASCULAR
DISEASE
P. falciparum has a unique capability of producing micro-
vascular obstruction. RBCs infected with parasites
develop knob like structures on their surface membrane;
these knobs have unique capability of inducing adhesion
molecules like ICAM-1 (intracellular adhesion molecule-1)
on the endothelial surface of micro-capillaries. With the
help of a histidine rich protein, secreted by parasites,
these knobbed-RBCs get adhered to induced receptors
on the endothelial cells–cytoadherence is the name given
to this process. Through cytoadherence P. falciparum
parasitized RBCs sequester out of microcapillaries and
complete their life cycle into perivascular compartment.
A similar process of receptor induction also transpires
on the non-parasitized RBCs – induced adhesion
Figure 9.33.3: Pathophysiology of P. falciparum malaria
molecules facilitate clumping between parasitized and
non-infected RBCs. This process of clumping is termed
as rosseting. These twin processes of sequestration and
rosseting result into micro-vascular blockade (Fig. 9.33.3),
causing decreased organ blood flow and consequent
organ tissue damage.
There is a varying degree of susceptibility of organ
systems for this microvascular obstruction, brain, lung,
liver, intestine, and bone marrow appear particularly
susceptible. Depending upon predominant organ system
involvement complicated P. falciparum malaria could
clinically manifest as cerebral malaria, renal malaria,
pulmonary malaria, etc. In authors experience prevalence
of these complicated P.F. malarial forms varied from
year-to-year. Differences in predilection for the micro–
vasculature involvement among different interspecies
strains could possibly be an underlying reason.
UNCOMPLICATED MALARIA
Clinical Forms and Presentations
Clinical course of uncomplicated malaria is believed to
be consisting of paroxysmal bouts of fever associated
with chills and rigors. However in pediatric age this
intermittent pattern of fever is invariably absent and
instead an irregular fever with respiratory or gastro-
intestinal symptoms could mark the onset of the disease.
Clinical manifestations vary a great deal in different
pediatric ages. Three arbitrary age groups are identifiable
for their diverse clinical presentations:
1. Neonate to early infancy
2. Late infancy to early childhood
3. Late childhood.

1. Neonates and Early Infancy
In contrast to bacterial infections malaria is invariably
mild in neonates and young infants. Hepatospleno-
megaly, anemia, with or without fever are usual
presentations in this age group. Presence of passively
acquired maternal protective antibodies, high number
of Hbf containing senescent RBC, and a milk-diet
deficient in para-aminobenzoic acid are some of the
factors which wield malariostatic influence at this age.
2. Late Infancy to Early Childhood:
(Six Months to Five years)
With the waning of all the malariostatic factors, late
infancy and early childhood has become most susceptible
age for malarial infection. During this age malaria not
only occurs more frequently, it often gets complicated.
Three types of symptom complexes dominate within
this age group:
a. Respiratory,
b. Gastrointestinal, and
c. Convulsive.
a. Respiratory: This is the commonest’ form of presen-
tation. At the onset, picture simulates ‘flu’ – child
suffers from mild cough and catarrh, while clinical
examination reveals facial and eye congestion. Within
a couple of days, treated or untreated these respiratory
symptoms abate and facial congestion is replaced by
pallor, which is particularly discernible on the ear
lobule and malar area.
b. Gastrointestinal: Marked vomiting and loose stools
characterize this form of malaria. Loose stools
are usually greenish, mucoid and are associated
with abdominal colic and tenesmus. Vomiting and
diarrhea both respond best to antimalarial treatment.
c. Convulsive: Convulsions commonly occur during
malarial fever. Malaria should be considered as first
cause of febrile convulsion in endemic area. Absence
of signs of organic neurological involvement
differentiates these patients from cerebral malaria.
3. Late Childhood
By late childhood malarial presentation starts evolving
into classical paroxysmal pattern. Malarial paroxysm
comprises of three successive stages namely cold stage,
hot stage and sweating stage. Depending on infective
species, paroxysm tends to recur on tertian, sub-tertian
Immunization and Infectious Diseases 427
or quotidian frequencies, however it is worth knowing
that this paroxysmal form of malarial fever is not a
regular feature of falciparum infection, instead an
irregular pyrexia without any specific pattern is a
common characteristic of falciparum malaria.
Anemia and hepatosplenomegaly are constant
features of all types of malarial infections. A faster and
greater enlargement of the spleen compared to liver is
commonly observed in P. vivax malaria. Conversely liver
enlargement precedes splenic growth and is significantly
more in P. falciparum infection.
DIAGNOSIS
Blood Smear Examination
In 1881, Laveran discovered malaria parasites in the
blood smear of a dying patient, since then demonstrating
parasite in the blood film has remained a cornerstone
for malarial diagnosis.
The procedure consists of collecting a finger-prick
blood sample, preparing a thick and thin blood smear,
staining the smear (most frequently with Giemsa), and
examining the smear through a microscope (preferably
with a 100X oil immersion objective) for the presence of
malaria parasites.
Both thick and thin film examinations are essential,
while thick film facilitates easy detection of parasite, thin
film is necessary for species identification.
Advantages
1. High sensitivity: When used by skilled and careful
technicians, microscopy can detect densities as low
as 5-10 parasites per μl of blood, however in field
conditions, the detection capabilities of a typical
microscopist might be just about 100 parasites per μl
of blood.
2. Very informative: Parasites can be characterized in
terms of species (P. falciparum, P. vivax, P. ovale, and/
or P. malariae) and life cycle stages (e.g. trophozoites,
schizonts, gametocytes); moreover, the parasite
densities can be quantified (from ratio of parasites
per number of leukocytes or erythrocytes). Such
quantifications are helpful to demonstrate hyper-
parasitemia and to assess parasitological response to
antimalarial therapy.
3. Relatively inexpensive: Microscopy is inexpensive; cost
estimates are just 4 to 5 rupees per slide in field
conditions.
428 IAP Textbook of Pediatrics
Disadvantages
Microscopy is not without disadvantages. Biggest
problem is its dependence on good techniques, quality
reagents and microscopes and, well trained techni-
cians. Unfortunately these conditions are often not
available, particularly in the more peripheral levels of
the health care system. There are often long delays in
providing the microscopy results to the clinician, so
that decisions on treatment are commonly taken
without the benefit of the results. Rapid detection tests
(RDT) have recently been developed to circumvent
many of these issues.
Rapid Detection Tests
These tests are based on immunochromatographic
detection of antigens derived from malaria parasites in
lysed blood. Tests employ a dipstick or test strip bearing
monoclonal antibodies directed against the target
parasite antigens. Advantages are that tests do not
require any technical expertise and results are available
within few minutes.
RDTs: Targeted Antigens
1. Histidine-rich protein II HRP-II: It is a water-soluble
protein produced by trophozoites and young (but not
mature) gametocytes of P. falciparum. Commercial kits
currently available detect HRP-II from P. falciparum
only.
2. Parasite lactate dehydrogenase (pLDH): Enzyme
is produced by both asexual and sexual stages
(gametocytes) of malaria parasites. Test kits currently
available detect pLDH from all four Plasmodium species
that infect humans. They can distinguish
P. falciparum from the non-falciparum species, but
cannot distinguish between P. vivax, P. ovale and P.
malariae.
RDTs: Test Performance
Test performance of RDTs has been adequately assessed
in diverse clinical situations, in both endemic and non-
endemic countries.
• RDTs may detect all four Plasmodium species that
infect humans, or may detect only falciparum
depending on the antigens on which they are based.
• Present RDTs fail to differentiate reliably between
P. vivax, P. ovale and P. malariae, although research to
develop such a test is continuing.
• Compared with expert microscopy, RDTs generally
achieve a sensitivity of >90% in the detection of
P. falciparum at densities above 100 parasites per
μl blood, however with low parasitemia (below the
level of 100 parasites per μl blood), sensitivity
decreases markedly.
• HRP-II tests can remain positive for 7-14 days
following chemotherapy in a substantial proportion
of individuals, even though these patients no longer
have symptoms or parasitemia. Such degrees of
persistent positivity are apparently not encountered
in tests targeting other antigens.
• Sensitivity for P. vivax with pLDH kits is comparable
to that for P. falciparum.
RDTs: Advantages
• RDTs are easy to perform and interpretation is simple
enough to be grasped even by an illiterate.
• There is little difference in interpretation among
individual users.
• RDTs do not need any special equipment or training.
• Technique can be learnt within few hours with good
retention of skills over a one-year period.
• Because RDTs detect circulating antigens, they are
capable of detecting P. falciparum infection even when
the parasites are sequestered in the deep vascular
compartment. In women with placental malaria (as
demonstrated by placental smears), RDTs have
successfully detected circulating HRP-II even though
the blood smears were negative due to sequestration
of P. falciparum in the placenta.
• RDTs are relatively robust–most kits can be shipped
and stored under ambient conditions.
RDTs: Disadvantages
• Commercially available RDTs targeting HRP-II can
detect only P. falciparum; in areas where other
Plasmodium species are co-endemic (P.vivax in our
country) such kits are likely to miss other infections.
• RDTs targeting HRP-II of P. falciparum could give
positive results for fortnight beyond parasite
clearance as confirmed by microscopy. This may
create unnecessary confusion in relation to treatment
failure and drug resistance.
• Kits that detect both P. falciparum and non-falciparum
species are unable to differentiate between P. vivax,
P. ovale and P. malariae.

• RDTs are not quantitative, hence are useless for
prognostication.
• The RDTs are significantly more expensive than
microscopy.
MANAGEMENT OF UNCOMPLICATED MALARIA
In uncomplicated malaria following points need due
consideration before starting antimalarial therapy:
1. Hydration status
2. Ability to take oral medication
3. Assessment of prior therapy
4. Anemia.
Hydration Status
Febrile malarial patients are usually dehydrated.
Anorexia, nausea, vomiting, pyrexia and diaphoresis all
cumulatively result in poor hydration and hypoglycemia.
Parents need to be instructed to encourage oral water
and glucose supplements.
Ability to Take Oral Medications
Administration of bitter antimalarial drugs to children
is a pretty difficult task for the parent. Following
measures may prove to be helpful in overcoming this
problem.
a. Antimalarials are better retained if given, after one
or two hours of antiemetic and antipyretic treatment.
b. Formulations containing higher concentrations in
smaller volume are better tolerated.
Patients who are unable to take oral medications
should receive antimalarials parenterally or rectally till
patient could swallow and retain oral drugs.
Assessment of Prior Treatment
History of prior antimalarial drug intake is very
important. Two points need special consideration.
a. Previously taken antimalarial drugs may cause drug
interaction or result in overdosing and toxicity.
b. Persistence of fever and parasitemia, in a patient who
has received antimalarial within last three to seven
days, is an indicator of treatment failure.
Anemia
Anemia is a constant accompaniment of malaria, many
a times it is severe enough to compromise cardiovascular
Immunization and Infectious Diseases 429
function. Restricted activity, exertional dyspnea and
persistent tachycardia rather than arbitrary Hb level,
should form indications for blood transfusion.
OBJECTIVES OF ANTIMALARIAL DRUG USES
Antimalarial drugs are used with two main objectives:
1. Complete parasitological cure.
2. Restricting drug resistance development.
Since its introduction chloroquine has been the
mainstay of antimalarial treatment. However for last few
decades P. falciparum had acquired significant resistance
to it. In some instances it might still deliver clinical relief,
but in majority of cases it fails to produce total
parasitological eradication and consequentially patient
is left out with subclinical, submicroscopic parasitemia.
Being a long acting drug chloroquine remains in patients
blood for weeks together in subtherapeutic doses;
exposure of malaria parasites to these subtherapeutic
concentrations of chloroquine fuels the resistance.
Additionally there are evidences that continued use of
chloroquine, in areas with prevalent chloroquine
resistance for that sake any failing drug ensues increased
gametocyte proliferation, this augmented gametogenesis
amplifies infectivity and a resultant drug resistant
malarial spread.
Status of other antimalarial drugs is no better–efficacy
of amodiaquine, sulfadoxin-pyremethamine, quinine
and mefloquine has declined to the level where these
drugs cannot be trusted to affect complete parasitological
cure.
Artemisinine Compounds
Discovery and development of artemisinine derivatives
have equipped world with highly efficient class of
antimalarial drugs. Fortunately this group is yet
unaffected by resistance problem. More over availability
of derivatives in various formats (artisunate as intra-
venous injections, artemether and artemotil as intra-
muscular preparations, artisunate and artemether as oral
tablets, and artemisinine as rectal suppository) gives
distinctive freedom to use them at various levels of
medical care, for varied severity of disease.
Artemisinine derivatives act at a very early ring stage
of P. falciparum much before parasites acquire means to
develop pathogenetic excrescence. This unique capability
prevents cytoadherence and rosseting and there by
forestall complications.
430 IAP Textbook of Pediatrics
Artemisinine compounds (AC) also have a very
striking parasiticidal intensity, they reduce parasite
numbers by a factor of approximately 10,000 in each
asexual cycle, which is more than other current anti-
malarials (which reduce parasite numbers 100- to 1,000-
fold per cycle). AC diminish parasitemia to such low levels
that very few parasites are left out for gametocytogenesis.
This negative impact on gametocyte formation is greatly
helpful in preventing malarial transmission as well as drug
resistance.
Though drugs posses enough antimalarial properties
on their own, there is realization that drugs need
protection and resistance can be prevented, or consider-
ably slowed down by combining antimalarials; hence
authorities world over ( WHO, NVBDCP, IAP) mandate
that for P.falciparum malaria artemisinine derivatives
must only be used in combination (ACT) with other
effective antimalarial drug.
Artemisinine Combination Therapy (ACT)
ACT is clearly superior to monotherapies. Addition of
three day course of artisunate (AS) to monotherapies like
amodiaquine (AQ), mefloquine (MQ) or sulfadoxine –
pyrimethamine (SP) results in rapid symptom resolution,
fewer parasitological failures at 28 days and lesser
gametocyte carriage. Shorter courses of ACs (less than
three days), meet with frequent treatment failure,
therefore not recommended.
ACs are eliminated rapidly hence whenever they
are used in combination with short acting drugs
(tetracyclines, clindamycin), a 7-day course is given; on
the other hand shorter course of treatment (3 days) is
sufficient if ACs are given in combination with slowly
eliminated antimalarials. Within three days ACs
drastically decrease parasites in the body. However
complete parasitic clearance depends on partner
medicine which should be effective and persisting at
parasiticidal concentrations until all the infecting
parasites have been killed. Slowly eliminated partner
affords better protection to ACs from resistance
development.
ACT: Available Options
There are minor differences in oral absorption and
bioavailability between the different artemisinine
derivatives however these differences do not have any
bearing on clinical efficacy of ACTs; rather it’s the
properties of the partner medicine which determine the
value and selection of combination.
Recommended ACTs are: Artesunate + mefloquine,
Artemether-lumefantrine, Artesunate + sulfadoxine-
pyrimethamine, Artesunate + amodiaquine.
Artesunate + mefloquine
Both drugs are available as separate tablets containing
50 mg of artesunate and 250 mg of mefloquine,
respectively.
Recommended therapy
Artesunate 4 mg/kg BW of given once a day for 3 days +
25 mg base/kg BW of mefloquine usually split over two
to three days.
Nausea, vomiting, dizziness, dysphoria and sleep
disturbance are generally associated with mefloquine.
Split doses given either as 15 mg/kg on the second day
followed by 10 mg/kg on third day or as 8.3 mg/kg per
day for 3 days are recommended to diminish MQ related
side effects.
Artemether-lumefantrine [A-L]
Combination is available as co-formulated tablets
containing 20 mg of artemether and 120 mg of lume-
fantrine.
Recommended therapy
A 6-dose regimen of artemether-lumefantrine twice a day
for 3 days calculated as artemether 3.2 mg/kg BW per day.
Lumefantrine absorption needs fatty meal for
adequate GI absorption; inadequate fat intake may result
into poor blood levels and a consequent treatment failure,
so it is essential that patients or care givers are instructed
to take A-L with milk or other fat-containing food-
particularly on 2nd and 3rd day of therapy.
Artesunate + sulfadoxine–pyrimethamine [A + S-P]
Combination is available as separate tablets of artesunate
50 mg and sulfadoxine-pyrimethamine co formulation
of 500mg and 25 mg sulfadoxin and pyrimethamine
respectively.
Recommended therapy
Artesunate 4 mg/kg BW given once a day for 3 days
and a single dose of sulfadoxine-pyrimethamine
(calculated as 1.25 mg base/kg BW of pyrimethamine)
on day 1.
Usefulness of this combination is dependent on
efficacy of S-P; in many areas P.falciparum has already
acquired more than 20% resistance to this combination;
continued uses of co-trimoxazole (trimethoprim-

sulfamethoxazole) as chemotherapeutic agent is likely
to deteriorate this situation further.
Artesunate + amodiaquine
Combination comprises of separate tablets containing 50
mg of artesunate and 153 mg base of amodiaquine,
respectively.
Recommended therapy
Artesunate 4 mg/kg BW daily for 3-days and amodia-
quine 10 mg base/kg BW, daily for 3-days.
Combination efficacy is already compromised as at
many places amodiaquine 28-day cure rates are already
low and likely to further decrease with continued uses
of chloroquine and amodiaquine as monotherapies
moreover amodiaquine is not freely available.
ACT: Selection
ACT selection in a given country or area is based on the
level of resistance to the partner medicine. Areas with
higher resistance to amodiaquine, and sulfadoxine-
pyrimethamine, ACT of choice could be artesunate +
mefloquine or artemether-lumefantrine.
ACT: Safety
Except for urticaria ACs have remarkably secure profile.
ACTs safety largely depends on partner drug, many of
these drugs are risky in certain situations: tetracycline in
lactating women, S-P in neonates, MQ in infancy.
Clindamycin could be a suitable partner in some of these
conditions–pregnancy, lactating women, neonates,
infants.
AC: Monotherapy
In a rare unfortunate situation when partner drug is
totally unsuitable, ACs could be used as monotherapy;
however in such circumstances, to avoid recrudescences,
ACs should be used for long enough duration (7-days).
ACT: Treatment Failure
Persistence or recurrence of fever and or parasitemia
within two weeks of treatment is considered as treatment
failure. Such patient needs second-line treatment,
although before going for the next line of treatment one
must thoroughly ascertain that patient had completed
previous course.
Immunization and Infectious Diseases 431
Second-line Treatment
In order of preference following second-line treatments
are recommended:
1. Alternative ACT known to be effective in the region,
2. Artesunate + tetracycline or doxycycline or clinda-
mycin,
Artesunate (2 mg/kg BW once a day)
+
• Clindamycin (10 mg/kg BW twice a day) or
• Doxycycline (3.5 mg/kg BW once a day) or
• Tetracycline (4 mg/kg BW four times a day).
Any of these above combinations should to be given
for 7 days.
3. Quinine + tetracycline or doxycycline or clindamycin.
Quinine Therapy
Dose
Quinine is used in dose of 10 mg of salt/Kg BW orally
three times daily for a period of 7 to 10 days. For those
who are unable to take drug orally, it can be given intra-
venously, in the same dose, dissolved in dextrose solution
(1 mg of quinine/ml of dextrose solution, 10 ml/Kg BW,
given slowly over four hours, every 8 hourly).
Side Effects
Quinine therapy is generally crippled with side effects.
Mild: A symptom complex of adverse reactions known
as cinchonism occurs in patients taking quinine. This is
characterized by giddiness, light headedness, tinnitus,
transient hearing loss and blurring of vision. Cinchonism
does not necessitate discontinuation of quinine therapy.
Severe: Delayed atrioventricular conduction, bradycardia
and postural hypotension are serious cardiovascular side
effects of quinine therapy. Quinine allergy could manifest
as urticaria, asthma, edema of eyelids and mucus
membrane. It may also result in hemolysis, and
thrombocytopenia.
Induction of hypoglycemia is a particularly trouble-
some feature of quinine therapy.
Problems with Quinine Uses
Quinine has a rapid schizontocidal action; however it
needs to be used in longer (7-day) course for radical cure
of P. falciparum malaria. This long course creates problems
of compliance resulting in incomplete treatment and
recrudescence.
432 IAP Textbook of Pediatrics
Making Patient Non-infective
Gametocytes are usually formed by the second week of
malaria-infection, and then last in the body for two to three
months. During this period such person remains infective
to mosquitoes and there by help in the malarial transmission
process. Up till now primaquine was the only effective
gametocytocidal drug for P. falciparum species. Patients
treated with quinine should receive single dose of
primaquine (0.75 mg/ kg BW) at the end of quinine therapy.
With ACT gametocyte formation is very minimal.
Moreover it possesses intrinsic gametocytocidal
properties, hence no additional gametocytocidal drug
(primaquine) is needed with ACT.
FEVER MANAGEMENT
Fever is an integral part of malaria. Fever could be
associated with mild constitutional symptoms of nausea,
vomiting, anorexia and body aches but could also cause
seizures.
Antipyretic treatment was found to have higher
parasitic levels and delayed clearance; however a close
scrutiny revealed that it is due to interference with
process of cytoadherence, which in fact is helpful to
patients, therefore there is no reason to deny antipyretic
treatment in malaria.
Round the clock uses of acetaminophen 15 mg/kg
BW every 4 hours given orally is safe and well tolerated.
Ibuprofen (5 mg/kg BW) would be another alternative.
In high fever tepid sponging with tape water could have
an additive effect.
MANAGEMENT OF VOMITING
Vomiting is common in acute malaria and creates
problem with oral medications. Though studies of their
efficacy are lacking being relatively harmless they are
widely used.
MANAGEMENT OF SEIZURES
In children seizures are very common in malaria
particularly with falciparum infection. Most of the times
they are febrile convulsions yet in a few cases they may
be manifestation of cerebral malaria. A convulsing child
must be treated with anticonvulsants, however prophy-
lactic anticonvulsants are needless in otherwise
uncomplicated malaria.
UNCOMPLICATED P. VIVAX MALARIA
Antimalarial Drug Therapy
1. Treatment of Present Malaria Attack
A three-day course of chloroquine is sufficient enough
to terminate P. vivax attack.
Dosages and regimens: Chloroquine is used in a dose of
25 mg of base/Kg BW given over three days. Two
commonly employed regimens are as follows:
a. 10 mg of chloroquine base/Kg BW given as loading
dose on day-1 to be followed by 5 mg of base/Kg BW
after 6 to 8 hours and than 5 mg of base/Kg BW given
on day-2 and day-3.
b. 10 mg of base/Kg BW on day-1
10 mg of base/Kg BW on day-2
5 mg of base/Kg BW on day-3
Though pharmacokineticaly first regimen is superior;
the second one is simpler and in clinical practice has
proved equally effective.
Side effects: In therapeutic doses, given orally, chloroquine
is remarkably safe drug. Taken empty stomach it may
cause nausea and vomiting. Few cases may have
dizziness and blurring of vision. In dark complexioned
adults, pruritis of soles and palms could be a troublesome
side effect; fortunately it is rare in children.
Drug resistant P.vivax: P.vivax is highly sensitive to
chloroquine; still there are occasional reports of chloro-
quine resistance from different regions of the world
(Indonesia, Papua New Guinea, Myanmar and India).
Except Papua New Guinea, at most of the places resistance
has been transient and did not need change in drug policy.
With sole exception of sulfadoxin and pyrimetha-
mine, P. vivax is sensitive to almost all blood schizonto-
cidal drugs. Chloroquine resistant P. vivax malaria could
be easily managed with quinine, mefloquine, or ACT.
2. Prevention of Relapse in P. vivax
In 1980 it was recognized that sporozoites of P. vivax
infection consists of polymorphic strains. These strains
in varying proportion differentiate into developing
schizonts or into dormant forms known as the
hypnozoites. These hypnozoites for a long time remain
dormant in the hepatocytes and then at a predetermined
time, they awaken, proliferate and produce a clinical

relapse. In an untreated case, relapse continue till all the
hypnozoites are exhausted from liver. These hypnozoites
are sensitive only to 8-aminoquinolines (primaquine,
bulaquine, tafenoquine); a course of primaquin can
destroy these hypnozoites and thereby can prevent
relapses.
Vivax relapses: P. vivax is polymorphic infection; the
frequency and pattern of relapses varies widely from
place to place; whereas 50–60% of P. vivax infections in
South-East Asia relapse, rate is just 15–20% in Indian
subcontinent.
In terms of time frame relapses have two patterns:
• Short-term relapse: Occurring within couple of
months.
• Long-term relapse: Occurring over 6-9 months.
Anti-relapse treatment must be set against the
prevalent relapse frequency and pattern.
The curative efficacy of primaquine is dose dependent;
a full course of 14-days therapy (0.25 mg/kg BW)
is mandatory, short course of primaquine widely
recommended (such as 5-day regimens) is inadequate
for prevention of relapses.
There has been debate as to whether primaquine
should be given in high transmission areas. In such areas
there always is a chance for re-infection. Starting a new
cycle needing frequent primaquine courses has poor risk
benefit ratio. Hence certain authorities recommend blood
schizontocidal drugs for every P. vivax attack whether
relapse or reinfection, in high transmission areas. In
countries like ours where transmission is seasonal and
has wide fluctuations, a modified strategy could be
adopted. In India P. vivax infection prevails between
March to October with high transmission between May
to July. Person suffering from P. vivax malaria in high
transmission season may be treated with full course of
chloroquine; supplemented by weekly suppressive
therapy for few months until high transmission season.
Anti-relapse treatment should be deployed for vivax
malarial attack occurring during non-epidemic season
or nearing the end of the epidemic.
Primaquine resistant hypnozoites: A 14-day course of 0.25
mg/kg BW of primaquine is usually sufficient to cure
P.vivax liver stage infection. However in South-East Asia,
particularly Indonesia, and in Oceania vivax hypnozoites
are relatively insensitive to primaquine, needing higher
doses (0.5 mg base/kg BW per day).
Immunization and Infectious Diseases 433
Primaquine and G6PD deficiency: Glucose-6-phosphate
dehydrogenase deficiency is an inherited sex-linked
disorder where in there is an increased susceptibility to
oxidant hemolysis. Primaquine being a strong oxidant
drug could induce severe hemolysis a G6PD deficient
patient. There is wide community-wise variation in
G6PD deficiency prevalence. Parsees, prajapaties,
sindhies and tribals have much higher incidence.
It is highly desirable to know G6PD status before
prescribing primaquine. In a situation where testing is
infeasible and primaquine is indispensable parents
should be instructed to watch for urine color after
primaquine administration; any change in urine color to
tea color warrants immediate stoppage of drug and
patient should immediately be taken to hospital.
SEVERE AND COMPLICATED MALARIA
Parasitemia and Malaria Severity
In general severity of malaria is in proportion to the level
of parasitemia; however it may not always be so.
Cytoadherence and sequestration are the major patho-
genetic determinant of malaria severity. A person with
good anti-sequestration mechanism may not suffer
from complicated malaria; on the contrary higher
sequestration even with low parasitemia may result in
complicated malaria.
Endemic Forms, and Age Distribution of
Severe Malaria
In stable malaria severe and complicated malaria occurs
mainly in nonimmunes and hence it is more common
among infants and children. However in the
communities with unstable, epidemic form of malaria
(as it is in our country) all ages including adulthood are
vulnerable to severe malaria.
As per WHO, following situations are considered as severe
and complicated malaria:
1. Severe prostration
2. Impaired consciousness, altered behavior
3. Multiple convulsions
4. Respiratory distress, acidotic breathing
5. Abnormal bleeding
6. Jaundice
7. Hemoglobinuria
8. Circulatory collapse, shock, algid malaria
9. Hyperpyrexia
10. Severe anemia
434 IAP Textbook of Pediatrics
11. Hypoglycemia
12. Acidosis
13. Renal impairment
14. Hyperlactatemia
15. Hyperparasitemia.
Some of these complications such as cerebral malaria,
anemia, hypoglycemia, hyperpyrexia and respiratory
distress are more common in children while others such
as renal impairment, jaundice, and pulmonary edema
are relatively frequent in adults. Assessment and investi-
gations are generally dictated by clinical presentations.
However appraisal of pallor, level of consciousness,
urinary output, and hemodynamic is integral to every
suspected case of severe and complicated malaria.
Similarly, following investigations are also essential in
the management of severe and complicated malaria.
i. Hemogram including platelet count
ii. Smear examination for parasites, (Presence of
P. falciparum schizonts in smear examination is
always an indicator of severe malaria)
iii. Blood sugar level
iv. Serum bilirubin and SGPT
v. Blood urea and serum creatinine
vi. Urine examination, routine, microscopic and
biochemical tests for hemoglobin and urobilinogen.
Complications
1. Impaired Consciousness and/or Altered Behavior
P. falciparum parasites have a special proclivity for
sequestrating into brain microvasculature and hence
neurological syndrome is the commonest form of
complicated malaria. Multiple seizures could portent the
onset of cerebral malaria, generalized hypotonia,
brainstem signs (abnormalities of corneal reflex, papillary
reflex, doll’s eye reflex, etc), opisthotonus, and retinal
changes are common neurological elements.
It is vital to realize that besides cerebral malaria there
are other elements which could be causal or contributory
to neurological dysfunctions. Covert epilepticus,
prolonged postictal state and severe metabolic derange-
ment like hypoglycemia, hyperpyrexia, and acidosis can
produce clinically indistinguishable syndrome from
classical cerebral malaria. Managements of these
problems are straightforward with strikingly beneficial
results. Therefore besides frequent evaluation of level of
consciousness; taking rectal temperatures, assessing
blood glucose levels and blood gases assumes equal
importance in such patients. Trial of appropriate
anticonvulsant could also be rewarding in such
conditions. Ruling out meningitis is vital in any patient
presenting with fever and neurological involvement;
proper antibiotic therapy should urgently be instituted
if for some reasons CSF examination is deferred or not
carried out. Frequent startling, nucho-occipital headache
are some of the early warning signals of neuro malaria.
2. Multiple Convulsions
Convulsions are common in malaria, particularly in
P.falciparum infection. Convulsions could be generalized
or focal; some seizures are covert or subtle. Covert
seizures may be suspected if patient manifests with
repeated facial twitching, eye deviation, irregular
breathing and excessive salivation.
Seizures in malaria are multifactorial: microvascular
obstruction leading to altered cerebral metabolism is the
most important element; however other factors like
hypoglycemia, and hyperpyrexia could also be causal or
may lower seizure threshold. It is important to identify
hypoglycemia and hyperpyrexia as they offer relatively
easy management and better outcome.
Repeated seizures carry a poor prognosis; mortality
rates as well long-term sequelae both may increase.
Convulsions should be energetically treated with
benzodiazepines and phenytoin. Phenobarbitone in
doses of 20 mg/kg BW is found to be associated with
better seizure control, yet inexplicable increase in
mortality. Prophylactic anticonvulsant uses are undesir-
able: it doesn’t improve prognosis, conversely it is found
to be detrimental.
3. Severe Anemia
Mild to moderate anemia is an integral part of malarial
clinical presentation. However in certain cases anemia
could be a presenting feature, such patients have low
hemoglobin (Hb less than 7 g/dL, PCV < 20%) and
present with palpitation, tachycardia and dyspnea
(Fig. 9.33.4). Lactic acidosis is a common accompaniment
of severe anemia and adds greatly to respiratory distress;
unless transfused urgently such patients carry very high
mortality.
Causes of Anemia
Anemia in malaria is multifaceted and multifactorial.
Hemolysis, dyserythropoiesis, and deficiency of hemato-
poietic factors are major contributory factors for malarial
anemia.
 Immunization and Infectious Diseases 435

supplements during malaria endemic seasons are found

to be associated with increased recurrences rate.

4. Hemoglobinuria–Dark Red Colored Urine

Mild hemolysis is universal with any malaria; nevertheless
massive intravascular hemolysis (Figs 9.33.5 and 9.33.6)
presenting as red smoky urine and jaundice could also be a
feature of severe malaria. Serial estimation of Hb,
reticulocyte count, and LDH are essential to gauze degree
of hemolysis. Evaluation of Coomb’s test and assessment
of G6PD status should regularly be done in cases presenting
with hemoglobinuria. A repeat G6PD estimation after few
months is mandatory as following massive hemolysis neo-
RBCs would result into falsely normal G6PD estimation.
Figure 9.33.4: Severe pallor (P. falciparum)

Hemolysis
Mild compensated hemolysis is an integral feature of
malaria pathology. Destruction of parasitized RBC is
important cause of anemia, but RBC destruction is much
beyond the parasitized cells. Immune mediated RBC
damage is a popular theory, but Coomb’s positivity rates
fail to support it.
Lately it is realized that in malarial infection non-
parasitized RBCs develop marked rheological changes
and consequentially loose their deformability. These
poorly deformable RBCs are removed from circulation
by splenic pitting process. Figure 9.33.5: Hemolytic jaundice

Dyserythropoiesis
In an overtly hemolytic disease like malaria reticulocytosis
should be an essential appearance; conversely despite
considerable anemia many malarial patients have
reticulocytopenia. Bone marrow studies in such patients
typically reveal dyserythropoiesis, these bone marrow
changes persist much beyond the parasitic clearance, and
are largely responsible for lasting anemia. Malarial toxins
are believed to be responsible for bone marrow impairment.

Hematopoietic Factor Deficiency

Deficiency of essential hematopoietic factors also
contribute to malarial anemia. Rapid turn over of RBC
do need folic acid and vitamin B12 supplements,
however except in situations of intravascular hemolysis
there is no iron loss in malaria and iron supplements are
not immediately needed in malaria, contrarily iron Figure 9.33.6: Hemoglobinuria
436 IAP Textbook of Pediatrics

Blackwater fever frequently described in old African

literature is no more a common occurrence.

5. Jaundice
Jaundice in malaria is not uncommon. Patients suffering
from significant hemolysis do have indirect bilirubinemia
(Fig. 9.33.5) and mild jaundice; on the other hand certain
section of malarial patients has obvious direct bilirubi-
nemia, and impaired hepatic functions; titled as malarial
hepatitis. This complication is more common in older
children and adolescents. Liver biopses done at few
centers reveal parasitic sequestration in billiary canaliculi.
Figure 9.33.7: Petechiae
Patients of malarial hepatitis having neurological
element, could have an indistinguishable clinical picture
from hepatic encephalopathy. Presence of asexual and postural hypotension is pretty common. Manson in
parasitemia differentiates these cases from hepatic 1898 described a malarial complication which was
encephalopathy. Identification of this section of cases is characterized by syncope, collapse and cold body surface
extremely vital as antimalarial treatment in these patients in the wake of elevated rectal temperature and was
would provide rewarding therapeutic responses. termed as algid malaria. Shock and syncope could be a
manifestation of GI hemorrhage, pulmonary edema and
6. Respiratory Distress splenic rupture. Isolation of Gram-negative bacteria in
Malaria could manifest with fever and breathing 1987 by Mabey et al from malarial patients presenting
difficulty. Deep and rapid breathing devoid of ausculta- with symptoms of shock and syncope established
tory chest signs or abnormal radiographic picture is a another key cause for these cases. Following this
common clinical presentation. Metabolic acidosis, with discovery appropriate antibiotic coverage has become
or without hyperlactatemia is the principal underlying customary in malarial patients presenting with shock.
metabolic disorder.
Associated with cerebral malaria, and/or anemia, 9. Hypoglycemia
metabolic acidosis may carry a whooping mortality of
Though anorexia, nausea and vomiting are common in
35%. Pulmonary edema and ARDS are other dreaded
malaria, yet clinically significant hypoglycemia is unrelated
complications of severe malaria; fortunately they are rare
to glycogen depletion in the liver and instead is caused by
in pediatric age group.
parasitic glucose consumption and quinine induced insulin
7. Abnormal Bleeding secretion. Symptoms of hypoglycemia are varied and
include anxiety, hunger, tremors, sweating, palpitation,
Hemostatic abnormalities are uncommon in children,
dizziness, headache, confusion, clouding of vision, altered
minor problems like skin petechiae (Fig. 9.33.7), nasal
behavior, convulsion and unconsciousness.
and gum bleed and subconjunctival hemorrhages are
As it is very difficult to differentiate symptoms of
seen in occasional cases. The major hemorrhages reported
hypoglycemia from that of falciparum malaria and,
are gastrointestinal and, that has invariably been
hypoglycemia is integral to severe malaria possibility of
associated with steroid therapy.
hypoglycemia should always be considered, assessed
Prothombin time prolongation and mild to moderate
and treated in severe malaria.
thrombocytopenia are not unusual to be seen in severe
malaria but without clinical hemorrhages these changes
10. Hyperpyrexia
do not warrant therapeutic consideration.
Hyperpyrexia may present as an independent entity or
8. Circulatory Collapse may complicate course of other forms of malaria, it may
In majority of malaria patients, because of hypovolemia be present from onset or may suddenly develop during
and vasodilatation, blood pressure is on the lower side, a course of apparently mild attack. Pyrexia above 38.5°C

may increase the incidence of convulsion and above
40.5°C may cause delirium, coma and other neurological
problems. Hyperpyrexia induced neurological changes
may create diagnostic confusion with true cerebral
malaria.
In a shivering malarial patient skin temperature may
be much lower than the core temperature; assessing rectal
temperature is a better practice in such cases.
11. Hyperparasitemia
Hyperparasitemia has an increased risk for malarial
severity, most of these patients have vital organ
dysfunction but there are few cases which do not have
any evidence for severe disease. These patients have
symptomatology of uncomplicated malaria; however
they carry a higher risk for treatment failure and may
any time progress to severe malaria.
Defining hyperparasitemia is contentious; although
parasitemia of > 5% in a low-transmission setting and >
10% in a higher transmission settings are generally
agreed levels.
Management of uncomplicated hyperparasitemia is
unsettled. Oral treatment may or may not succeed hence
some authorities suggest initial parenteral treatment.
These cases also need longer duration of therapy–seven
days of artemisinine compound + full course of partner
drug.
Severe and Complicated P. vivax Malaria
By and large complications with P.vivax are uncommon,
nevertheless occasionally P.vivax could create problems
like anemia, mild hemolytic jaundice, hyperpyrexia and
splenic rupture.
Off late reports from Bikaner a city of state of
Rajasthan suggest changing nature of P. vivax. Patients
presenting with various complications like cerebral
malaria, severe anemia, malarial hepatitis, renal
impairment, etc. revealed only P.vivax antigen when
investigated with sophisticated technique of PCR.
Management of Severe and Complicated Malaria
Treatment Objectives
Avoidance of death and permanent disabilities are the
most vital goals while treating severe and complicated
malaria. Prevention of recrudescence, transmission, and
resistance development assume secondary importance
in such situations.
Immunization and Infectious Diseases 437
Severe and Complicated Malaria:
Principles of Management
1. Choice of appropriate antimalarial
2. Supportive treatment
3. Avoidance of harmful and/or useless drugs.
1. Antimalarial Drug Therapy for
Severe and Complicated Malaria
Severe and complicated malaria is a medical emer-
gency. The chosen antimalarial drug should be able to
achieve effective therapeutic concentrations quickly.
The cinchona alkaloids (quinine and quinidine) and
the artemisinine derivatives (artesunate, artemether
and artemotil) are the only classes of drugs which
are capable of attaining speedy parasiticidal concen-
trations. Because of extensive resistance chloroquine should
never be used in the treatment of severe and complicated
malaria.
Artemisinine Compounds
Artesunate, artemether, artemotil artemether, and rectal
artemisinine (rectal), all have been used in the treatment
of severe malaria.
Drug of choice: Pharmacokineticaly artesunate is superior
compared to artemether and artemotil. Being water
soluble it could be given either by intravenous or intra-
muscular injection. Randomised trials comparing
artesunate with quinine from South-East Asia clearly
suggest that artesunate is the drug of choice for treatment
of severe malaria. In a head to head trial, compared with
quinine; it reduced mortality by 34.7%.
Artemether and artemotil have comparable anti-
malarial properties with artesunate but both suffer from
erratic absorption from intramuscular injection; in severe
malaria there is a possibility of treatment failure because
of such unreliable absorption. Availability of artesunate
as intravenous injection makes it a preferred drug while
treating dire emergency of severe malaria.
Dosage
Recommended dosages of artesunate are: 2.4 mg kg/BW IV
or IM given at admission time “0” hours, repeat at 12
hours then at 24 hours, and subsequently continue once
a day.
Artesunate is dispensed as a powder of artesunic acid.
This is dissolved in sodium bicarbonate (5%) to form
sodium artesunate. The solution is then diluted in
438 IAP Textbook of Pediatrics
approximately 5 ml of 5% dextrose and given by
intravenous injection or by intramuscular injection to the
anterior thigh.
The solution needs to be prepared anew for each
administration and should not be stored. Artesunate does
not require any dose adjustment in cases with hepatic or
renal compromise.
Recommended dosages of artemether are: 3.2 mg/kg BW IM
given on admission 0 hours then 1.6 mg/kg BW per day.
Follow-on Treatment
After initial parenteral treatment, once the patient could
tolerate oral therapy, it is crucial to continue and
complete treatment with an effective oral antimalarial.
A full course of oral ACT (artesunate + amodiaquine or
artemether-lumefantrine) should be given.
Mefloquine is associated with higher neuropsychiat-
ric complications whenever it is used for cerebral malaria.
Therefore it is worth avoiding it as ACT partner if the
patient had initially presented with impaired conscious-
ness or abnormal behavior.
Quinine
Intravenous quinine is an important drug for severe
malaria. Although artesunate proved better than quinine
in severe malaria in regions with low transmission and
unstable form of community malaria; in settings of high
transmission and stable form of community malaria such
superiority is yet to be established.
Loading dose: To achieve minimal inhibitory concentration
quickly, a loading dose of quinine is necessary. With a
loading dose parasite clearance is found to be faster. The
dose is 20 mg/kg BW of quinine salt given by constant
rate controlled intravenous infusion over 4 hours.
Loading dose should be avoided if patient had earlier
received quinine, quinidine or mefloquine.
Maintenance dose: Maintenance dose is 10 mg/Kg BW of
salt given by intravenous infusion over 4 hours every 8
hourly, till patient is unable to take drugs orally. If after
48 hours of parental therapy patient is still incapable of
taking oral treatment then it is advisable to reduce
maintenance dose by half. Patients with hepatic or renal
failure also need appropriate dose reductions.
Side effects: Hypoglycemia is the commonest side effect
of quinine therapy. Its occurrence is very much related
to rate of quinine infusion, induction of hypoglycemia is
much higher when drug is infused rapidly.
Follow-up oral treatment After two to three days, majority
of the patients are in a position to take a drug orally.
Hepatic clearance of quinine becomes faster during
afebrile phase, accordingly higher doses of quinine are
required to maintain necessary MIC, and hence quinine
doses should not be reduced during recovery period.
During follow on treatment quinine could be
supplemented with either clindamycin or doxycycline,
as per age suitability.
Antimalarial drug therapy for severe and complicated
P.vivax malaria: Antimalarial drugs for severe and
complicated P. vivax malaria are essentially same as that
for P. falciparum malaria. Artesunate is the drug of choice,
artemether and quinine could be other options.
SUPPORTIVE TREATMENT
Patients with severe malaria demand meticulous nursing
care, preferably in an intensive care unit.
Supportive treatment depends on malarial compli-
cations. Aspects which need special considerations are
discussed below:
1. Frequent clinical assessment should be made.
Assessment must comprise of:
a. Recording of vital signs
b. Respiratory rate and pattern
c. Coma score
d. Urine output
e. Blood glucose.
2. Convulsions should be treated promptly with
intravenous or rectal diazepam or intramuscular
paraldehyde.
3. Avoid routine use of phenobarbitone (Higher death
rate in patients treated with phenobarbitone).
4. Perform a LP to rule out meningitis; use proper
antibiotic coverage in case CSF examination is
infeasible or is deferred for some reasons.
5. Suspect hypoglycemia in any case showing sudden
deterioration, infuse IV glucose (0.3-0.5 g/kg BW of
glucose) if blood glucose is < 40 mg/l.
6. Measure rectal temperature. Use antipyretic and
cold sponging for hyperpyrexia.
7. Proper management of fluid and electrolyte.Children
with malaria are usually dehydrated and tolerate
fluid boluses quite well conversely adults with
severe malaria are rather vulnerable to fluid
overload and may lend into pulmonary edema
particularly with element of ARF.

8. Consider blood transfusion for severe anemia (Hb
less than 7 g/dL in low transmission zone, less than
5 g/dL in high transmission zone).
9. Consider plasma transfusion, Vit-K supplementa-
tion, and avoidance of certain drugs (aspirin) in
malaria with bleeding diathesis.
10. Rule out other causes of hepatobiliary involvement
in malarial patients presenting with jaundice.
11. Consider propped up position, oxygen supplemen-
tation and furosemide for pulmonary edema.
12. Consider appropriate antibiotics, fluid replacement,
oxygenation, and dopamine for shock.
13. Management of lactic acidosis. Lactic acidosis has
significantly adverse effect on malarial prognosis,
therefore measures to increase tissue perfusion,
oxygenation and correction of acidosis by sodium
bicarbonate need priority considerations in severe
malaria.
14. Keep a low threshold for antibiotic therapy parti-
cularly if patients continue running fever despite
parasitic clearance. Associated salmonella infection
with malaria is pretty common. Secondary
pneumonia in malaria should be treated with a
third-generation cephalosporin; however aspiration
pneumonia in an unconscious patient should receive
penicillin or clindamycin.
AVOIDANCE OF USELESS ANCILIARY TREATMENT
Additional supportive strategies like heparin, prosta-
cyclin, deferoxamine, pentoxifylline, low molecular
weight dextran, urea, high-dose corticosteroids,
acetylsalicylic acid, deferoxamine, anti-tumor necrosis
factor antibody, cyclosporin, dichloroacetate, adrenaline
and hyperimmune have been suggested in severe malaria
yet hardly any of these strategies could prove their
therapeutic utility, on the contrary many of them have
proved harmful.
Corticosteroids
Steroids were in use, in severe malaria, for treatment of
cerebral edema, shock hemolysis, thrombocytopenia and
pulmonary edema. In double blind studies use of steroids
was found to increase duration of coma, incidence of
gastrointestinal bleeding and incidence of secondary
bacterial infection, following these observations steroids
are no more recommended for severe malaria.
Mannitol and Urea
Mannitol and urea were earlier used with an aim to
reduce cerebral edema. But with the realization that brain
Immunization and Infectious Diseases 439
edema is not a significant feature of neurological malaria
this use is given up.
Dextran
Low molecular weight dextran were recommended to
reduce blood viscosity however due to inevitable anemia.
Blood viscosity is never high in malaria and more over
as dextran can worsen a bleeding diathesis, their use is
unjustified.
For IAP- Infectious Diseases Chapter Protocol for
management of malaria, please see Chapter 36.11.1,
Page No. 1525.
BIBLIOGRAPHY
1. Adak T, Sharma VP, Orlov VS. Studies on the Plasmo-
dium vivax relapse pattern in Delhi, India. American
Journal of Tropical Medicine and Hygiene 1998;59:
175-9.
2. Adjuik M, et al. Artesunate combinations for treatment
of malaria: meta-analysis. Lancet 2004;363:9-17.
3. Artemether-Quinine Meta-analysis study group. A meta-
analysis using individual patient data of trials comparing
Artemether with quinine in the treatment of severe
falciparum malaria. Trans R Soc Med Hyg 2001;95:1-14.
4. Baird JK. Chloroquine resistance in Plasmodium vivax.
Antimicrobial Agents and Chemotherapy 2004;48:
4075-83.
5. Brewster DR, Kwiatkowski D, White NJ. Neurological
sequelae of cerebral malaria in children. Lancet 1990;
336:1039-43.
6. Dua VK, Kar PK, Sharma VP. Chloroquine resistant
Plasmodium vivax malaria in India. Tropical Medicine
and International Health 1996;1:816-9.
7. Dua VK, Sharma VP. Plasmodium vivax relapses after 5
days of primaquine treatment, in some industrial
complexes of India. Annals of Tropical Medicine and
Parasitology 2001;95:655-9.
8. Handunnetti SM, et al. Features of recrudescent
chloroquine-resistant Plasmodium falciparum infections
confer a survival advantage on parasites, and have
implications for disease control. Transactions of the Royal
Society of Tropical Medicine and Hygiene 1996;90:
563-7.
9. Hay SI, et al. Annual Plasmodium falciparum entomolo-
gical inoculation rates (EIR) across Africa: Literature
survey, Internet access and review. Transactions of the
Royal Society of Tropical Medicine and Hygiene 2000;
94:113-27.
10. Hien TT, Arnold K, Vinh H, et al.Comparison of
artemisinine suppositories with intravenous artesunate
and intravenous quinine in the treatment of cerebral
440 IAP Textbook of Pediatrics
malaria. Trans R Soc Trop Med Hyg 1992;86:582-3.
11. Hoffman SL, Rustama D, Punjabi NH, Surampaet B,
Sanjaya B, Dimpusdus AJ, et al. High-dose dexametha-
sone in quinine treated patient with cerebral malaria: A
double blind placebo control trial. Journal of Infectious
disease 1988;158:325-31.
12. Imwong M, et al. Association of genetic mutations in
Plasmodium vivax dhfr with resistance to sulfadoxine-
pyrimethamine geographical and clinical correlates.
Antimicrobial Agents and Chemotherapy 2001;45:
3122-7.
13. Kochar DK, Saxena V, Singh N, Kochar SK, Kumar SV,
Das A. Plasmodium vivax Malaria. Emerging Infectious
Diseases. www.cdc.gov/eid. 2005;11(1).
14. Lesi A, Meremikwu M. High first dose quinine for
treating severe malaria. In: The Cochrane Library, Issue
2, 2003.
15. McIntosh HM, Olliaro P. Artemisinin derivatives for
treating severe malaria (Cochrane Review). In: The
Cochrane Library, Issue 2, 2001.
16. Meremikwu M, Marson AG. Routine anticonvulsants for
treating cerebral malaria. The Cochrane Database of
Systematic Reviews Issue 2, 2002.
17. Meremikwu M, Smith HJ. Blood transfusion for treating
malarial anaemia (Cochrane Review). In: The Cochrane
Library, Issue 3, 2001.
18. Nosten F, et al. Effects of artesunate-mefloquine combi-
nation on incidence of Plasmodium falciparum malaria
and mefloquine resistance in western Thailand:
A prospective study. Lancet, 2000;356:297-302.
19. Pukrittayakamee S, et al. Therapeutic responses to
different antimalarial drugs in vivax malaria. Anti-
microbial Agents and Chemotherapy 2000;44:1680-5.
20. Robert V, et al. Gametocytemia and infectivity to
mosquitoes of patients with uncomplicated, Plasmodium
falciparum malaria attacks treated with chloroquine or
sulfadoxine plus pyrimethamine. American Journal of
Tropical Medicine and Hygiene, 2000;62:210-6.
21. Schuurkamp GJ, et al. Chloroquine-resistant Plasmodium
vivax in Papua New Guinea. Transactions of the Royal
Society of Tropical Medicine and Hygiene 1992;86:
9.34 Kala Azar (Visceral Leishmaniasis)
Leishmaniasis refers to a diverse group of diseases that
may affect the viscera, skin or mucous membranes caused
by infection due to the parasites of the genus Leishmania.
Of the various species that cause leishmaniasis, Leishmania
donovani is responsible for the disease in India: Kala azar
and post-kala azar dermal leishmaniasis. Kala azar or
121-2.
22. South-East Asian Quinine Artesunate Malaria Trial
(SEAQUAMAT) group. Artesunate versus quinine for
treatment of severe falciparum malaria: A randomized
Trial. Lancet 2005;366:717-25.
23. The use of rapid diagnostic tests. Geneva, Roll Back
Malaria, WHO Regional Office for the Western Pacific
and UNDP/World Bank/WHO/UNICEF Special
Programme for Research and Training in Tropical
Diseases 2004.
24. Van Vugt MV, et al. Efficacy of six doses of artemether
lumefantrine (benflumetol) in multidrug-resistant
Plasmodium falciparum malaria. American Journal of
Tropical Medicine and Hygiene 1999;60:936-42.
25. Warrell DA, et al. Dexamethasone proves deleterious in
cerebral malaria. A double-blind trial in 100 comatose
patients. New England Journal of Medicine 1982; 306:
313-9.
26. Warrell DA, Giles HM. Treatment and prevention of
malaria. Essential malariology, 4th edn. Edward Arnold
2000;268-312.
27. Warrell DA. Pathophysiology of severe falciparum
malaria in man. Parasitology, 1987;94(Suppl):S53-S76.
28. Warrell DA, Looareesuwan S, Warrell MJ, et al.
Dexamethasone proves deleterious in cerebral malaria:
A double blind clinical trial in 100 comatose patients. N
Engl J Med 1982;306:313-8.
29. White NJ. The treatment of malaria. N Engl J Med
1996;335:800-6.
30. White NJ, Waller D, Crawley J, et al. Comparison of
Artemether and chloroquine for severe malaria in
Gambian children. Lancet 1992;339:317-21.
31. WHO. Management and treatment of severe falciparum
malaria, practical chemotherapy of malaria. Report of a
WHO scientific group. TRS-805: 52-74 World Health
Organization.Geneva 1990.
32. WHO. Severe malaria in children. Management of severe
and complicated malaria. A Practical Handbook 2nd edn.
World Health Organization.Geneva 2000;27-40.
33. WHO. Guidelines for the treatment of malaria 2006.
34. Yadav RS, Ghosh SK. Radical curative efficacy of five-
day regimen of primaquine for treatment of Plasmodium
vivax malaria in India. Journal of Parasitology,
2002;88:1042-4.
Yogesh Jain, Rakesh Lodha
visceral leishmaniasis is the systemic manifestation of this
infection which may be fatal, if untreated. Kala azar is a
major public health problem in certain regions of India.
The disease is endemic in Ganga-Brahmaputra valleys
affecting especially Bihar, West Bengal and Assam.
Epidemics of this disease occur periodically.

PATHOGENESIS
The parasite, Leishmania grows into promastigote forms
inside the insect vector, sandfly (Phlebotomus). These
are injected into a susceptible host by the sandfly. The
parasite multiplies freely in its amastigote form inside
the mononuclear phagocytic cells throughout the visceral
reticuloendothelial system in spleen, liver, bone marrow
and lymphoid tissue. However, infection with L. donovani
is not synonymous with disease. For each case of kala
azar, there are 30 to 100 subclinical infections in an
endemic area. Malnutrition is a significant risk factor that
may precipitate active disease in a child suffering from
subclinical infection.
PATHOLOGY
The bone marrow is hyperplastic but shows some
dyserythropoiesis and maturation arrest. Erythrocytes
are sequestered in the spleen and also undergo
hemolysis. Beside, ineffective erythropoiesis and
immune mediated lysis also contribute to anemia.
Neutrophils and platelets are also sequestered and
destroyed prematurely. The liver and spleen enlarge
because of reticuloendothelial proliferation. There is
variable depression of synthetic functions of the liver
resulting in hypoalbuminemia. However, prothrombin
time is usually normal.
CLINICAL FEATURES
The clinical incubation period is usually 2 to 4 months,
however it may range from 1 month to as long as 2 years.
The clinical features on presentation reflect the chronicity
and the severity of the infection. Fever, hepatospleno-
megaly and pallor are seen in more than 95 percent of
cases and thus, are the cardinal features of this illness.
Epistaxis is common early in the disease. A large number
of patients develop darkening of the skin, especially on
the face, hands and the upper torso, that is the feature
which gives the disease its name kala azar.
In some cases of inadequately treated kala azar, a skin
condition called post-kala azar dermal leishmaniasis may
develop as all parasites are not eradicated (See Chapter
31).
Malnutrition may ensue because of the chronic nature
of this disease. Patients may also develop intercurrent
infection of the respiratory and gastrointestinal tract as
manifested by cough and diarrhea.
Kala azar has also been reported as an opportunistic
infection in HIV infected individuals.
Immunization and Infectious Diseases 441
DIAGNOSIS
It is mandatory to make a parasitological diagnosis by
demonstrating the parasite before starting treatment. The
parasite can be demonstrated in various tissue sites as
shown below. It is also necessary to quantitate the
parasite load by counting the number of parasites.
Site Sensitivity
Splenic puncture 95-98 %
Bone marrow 54-86%
Liver 70 %
Buffy coat preparation 70%
Lymph node 60%
Splenic puncture and bone marrow aspiration are the
commonly employed diagnostic techniques. In presence
of thrombocytopenia, splenic puncture is contra-
indicated. Additionally, parasite can be cultured on NNN
medium but this is not available everywhere. Polymerase
chain reaction (PCR) can also be used to diagnose this
infection. It is 90 percent sensitive.
Recently antigen detection test (RK-39) has been
found to have high sensitivity and specificity.
Various serological tests for kala azar are available.
The common techniques are indirect fluorescent antibody
test (IFAT), direct agglutination test (DAT) and enzyme
linked immunosorbent assay (ELISA). These tests have
over 95 percent sensitivity and specificity in diagnosis
of leishmanial infection. However, they do not distin-
guish between asymptomatic infections, past infection
or active kala azar. Therefore, it has limited role in clinical
diagnosis in endemic areas.
Pancytopenia is commonly seen. Anemia is seen in
all cases. Neutropenia is seen in 60 to 70 percent cases
and may be seen early in the course of the disease.
Thrombocytopenia may be seen in 50 to 60 percent of
children. Hypergammaglobulinemia with reversal of
albumin to globulin ratio is commonly seen; aldehyde
test which is based on this, is now obsolete because of its
low specificity and poor sensitivity in the first three
months of the infection.
COURSE AND PROGNOSIS
If untreated 80 to 90 percent patients die. Intercurrent
infections supervene especially pneumonia, tuberculosis,
dysentery and cancrum oris. However, with treatment,
majority would recover without sequelae. Later, up to
20 percent cases may develop a cutaneous manifestation
of this disease called post- kala azar dermal leishmaniasis
(PKDL).
442 IAP Textbook of Pediatrics
TREATMENT
The objectives of treatment are: (i) Cure the patient of the
leishmanial infection, (ii) Prevent relapse, and
(iii) Treat intercurrent infections. Ultimate cure is clinical
and parasitological cure with no relapse during six months
of follow-up. Parasitological cure is absence of parasites
in bone marrow or splenic aspirate taken after therapy.
Pentavalent antimonials are the fist line drug for this
disease. Sodium antimony gluconate (SAG) and meglu-
mine antimonite are antimonials which are administered
via intramascular or intravenous route. SAG is given in a
single daily dose of 20 mg/kg/day of antimony base for 3
to 4 weeks or 2 weeks after parasitological cure. Some
Indian authors recommend up to 40 days therapy also.
Local injection, site pain, and mild ECG changes are
common adverse effects. Usually, there is improvement
in wellbeing and response to fever occurs in a few days,
hemoglobin starts wising in the second week. The spleen
may not regress totally till one year later. However, bone
marrow /splenic aspirate at the end of treatment should
show parasitological cure. It the treatment is interrupted
or inadequate dose is administered; the response may not
be there. There may be a relapse which is much more
difficult to treat. Relapses usually occur within 6 months.
If antimonials fail to cure the patient, amphotericin B
1 mg/kg/day for 20 days by intravenous infusion or
pentamidine isothionate 4 mg/kg by intramuscular route
on alternate days for 5 to 52 weeks can be given.
Recently, an oral drug miltefosine has been found to
be effective for treatment of kala azar.
CONTROL
Besides case detection and therapy, spraying of sandfly
sites with residual insecticides is vital.
BIBLIOGRAPHY
1. Bhattacharya SK, Sur D, Karbwang J. Childhood visceral
leishmaniasis. Indian J Med Res 2006;123:353-6.
2. Murray HW, Berman JD, Davies CR, Saravia NG.
Advances in leishmaniasis. Lancet 2005;366:1561-77.
3. Wittner M, Tanowitz HB. Lesihmaniasis. In: Feigin RD,
Cherry JD, Demmler GJ, Kaplan SL (Eds): Textbook of
Pediatric Infectious Diseases. Saunders, Philadelphia.
2004;2730-8.
10.1 Anatomical Localization of Neurological Problems: CS Rajput, DP Karmarkar ........................................................................... 444
10.2 Normal Development and Malformations of Central Nervous System: Veena Kalra, Rashmi Kumar ....................................... 448
10.3 Degenerative Disorders of the Central Nervous System: Veena Kalra .......................................................................................... 453
10.4 Seizure Disorders in Children: Veena Kalra ....................................................................................................................................... 455
10.5 Infections of the Central Nervous System: Veena Kalra .................................................................................................................. 462
10.6 Coma in Children: CR Banapurmath, Shobha Banapurmath, G Guruprasad .................................................................................... 470
10.7 Brain Tumors in Children: KS Rana .................................................................................................................................................... 477
10.8 Raised Intracranial Pressure: AD Tewari, Kundan Kumar Mittal ........................................................................................................ 486
10.9 Benign Intracranial Hypertension: AD Tewari, Kundan Kumar Mittal ............................................................................................... 489
10.10 Motor Weakness in Infancy and Childhood—Clinical Approach: Vrajesh Udani ........................................................................ 491
10.11 Floppy Infant Syndrome: R Anandam, D Kalpana .............................................................................................................................. 495
10.12 Muscular Disorders in Children: K Pandian ....................................................................................................................................... 499
444 IAP Textbook of Pediatrics

10.1 Anatomical Localization of

Neurological Problems
CS Rajput, DP Karmarkar

A clear, precise and accurate history of the entire course of
the illness is imperative in neurological disorders. It often
leads to a provisional diagnosis and also helps to guide
the physician towards a more pointed and detailed
neurological examination. It helps to determine the
etiology, etiopathogenesis, course of events and possible
sites of lesions. The onset of disease whether it is acute,
subacute, chronic or acute exacerbation of a chronic illness
is important in clinical neurology. Similarly, the course of
the illness, whether progressive, static, regressive or
showing improvement from the time of insult are
important clues in distinguishing a degenerative brain
disorder from acute acquired insults. Common symptom
groups include delayed neurodevelopment, regression of
neurodevelopment, symptoms such as fits, motor
weakness, gait and tone abnormalities, altered sensorial
states, features of raised intracranial pressure, and sensory
symptoms. History should evaluate the details of each of
the above symptoms and also presence or absence of other
symptom groups. A holistic history is required to assess
the overall status.
Cerebral Lesions
The cerebral cortex functions in an integrated manner, yet
certain functions are more specifically controlled from
various specific sites. In cerebral cortical insults, the
localization or preferential involvement of various lobes
of the cortex can be obtained by history of symptoms
related to higher functions and specific signs as given in
Figure 10.1.1.
Hemiplegia
The clinical evaluation of a child with unilateral motor
symptoms is challenging due to difficulties in performing
a systematic motor examination and retaining the child's
cooperation through the procedure. Hence, history and
functional examination become important management
strategies. The position of the limbs, hands and feet, quality
and range of spontaneous movements, handedness,
involuntary movements, limb asymmetries should be
observed carefully before proceeding for a systematic
examination.

Figure 10.1.1: The effects of lesions of different lobes in cerebrum


Figure 10.1.2: Features of localization of hemiplegia lesions
History of onset of weakness is classified as acute, if
weakness develops within 24 hours of the onset, and it
usually implies a vascular or acute inflammatory etiology.
It is subacute, if it evolves in a few days and is common in
inflammatory or venous vasculopathies, and chronic, if
weeks elapse before full profile is manifest. This is often
due to space occupying lesions, degenerative brain
diseases, or subdural hematoma. The pattern and
distribution of weakness and clinical associations help to
localize anatomic sites of the lesion. The location may be
cortical, subcortical, at corona radiata, internal capsule,
midbrain, pons, medulla or high cervical cord. The clinical
Diseases of Central Nervous System 445
associations at various levels are indicated in Figure 10.1.2.
It is clear that clinical examination must attempt to
determine the site as precisely as possible.
The next important question to answer is the cause of
hemiplegia. Common etiological processes are listed below.
The details are dealt with in subsequent chapters.
Classification of Hemiplegia
Anatomical Classification
This classification helps in localization of the lesion.
1. Cerebral
446 IAP Textbook of Pediatrics

a. Cortical lesion Demyelinating

b. Subcortical lesion • Acute disseminated encephalomyelopathy
c. Lesion in the internal capsule • Multiple sclerosis
2. Brainstem—This includes midbrain lesions • Leukodystrophy
3. Pons Metabolic
4. Medulla • Hypoglycemia
5. Spinal • Hyperglycemia
a. Upper cervical • Uremia
b. Lower cervical Postepileptic congenital
• AV malformations
Clinical Classification • Moya-moya disease
Depending upon duration of illness, hemiplegia can be Miscellaneous
classified as: • Hemolytic uremic syndrome
a. Acute—within 24 hours • Homocystinuria
b. Subacute—2 to 4 days • Vasculopathies like systemic lupus erythematosus
c. Recurrent—Common causes are vasculopathies, • Hypersensitivity vasculitis
mitochondrial disorders, embolic episodes, sickle cell
disease, transient ischemic attacks, demyelinating Spinal Cord
diseases. Lesions of the spinal cord often lead to paraplegia or
d. Slowly progressive— More than 2 weeks duration. quadriplegia. The onset of weakness, pattern of prog-
Common causes are intracranial space-occupying ression, time taken for evolution of the full profile should
lesions, subdural hematoma, demyelinating diseases. be enquired into. The associated symptoms which need to
be interrogated include history of pain, girdle sensation,
Depending upon type of tone, It is also classified as:
radicular pain, sensory loss including touch, pain,
a. Spastic hemiplegia
temperature, pressure and posterior column sensations.
b. Flaccid hemiplegia.
Presence of paresthesias and sensory abnormalities are
often difficult to elicit in children. A definite sensory loss
Etiopathological Classification of Hemiplegia
level is hard to define and thus a useful parameter for
Vascular identification of site of spinal cord lesion is not available
• Thrombosis in childhood. Involvement of bladder and bowel control,
i. Arterial—arteritis perianal sensations and sphincteric tone are important.
ii. Venous—cortical venous thrombosis Presence of cutaneous dimple, lipoma, tuft of hair, spinal
• Embolism tenderness, perispinal swelling should be examined in
• Mitral valve disease, subacute bacterial endocarditis every patient.
(SABE) The major clinical features that help to localize site of
• Hemorrhage spinal cord lesions are given in Table 10.1.1. Lesions of
the spinal cord should be differentiated into compressive
Infective or noncompressive myelopathies, and extramedullary or
• Tuberculosis, pyogenic abscess, encephalitis intramedullary lesions. The clinical features that help in
Traumatic this regard are listed below.
• Subdural hematoma
Lesions Involving the Spinal Cord
• Extradural hematoma
and its Localization
• Intracranial hemorrhage
Paraplegia It is a symmetric paralysis of both lower
Neoplastic
extremities.
• Neurofibroma
• Meningioma Quadriplegia It is paralysis of all four extremities. It is
• Glioma also called as tetraplegia.
• Leukemia Monoplegia It is a paralysis of one extremity only.
 Diseases of Central Nervous System 447

TABLE 10.1.1: Features of localized lesions in spinal cord

Cord Clinical features Muscles paralysed Reflexes

segment
C3-4 Pain in neck and occipital pain Lower parts of trapezius,
paresthesia and weakness in supraspinatus and infraspinatus,
upper limbs early, muscles of upper limbs,
relative anesthesia of face diaphragm
Paralysis of 9th, 10th and
11th cranial nerves
Quadriplegia
C7 Paraplegia Triceps and extensors Triceps (C6-7) lost
of wrist and fingers
C8, T1 Spastic paralysis of trunk and Flexors of wrists and In upper limb—normal,
lower limbs fingers and muscles of exaggerated in lower limb
Paralysis of ocular sympathetic—sometimes hand
T6 Spastic paralysis of muscles Intercostals, upper and Upper abdominals
of abdomen and lower limbs lower rectus abdominis, and lower abdominals lost
oblique abdominis
T9-10 Spastic paraplegia Lower half of rectus Upper abdominals normal
abdominis Lower abdominals lost
T12L1 Spastic paraplegia Lower fibers of oblique
abdominis and transversalis, iliopsoas
L3-4 Spastic paraplegia Quadriceps, abductors Knee jerk (L2-4) lost
of hip ankle jerk + (S1-2)
S1-2 Flexion of hip, adduction of Glutei, calf muscles, Knee jerk and
thigh, extension of knee and anterior tibial and peroneal, ankle jerk lost,
dorsiflexion of foot possible small muscles of plantar reflexes lost
All other movements in lower foot
extremities weak
S3-4 No paraplegia. Retention of Paralysis of external Anal and bulbocavernous
urine and feces sphincter reflexes lost. DTR normal
Cauda 1. Whole cauda—anesthesia Paralysis of lower Absent deep reflexes
equina below folds of groin, including limb
genitals, loss of control
of bladder and rectum
2. Upper sacral and L5—sensory Paralysis of gluteal, Knee jerk and
loss over front and posterior hamstrings and all ankle jerk lost
and outer aspect of thigh muscles below knee
3. Below S2—saddle-shaped No paralysis of lower All reflexes
area of anesthesia, incontinence limbs in lower limb normal
of urine and feces
4. S4-5 and coccygeal roots— Paralysis of levator ani
anesthesia of anus and rectum

DTR—Deep tendor reflex

Causes of Paraplegia Paraplegia in flexion The pyramidal tracts are severely

Cortical causes—Cortical venous thrombosis, cerebral
palsy, spinocerebellar hereditary spastic paraplegia
Spinal causes—Transverse myelitis, epidural abscess,
herpes zoster myelitis, GB syndrome, poliomyelitis,
trauma, and tuberculous osteomyelitis of vertebra.
affected, and there is a lesion of descending spinal path-
ways. The legs become progressively more flexed at knee
and hip, and stimulation provokes painful flexor spasm.
Paraplegia in extension When spinal lesion is incomplete
and affects principally the pyramidal tracts, the tone in
lower limbs is increased in extensor muscles.
448 IAP Textbook of Pediatrics
TABLE 10.1.2: Features of cord compression
Extramedullary intradural
• Radicular pains, common
• Paresthesia, rare until late
• Muscle fasciculations, rare
• No dissociated loss of sensation
• Bladder and rectal disturbance, late
• Rising level of sensory disturbances as
peripheral tracts are affected more
• Brown-Séquard syndrome may occur
• No sacral sparing
• Spasticity and other pyramidal signs pronounced
• Little or no muscle atrophy
• Trophic skin changes, absent
• Vertebral column may be sensitive to local pressure
• Spinal fluid changes, frequent
Cord Compression
Table 10.1.2 depicts comparative features of extra-
medullary and intramedullary cord compression.
Brown-Séquard Syndrome
If there is a partial affection of the cord, it might lead to
Brown-Séquard syndrome which is characterized by the
following:
1. Loss of motor control (pyramidal tract) below the level
of lesion on the same side
2. Loss of posterior column sensations below the level of
lesion on the same side
10.2 Normal Development and Malformations
of Central Nervous System
NORMAL DEVELOPMENT
A thickening of ectoderm occurs dorsally in the first month
of gestation, forming the neural plate. This gets indented
centrally and is flanked by ridges (neural folds). These
fuse in the midline forming the neural tube with apertures
at both ends—the anterior and posterior neuropores. The
anterior and posterior neuropore fuse by the 26th and
29th day of gestation respectively. The rostral segment of
Intramedullary (Intrinsic lesions of spinal cord)
• Radicular pains rare
• Paresthesia occur in all stages
• Muscle fasciculations, common
• Dissociation of sensations, common
• Bladder and rectal disturbances, early
• Descending level of sensory disturbances
• Persistent Brown-Séquard syndrome, very rare
• Sacral sparing
• Spasticity, less pronounced
• Characterized by muscle atrophy
• Trophic skin changes, common
• No local tenderness of spine
• Spinal fluid changes, rare
3. Loss of pain and temperature sensations on the
opposite side 2 to 6 segments below the lesion.
BIBLIOGRAPHY
1. Behrman, Kliegman, Arvin: Nelson Textbook of Paediat-
rics (15th edn) 1996.
2. Christopher RW, Edwards, Lan AD: Boucher, Davidson's
Principles and Practices of Medicine, 1991.
3. Chusid IG: Correlative neuroanatomy and functional
neurology (16th edn) 1976.
4. Patten J: Neurological differential diagnosis.
5. Walton J: Brains Diseases of the Nervous System
1985.
Veena Kalra, Rashmi Kumar
the neural tube develops three regional dilatations or
vesicles, whose cavities eventually form the cerebral
ventricles and aqueduct. These vesicles develop into the
prosencephalon, mesencephalon and rhombencephalon.
The walls of these structures have three layers namely,
the ventricular (or ependymal), the mantle and the margi-
nal layers. The prosencephalon further differentiates into
cerebral hemispheres and diencephalon, while the

rhombencephalon differentiates into mesencephalon (later
pons and medulla) and myelencephalon (later medulla
oblongata). These subdivisions are complete by 36 days
of gestation.
The cerebral hemispheres with subdivisions of limbic
system, basal ganglia and cerebral cortex are distinct by
three months of gestation. Sulcal differentiation starts in
the 3rd month in the Sylvian fissure. By the 5th and 6th
month of gestation, the primary fissures and lobes of the
brain are visible.
MALFORMATIONS
Malformations of the central nervous system may be minor
or major. Most of them have significant clinical
implications, as even minor malformations may be
associated with seizures, focal neurological deficits or
delayed neurodevelopment. Approximately 3 percent of
live newborns and 7 percent of stillbirths have CNS
malformations. Genetic and nongenetic causes may be
responsible, e.g. infections, drugs, maternal irradiation
and other environmental insults. Malformations can be
broadly grouped into:
• Dysraphisms and malformations of neural tube clo-
sure;
• Malformations of embryogenesis and neuronal migra-
tion;
• Malformations of size and shape of head;
• Abnormal CSF dynamics; and
• Abnormalities in brain size.
The common ones that require familiarization include
hydrocephalus, microcephaly, neural tube defects, and
disorders of cell migration.
HYDROCEPHALUS
This results from an increased volume of cerebrospinal
fluid due to either increased production, obstruction in its
path or impaired absorption resulting in increased
ventricular size. The ventricles not only become dilated
but the pressure is usually increased, resulting in
increased periventricular white matter pressure, peri-
ventricular ooze and blunting of horns of ventricles. When
the ventricles dilate as a compensation for decreased brain,
it is called hydrocephalus ex vacuo (Table 10.2.1).
Pathophysiology
CSF is secreted by the choroid plexus in the lateral
ventricles by plasma ultrafiltration and active secretion.
This involves active transport of sodium and is energy
dependent. The total volume of CSF is about 50 ml in an
Diseases of Central Nervous System 449
TABLE 10.2.1: Etiology of hydrocephalus
Congenital Acquired
1. CSF flow obstruction 1. Postmeningitis—TBM,
–Aqueductal stenosis chronic, acute menin-
–Arnold-Chiari malformation gitis
–Dandy-Walker malformation 2. Posterior fossa tumors
2. Intrauterine infections 3. Cortical atrophy
3. Intracranial bleeds (Hydrocephalus
4. Congenital tumors ex vacuo)
infant, and 150 ml in an adult. About 20 ml of CSF is
produced per hour. It then circulates through the 4th
ventricle and reaches the basal cisterns via the foramina
of Luschka and Magendie, and subarachnoid spaces at
the base and cortex of the brain. The pressure gradient
between the ventricles is about 180 mm of water, and the
veins is about 90 mm of water. The CSF is absorbed mainly
through the arachnoid villi into the vascular system, due
to this hydrostatic pressure. Hydrocephalus resulting
from obstruction within the ventricular system is called
obstructive hydrocephalus, whereas that resulting from
obliteration of the subarachnoid cisterns or decreased ab-
sorption is called communicating hydrocephalus.
Congenital Hydrocephalus
Hydrocephalus may be present at birth or develop shortly
thereafter, due to:
1. Aqueductal stenosis It could be inherited as an X-linked
recessive trait or may result from intrauterine infections
such as toxoplasmosis.
2. Arnold-Chiari malformation It is characterized by
cerebellar elongation and downward displacement. It
has varying severity. In the commonest type of Chiari
malformation (type 2), the cerebellum and medulla
oblongata are shifted caudally with distortion and
obstruction of CSF pathways. This malformation is
often associated with myelomeningocele or other
neuronal migration defects.
3. Dandy-Walker malformation This is a cystic malfor-
mation of the cerebellum and 4th ventricle, which
occurs due to atresia of the foramina of Luschka and
Magendie. It may also be associated with other brain
malformations.
4. Intrauterine infections, intracranial bleeds, congenital
tumors and many genetic and chromosomal
syndromes, may be associated with congenital hydro-
cephalus.
450 IAP Textbook of Pediatrics
Acquired Hydrocephalus
This may be communicating or noncommunicating (obs-
tructive). In obstructive hydrocephalus, the CSF flow may
be obstructed at any site along its path. Common sites of
obstruction include aqueduct of Sylvius and fourth
ventricular outflow foramina. In communicating
hydrocephalus, there may be increased production at the
choroid plexus or decreased absorption at the subara-
chnoid spaces. This commonly follows chronic meningi-
tis including tuberculosis and acute meningoencephalitis.
Obstructive hydrocephalus may be associated with
congenital malformation, tumor, periaqueductal stenosis,
cystic lesions or due to fibrosis, following intraventricular
hemorrhage. The ventricles above the site of obstruction
become dilated, and this helps to differentiate obstructive
from communicating hydrocephalus.
Clinical Features
A large or rapidly increasing head size with prominent
forehead is the single most important clinical feature. Head
size can increase due to many causes. The sutures and
fontanels remain unduly prominent and have delayed
closure. Macewen's or crackpot sign may be positive and
prominent veins are seen on the scalp. Child may have
impaired upward gaze (sunset sign), cranial nerve palsies,
increased tone in the limbs and brisk tendon jerks may be
detected due to compression of the white matter. The signs
are more severe in lower limbs. Features of raised
intracranial pressure like papilledema, ophthalmoplegia,
bradycardia, abnormalities in respiratory rate and rhythm,
and constipation may occur. Optic atrophy may occur.
Not uncommonly, children experience frequent
headaches, head banging and vomiting due to increased
intracranial pressure. Serial measurement of head size is
an important clinical parameter to be recorded.
It must be remembered that all large heads are not due
to hydrocephalus. Important differential diagnosis include
macrocephaly and megalencephaly, associated with
metabolic CNS diseases, neurocutaneous syndromes,
subdural effusion and large head due to skeletal disorders
like achondroplasias, hemolytic anemias and familial
large heads.
Management
Management includes making a precise diagnosis. Cranial
ultrasound is useful to screen ventricles or subdural space
provided fontanel is open. Subsequently a CT scan is
necessary to demonstrate ventricle size, periventricular
ooze (an indication of increased ventricular pressure),
thickness of cortical mantle, coexisting lesions and
possible etiology. Hydrocephalus often gets arrested
spontaneously. Surgical intervention is not required in
all. In established and progressive hydrocephalus or
where vision or life is endangered, surgical intervention
is mandatory. A variety of shunts are available—
ventriculoperitoneal, ventriculoatrial, etc. The former is
preferred. Infections, shunt block and child outgrowing
the shunt are some of the commonly encountered compli-
cations. The choice should be appropriate and close
follow-up maintained. Medical management should be
instituted if surgery is not indicated. Acetazolamide, 50
mg/kg/day or glycerol may be added for control of
symptoms and raised pressure associated with hydro-
cephalus.
Prognosis
Prediction of outcome is difficult, based on the size of the
cortical mantle at the time of operation. Hydrocephalic
children have lower intelligence quotients and a higher
risk of developmental disabilities—especially in visual,
memory and performance fields than the general
population.
CONGENITAL ABNORMALITIES OF THE SKULL
Normal development The skeletal system develops from
the mesoderm during the 3rd week of gestation. The bones
of the skull are well developed by the 5th month of
gestation and are separated by fibrous sutures and
fontanels.
Microcephaly
It is a condition in which the head circumference is more
than 2 standard deviations below expected norm for age,
sex or gestation. Microcephaly may be primary or
secondary. Except in premature closure of sutures
(craniosynostosis), it reflects a small sized brain. Primary
microcephaly is seen in various genetic and chromosomal
disorders and results from a variety of insults like
migration defects, microgyria, agenesis of corpus
callosum, gray matter heterotopias, etc. It may be familial,
inherited as an autosomal recessive disorder or may result
from an unidentified cause. Microcephaly may also follow
severe insults like CNS infections, metabolic disorders,
intrauterine infections, maternal addictions and other

causes. Secondary microcephaly results from both
perinatal and acquired insults causing destruction of the
brain. The lesions include gliosis, atrophy, cystic
degeneration, porencephaly and encephalomalacia,
depending upon the site and nature of lesion. But primary
and secondary microcephaly result in variable degrees of
mental impairment, hyperkinesia or a broad display of
neurologic disorders. It is important to assess neurologic
development, as some children may have microcephaly
with normal mentality. The cause is often difficult to
establish. Treatment of associated symptoms and
prevention of the preventable causes should be attempted.
Craniosynostosis should be excluded.
Craniosynostosis
It implies premature closure of one or more cranial sutures.
A skull deformity is usually evident and a bony ridge is
felt at the suture. If only one suture is involved, no
neurological deficits are seen and the problems are mainly
cosmetic, but if multiple sutures are fused, brain growth is
restricted and increased intracranial tension may result.
Associated developmental defects of face, orbit and CNS
may be present.
There are some genetic disorders and syndromes asso-
ciated with craniosynostosis. Crouzon syndrome, an
autosomal dominant disorder, is characterized by
brachycephaly (due to bilateral closure of coronal sutures),
proptosis, maxillary hypoplasia and hypertelorism. Apert
syndrome is associated with premature fusion of multiple
sutures—coronal, squamous, sagittal and lambdoid. This
autosomal recessive condition is associated with clover
leaf like skull, syndactyly and mental retardation. Pfeiffer
syndrome is associated with turricephaly, prominent
widely spaced eyes and broad, short thumbs and great
toes.
Diagnosis of craniosynostosis can be confirmed by
plain X-ray skull, which shows hyperostotic bony sutural
fusion. Surgical intervention is required to reduce
intracranial pressure, provide space to the growing brain
and for cosmetic reasons. Other defects of sutural fusion
include scaphocephaly, plagiocephaly, tugonocephaly
and turricephaly depending on the shape the skull
assumes.
DISORDERS OF THE CELL MIGRATION
These disorders present a wide range of severity, with
minor abnormalities of no clinical significance on the one
hand, and devastating malformations on the other.
Diseases of Central Nervous System 451
Neuronal Heterotopias
A defect in radial migration of neurons before the 5th
month of gestation, leads to clusters of subcortical neurons
or heterotopia. These neuronal clusters can be detected in
the white matter pathologically or on MRI scans.
Heterotopias are implicated in patients with partial
seizures and developmental dyslexia.
Lissencephaly (Agyria)
This is a rare disorder, associated with absence of cerebral
sulci and gyri, giving the appearance of a fetal brain. About
15 to 20 percent have deletions of chromosome 17p13.3.
Some infants may have a typical facial appearance with
prominent forehead, bitemporal hollowing and short nose
with upturned nares.
Pachygyria
The gyri are widened and show dense gliosis, detectable
on MRI scan. Clinical features include spasticity, mental
retardation and seizures.
Schizencephaly
This disorder is characterized by unilateral or bilateral
clefts in the cerebral cortex that results from a defect in cell
migration in the first trimester of pregnancy.
Agenesis of Corpus Callosum
Commissural plate damage during early embryogenesis
results in this malformation. The clinical spectrum varies
in severity from profound mental and motor defects with
seizures to an asymptomatic child. Associated migration
defects, porencephalic cysts and hydrocephalus may be
observed and may be associated with trisomies (8,18). The
Aicardi syndrome occurs in females, consists of agenesis
of corpus callosum, resistant seizures, severe mental
retardation, vertebral malformations and ocular
colobomas. CT or MRI scan reveals agenesis of corpus
callosum, laterally shifted frontal horns, and abnormally
high position of the 3rd ventricle, between the lateral
ventricles. Intrauterine diagnosis by ultrasound is feasible.
Prognosis is poor.
Porencephaly
This refers to the presence of cysts or cavities within the
brain, which may be developmental or acquired.
Developmental cysts are due to defect in cell migration.
452 IAP Textbook of Pediatrics
They are frequently located in the sylvian fissure area and
communicate with both subarachnoid space and ventricle.
NEURAL TUBE DEFECTS (DYSRAPHISM)
This group of congenital anomalies of the CNS results
from failure of the neural tube to close spontaneously. The
precise cause is unknown. Many factors such as radiation,
drugs and abnormal nutritional status acting at a critical
period of gestation as well as genetic determinants may
be causative.
Spina Bifida Occulta
This is a common anomaly affecting about 5 percent of the
population. Affected persons are usually asymptomatic
but may have a patch of hair, a lipoma or pigmentation of
the low back.
Meningocele
This is a protrusion of meninges through a defect in
posterior vertebral arches. There is no accompanying
neural tissue and thus, no neurological deficit. The fluid
filled sac may be covered by intact skin in which case
surgery may be delayed.
Myelomeningocele
This constitutes the most severe form of dysraphism.
Etiology
Both genetic and environmental factors play a role in
etiology. Recurrence risk after birth, of one affected child
is 1.5 percent and increases to 5 percent after two affected
siblings. Folic acid deficiency is believed to play a role
and some recent studies suggest that daily administration
of folic acid around conception and early gestation,
reduces risk of neural tube defects. Valproic acid given
during pregnancy may increase risk.
Prenatal Diagnosis
Alpha-fetoprotein (AFP), a component of fetal CSF, leaks
out through the open defect and reaches high levels in
amniotic fluid. Its level in amniotic fluid thus serves as an
indicator of dysraphism. False positive and false negative
rates of this test are 0.5 percent and 2.5 percent respectively.
Besides, maternal serum AFP is also elevated in the 2nd
trimester and this serves as a good screening test.
Myelomeningocele can be diagnosed by ultrasound in
pregnancy.
Clinical Features
A sac like cystic midline structure is present on the back,
covered by a thin membrane which may leak. It may be
located anywhere along the neuraxis, but about 75 percent
occur in the lumbosacral region. Neurological deficit is
maximum with thoracic and high lumbar lesions. A variety
of problems are encountered: e.g. variable degrees of lower
motor neuron paralysis of the lower extremities, sensory
loss in the perineal area and lower limbs, sphincter
disturbance and neurogenic bladder and bowel.
Deformities such as hydrocephalus, clubfeet and
congenital dislocation of hips may be associated.
Prevention
The prospective mother should receive 5 mg of folic acid
daily beginning at least 6 weeks before conception and
continued in the first trimester of pregnancy.
Management
Management of myelomeningocele requires a multi-
disciplinary approach. Parents must be given detailed
information about the disorder, its prognosis and options
available. The decision for vigorous treatment of severely
affected babies has to be individualized. Standard
management includes prevention of infection and timely
closure of the defect. After repair of myelomeningocele, a
shunting procedure for hydrocephalus is required in most
infants.
Management of bladder dysfunction is one of the major
problems. Intermittent catheterization, prophylactic
antibiotics, reimplantation of ureters or external drainage
of bladder are sometimes required.
Prognosis is not satisfactory. It leads to early disabilities
if untreated, and intercurrent problems occur despite
treatment.
Encephalocele
It implies a midline cranial defect with protrusion of either
meninges, or meninges with underlying brain tissue
through it. The infant is born with a fluctuant round midline
mass, protruding through the cranium which is
transilluminant and has a positive cough impulse. It
occurs most commonly in the occipital region, but frontal,
nasal or nasofrontal encephaloceles may also be seen. The
lesion may be covered with skin. Children with meningoceles
have a good prognosis, whereas those with encephaloceles
are at risk of multiple problems, specially in presence of
congenital hydrocephalus, e.g. visual problems, seizures and

mental retardation. Antenatal diagnosis is possible by
ultrasound or AFP levels. Management includes reduction
and closure of the defect and ventriculoperitoneal shunting,
if hydrocephalus is present.
Anencephaly
This is a lethal malformation, commoner in females, in
which both cerebral hemispheres are absent. It may recur
in families. The infant is born with a defect in the cranial
bones with a soft mass of rudimentary brain, covered by a
thin membrane continuous with the skin. A deformed
head, large ears and cranial transillumination provide
diagnostic clues. Most infants are stillborn or die shortly
after birth. Antenatal diagnosis is possible by ultrasound
and raised AFP levels (> 1000 ng/ml) in maternal serum
and amniotic fluid. Anencephalic pregnancies are
commonly associated with polyhydramnios and spina
bifida. A combination of folic acid, riboflavin and ascorbic
acid reduces the recurrence risk.
Holoprosencephaly
There is failure of division of the prosencephalon into two
cerebral hemispheres. Only a single lobe is present with
no sagittal division. The defect arises before 23rd day of
gestation. It occurs more commonly in infants of diabetic
mothers, congenital infections, fetal alcohol syndrome,
10.3 Degenerative Disorders of the
Central Nervous System
Degenerative disorders of the central nervous system are
an important and not infrequently encountered entity in
childhood. Degenerative brain disease (DBD) is defined
as any disorder where there is progressive damage to the
brain with or without systemic involvement. These
disorders are often familial, inherited and need to be
accurately diagnosed and classified. Most are genetic
(autosomal recessive), while few are acquired, e.g. subacute
sclerosing panencephalitis. The importance of diagnosis
of DBD is that possible prevention by genetic counseling
and appropriate intervention is likely. They are clinically
Diseases of Central Nervous System 453
trisomy 13 and 18, deletions 18p– and 13q–, ring 18 and
triploidy. Majority of patients have severe developmental
delay, spasticity, failure to thrive and seizures.
Neuroimaging techniques confirm the diagnosis.
Various combinations of median facial defects are
associated with holoprosencephalic brain. These include
cyclopia, ethmocephaly, cebocephaly and premaxillary
agenesis.
Megalencephaly
The brain weight and size are more than 2 standard
deviations above the mean for age and sex. It should be
distinguished from macrocephaly or large head which
does not necessarily mean large brain. A wide variety of
conditions may be associated with megalencephaly,
including neuronal heterotopias and migration defects.
In such cases, mental retardation and epilepsy are usually
present. A large brain may also occur with tuberous
sclerosis and neurofibromatosis, in some patients with
storage disorders such as Tay-Sachs disease and Canavan
and Alexander leukodystrophy. Megalencephaly also
occurs as a benign familial feature, affecting more males
than females. In most cases, one parent usually the father,
was also found to have a large head, suggesting an
autosomal dominant mode of inheritance.
Veena Kalra
characterized by progressively increasing neurological
incapacitation and loss of acquired milestones and
developmental events. Onset of inherited disease can occur
at any age. Failure to attain any milestones is usual, if
insult occurs perinatally. The common occurs if insult
perinatally. The common presentation is an apparently
normal or nearly normal development followed by
progressive deterioration. This deterioration often follows
specific patterns, and affects different parts of the central
nervous system initially. The progressive course is often
characteristic. The age of onset, pattern of progression of
454 IAP Textbook of Pediatrics

different neurological disease states and the age at
incapacitation provide useful diagnostic clues. A useful
clinical approach is to broadly classify them into degenera-
tions that predominantly affect gray matter versus white
matter. Eventually in both, the entire nervous system tends
to become affected and the end-stage picture of all of them
is generally similar. The initial course of the illness is crucial
and needs to be elucidated carefully. The patterns in both
gray and white matter disorders merge imperceptibly.
APPROACH TO A PATIENT SUSPECTED TO HAVE A
NEURODEGENERATIVE DISEASE
Useful Questions
Till what age was the child normal; type of onset-acute/
insidious/chronic; any precipitating factor; family history:
X-linked inheritance–Menke’s, Lesch-Nyhan, Hunter;
course–progressive/static/improving; development
status prior to onset of symptoms; specific symptoms:
cognition, seizures, behavioral disturbances, speech and
language (gray matter), tone changes, ataxia, gait
difficulties (white matter), visual/hearing problems
(white/gray matter); symptoms pertaining to other
systems and syndromes.
Physical Examination
Head circumference; facies; hair; eyes; stature;
hepatosplenomegaly; cardiac dysfunction; hyperacusis,
hearing loss; and hernia.
The gray matter disorders are characterized by
seizures, progressive cognitive or intellectual deterio-
ration, loss of recognition, visual and hearing impairment
which is central in origin rather than of end-organ type.
Different types of variably severe seizures characterize
the early phase of the disease. Motor ability is preserved
better and till later in the course of the diseases. Spasticity
is not very severe (Table 10.3.1).
In white matter degenerations, characteristic early
symptoms include progressive increase in tone, variable
spasticity or rigidity associated with brisk tendon jerks
and clonus. In older children, gait disturbances herald
the onset along with spasticity. Seizures are usually not
an early feature. Dementia and loss of socioadaptive
milestones occur late in the course. Fundus examination
to look for changes in the optic nerve and retina are
frequently useful to distinguish white matter from gray
matter disorders. Advanced stages do not present clear-
cut distinctive features. Presence of associated
organomegalies, large head, hyperacusis, skin
pigmentation, urine and body odor and physical stigmata
may prove useful clues.
Investigations
Clinical manifestations are often variable and one has to
resort to detailed investigations for precise diagosis.
The important investigations include: EEG–back-
ground changes or spike and sharp waves are more often
associated with gray matter disorders. CT scan reveals
white matter changes suggestive of leukodystrophies.
Characteristically, the central white matter is prominent
with arborizing tentacles towards the periphery. Basal

TABLE 10.3.1: Clinical features of gray and white matters diseases

Gray White

Dementia Early Late

Seizures Early and prominent Late
Disturbed tone, gait, reflexes Uncommon and late Most prominent feature
Basal ganglia signs and symptoms Present Absent
Retinitis pigmentosa May or may not be present Absent
Imaging (preferably MRI) Identifies cortical atrophy, Good diagnostic yield for white matter
Good for diseases of basal ganglia, disease, demyelinations
cerebellar atrophies and mito-
chondrial disorders
Electro retinogram (ERG) May be abnormal (NCL) Normal
VER Usually normal Abnormal BERA, Amp of V, Wave III-IV,
BERA interpeak latency

ganglia changes are seen in Wilson, mitochondrial
disorders, Fahr’s syndrome, migration disorders etc.
Nonspecific atrophy is a common observation.
Choice of Investigations
Gray matter disease: Bone marrow for storage cells; arterial
blood CSF lactate and pyruvate for organic aciduria inborn
errors of metabolism, mitochondrial disorders; urine
copper, serum ceruloplasmin in suspected Wilson disease;
hair microscopy; skin conjunctival, rectal biopsy or
lymphocytes; enzyme analysis in leukocytes, skin
fibroblasts or tissue–lysosomal storage disease; urine
oligosaccharides, skeletal survey and specific lysosomal
enzymes; CSF antimeasles antibodies for SSPE; HIV.
White matter disease: Urinary metachromatic granules,
arylsulfatase A, B and C in parents and patients, conduction
velocity in peripheral motor and sensory nerves; plasma-
very long chain fatty acids (VLCFA) for
adrenoleukodystrophy; N-acetyl aspartic acid in urine for
Canavan disease; galactosylceramidase for Krabbe disease.
White matter changes are generalized in meta-
chromatic leukodystrophy and infantile form of Krabbe’s
disease. The X-linked variety of leukodystrophy called
10.4 Seizure Disorders in Children
A seizure is defined as a sudden, paroxysmal electrical
discharge from the central nervous system resulting in
involuntary, motor, sensory or autonomic disturbances
with or without alteration in sensorium. It is a common
symptom in childhood practice. The manifestation of the
seizure depends upon the threshold of the brain to manifest
a clinical seizure. The age and neurodevelopmental
maturity status determine the clinical manifestations and
type of seizure disorders encountered.
Magnitude
Almost 5 percent of children are at risk of experiencing a
seizure. Half of them encounter the first seizure in infancy.
Prevalence is greater in the neonatal period (almost 1% in
term and 20% in preterm). In infancy, febrile convulsions
are the most frequent form.
Diseases of Central Nervous System 455
adrenoleukodystrophy has white matter changes that are
more marked round the occipital horns. Evoked responses–
visual and brainstem auditory evoked response—provide
help in distinguishing gray and white matter disorders.
Gray matter storage diseases may be identified by specific
vacuoles in circulating lymphocytes and bone marrow.
Macular changes in the eye, identification of abnormal
storage material in the brain, rectal ganglia, bone marrow
and various organs are useful clues. Leukodystrophies
may reveal abnormal myelin and staining patterns in the
Schwann cells, in peripheral nerves, and in the urinary
sediment in metachromatic leukodystrophy. Enzyme
determinations from white blood cells and fibroblast are
useful to identify etiology of degenerative brain diseases
definitively.
Treatment
Most of them can only be managed symptomatically as
course is relentless. Specific treatment is present only in a
few conditions, e.g. Wilson disease, adrenoleuko-
dystrophy, Leigh disease, Menke’s disease. SSPE and HIV.
Enzyme replacement (Gaucher disease) and gene therapy
are possible approaches to treatment.
Veena Kalra
Etiology
Seizures can be provoked by intercurrent events like
dyselectrolytemia, hypoglycemia, hypocalcemia, hypoxia
and other metabolic disturbances. Common causes of
childhood seizures are listed in Table 10.4.1.
EPILEPSY
It is important to identify provoked seizures as they may
not require long-term anticonvulsant treatment. Seizures
unprovoked when recurrent, are termed, epilepsy. Seizures
may be classified according to: (i) the age at which they
present (neonatal seizures, seizures of infancy, seizures
occurring in childhood), (ii) the type of seizure (gene-
ralized or partial), and (iii) underlying etiology (idiopathic
or symptomatic).
456 IAP Textbook of Pediatrics
TABLE 10.4.1: Common causes of childhood seizures
Simple febrile convulsions
Infections of the central nervous system
(i) Acquired bacterial meningitis, tuberculous meningitis, aseptic
meningitis, encephalitis, cerebral malaria, tetanus, mumps encep-
halopathy, measles encephalopathy and Reye's syndrome.
(ii) Intrauterine infections.
Postinfectious or postvaccinal encephalopathy
Following pertussis vaccination, subacute sclerosing panencep-
halitis, postmeasles encephalopathy and chickenpox encepha-
lopathy, disseminated encephalomyelopathy.
Metabolic causes
Dehydration, dyselectrolytemia, acidosis, alkalosis, hypocalcemia,
hypomagnesemia and inborn errors of metabolism.
Space occupying lesions in the brain
Neoplasm, brain abscess, tuberculoma, cysticercosis.
Vascular
Arteriovenous malformations, intracranial thrombosis or hemorrhage
and consumptive coagulopathies.
Congenital malformations, migration defects.
Miscellaneous causes
Residua of birth trauma and birth asphyxia, heat stroke, acute brain
swelling, poisoning, lead encephalopathy, hypertensive
encephalopathy, breath holding spells, gray matter degeneration
and storage disorders.
Drugs and poisons
Toxic doses of phenothiazine, salicylate, diphenylhydantoin,
strychnine, carbon monoxide etc.
NEONATAL SEIZURES
Neonatal seizures are distinct from seizures occurring in
childhood. Incomplete myelination, lack of neuro-
transmitter, poor spread of epileptiform discharge and
lack of brain maturation result in atypical and poorly
organized seizures in the newborn. The etiology,
management, utility of investigations, choice and duration
of anticonvulsant therapy are also distinct in the newborn
period.
Clinical Profile
In the neonatal period, seizures may be atypical, bizarre,
and fragmentary. They are subtle and may present as
episodes of grimacing, blinking, frothing or apneic spells.
All of these may be missed, if the clinician is not alert. The
absence of generalized tonic-clonic seizures and the failure
of spread from one hemisphere to the other is well-known.
Unifocal or multifocal seizures present as rhythmic muscle
movements involving one or multiple parts of the body
without Jacksonian march. Tonic seizures are charac-
terized by extension of extremities and axial muscles.
These may occur in the absence of cortical discharges.
Presence of eye signs provide clue to their epileptic nature.
Myoclonic seizures are uncommon, may be erratic and
often coexist with other seizures. Clonic seizures are
uncommon in neonates.
Diagnosis of neonatal seizures requires a high
index of suspicion and knowledge about their varied
patterns. They may be confused with conditions like
jitteriness, apneic attacks, tremors and benign sleep
movements.
The EEG in neonates is an important diagnostic tool.
It may help to identify a seizure from a non-seizure state.
In neonates, all clinical seizures may not be associated
with EEG discharges because many events are subcortical.
The background activity varies with gestational age and
distinctly different patterns are observed at various
gestational ages. In neonatal seizures, discharges are not
as well defined and may be quite polymorphic. In
premature infants, the EEG findings tend to be more
stereotyped and spikes are uncommon.
Etiology
Major etiological groups of neonatal seizures are indi-
cated in Table 10.4.2.
Management
Management of neonatal seizures includes exclusion of
metabolic causes peculiar to this age by routine blood
testing for glucose, calcium, electrolytes and magnesium
and also exclusion of hypoxic, infective, neurometabolic
TABLE 10.4.2: Major etiological groups of neonatal seizures
• Hypoxic ischemic encephalopathy, birth trauma
• Intracranial hemorrhage
• Metabolic—hypoglycemia, hypocalcemia (early/late onset),
hypomagnesemia, pyridoxine dependency and deficiency, inborn
errors of metabolism of amino acids, carbohydrate metabolism,
organic acids and urea cycle
• Structural malformations
• Infections, bacterial meningitis, intrauterine infections, brain
abscesses, septicemia
• Drug withdrawal—sedatives, anticonvulsants, narcotics
• Genetic/familial
• Miscellaneous, unknown
 Diseases of Central Nervous System 457

pathology. Other metabolic causes should be simul- or depending upon the cause identified and presence of
taneously investigated. Therapy algorithm should include brain damage.
0.5 gm/kg IV of 10 percent dextrose followed by 5 ml/kg
of 5 percent calcium gluconate IV to control seizures. If no SEIZURES OF INFANCY AND CHILDHOOD
response, then phenobarbitone in a dose of 20 mg/kg of Seizures of infancy and childhood commonly include
IV may be given. Diazepam in a dose of 0.3 mg/kg of IV • Febrile convulsions
should be used for immediate control of seizures only. • Infantile spasms
The subsequent therapy depends on the cause identified. • Age dependent epileptic syndromes (Refer Table
Neonates with hypoglycemia or hypocalcemia should 10.4.3)
receive appropriate metabolic correction and maintenance • Seizures due to other causes.
therapy.
FEBRILE SEIZURES

Maintenance Therapy Febrile convulsions are generalized, tonic-clonic, brief and

Neonates with nonmetabolic seizures, or metabolic
seizures that fail to respond to calcium, glucose,
magnesium require anticonvulsant drug maintenance
therapy. Phenobarbitone in a dose of 3 to 5 mg/kg/day in
1 to 2 divided doses is the preferred anticonvulsant in
neonates. The duration of therapy is variable depending
on normalcy of neurodevelopment, seizure control;
usually 3 months is enough. Therapy may need to be
prolonged up to 2 years if seizures remain uncontrolled
self-limited events that occur in the presence of fever and
in absence of underlying neurological diseases. They
generally occur between 6 months to 5 years of age, rarely
last more than 15 minutes. Permanent sequelae are
uncommon. A genetic predisposition is often observed.
They may be classified as simple or complex febrile
seizures. Patients who transgress the above mentioned
criteria are termed complex febrile seizures. Risk of
subsequent afebrile seizures, partial complex seizures or
epilepsy is enhanced if the seizures were atypical,

TABLE 10.4.3: Classification of epilepsy

Generalized Localized
Generalized epilepsy may be i. Simple partial with elementary
i. Tonic-clonic (grand mal) sympotms and no impairment
ii. Tonic, clonic of consciousness with
iii. Absence, petit mal a. motor, b. sensory, c. autonomic, or
iv. Atonic, akinetic (minor motor) or d. mixed symptoms.
v. Bilateral epileptic myoclonus. ii. Complex partial seizures may be associated with
automatisms and impaired consciousness.
Syndromes Syndromes
• Idiopathic age related i. Benign childhood focal epilepsy
i. Benign neonatal convulsions with centrotemporal spikes or Rolendic epilepsy
ii. Childhood absence ii. Epilepsy with occipital paroxysms
iii. Juvenile absence iii. Juvenile myoclonic epilepsy, etc.
iv. Grand mal seizures on awakening
v. Generalized idiopathic
• Cryptogenic Symptomatic
i. West syndrome (infantile spasms) i. Chronic progressive epilepsy
ii. Lennox-Gastaut syndrome, ii. Epilepsia partialis continua.
epileptic encephalopathies iii. Seizures with temporal, frontal,
iii. Myoclonic astatic seizures parietal or occipital lobe mode
iv. Myoclonic absences. of presentations.
Undetermined syndromes
i. Neonatal seizures
ii. Severe myoclonic epilepsy of infancy
iii. Epilepsy with continuous spike waves during slow wave sleep
iv. Acquired epileptic aphasia.
458 IAP Textbook of Pediatrics
associated with neurodevelopmental delay, family history
of epilepsy, etc. Interictal EEG abnormalities are observed
in a small proportion.
Role of Lumbar Puncture
A diagnostic lumbar puncture is indicated if a neuro-
infection is suspected or in infants experiencing the first
episode of febrile seizures within the first year. In recur-
rent febrile seizures, a lumbar puncture is not necessary.
Any febrile illness with temperature more than 38ºC
can precipitate a seizure. The quickness of rise of tem-
perature is an important factor. Certain fevers have greater
predilection to precipitate a convulsion. Most febrile
seizures occur within the first 2 to 3 days of fever. A genetic
predisposition is strongly observed. The empiric risk of
febrile seizure after one affected child is 10 percent; it rises
to almost 50 percent if one parent had febrile seizure. Most
studies suggest a dominant mode of inheritance with
reduced penetration.
Presence of abnormal neurodevelopment, family
history of epilepsy or persistent neurological deficit should
arouse suspicion of a more sinister process. Subsequent
febrile seizures and epilepsy in later years are more
common in this group, and continuous prophylaxis may
become necessary.
Treatment of a Febrile Convulsion
This includes treatment of fever, management of the acute
episode and prophylaxis against future recurrence.
Treatment of the acute fever includes frequent monitoring
of temperature, use of antipyretics, and hydrotherapy.
Control of seizures can be achieved with diazepam,
lorazepam, etc. Acute treatment involves use of diazepam
by the intrarectal or intravenous route in a dose of 0.3 mg/
kg/dose.
Prophylaxis Against Recurrences
Prophylaxis may be intermittent, during acute febrile
episodes or continuous prophylaxis with anticonvulsant
drugs if intermittent prophylaxis fails and risk factors
suggest possibility of future epilepsy.
Intermittent Prophylaxis
Febrile convulsions are best prevented by intermittent
prophylaxis with diazepam or lorazepam. A solution of
diazepam in a dose of 0.3 mg/kg given twice to thrice daily
for the first 3 days of fever is currently recommended. It
reduces seizure recurrence risk by almost 80 percent. The
benefit is comparable to that observed by continuous daily
prophylaxis with either phenobarbitone or sodium
valproate. The added advantage is reduction of side effects.
The long-term benefit on subsequent afebrile seizures is not
clearly known. Studies with oral intermittent medication
with lorazepam, clonazepam or clobazan suggest similar
benefit. Lorazepam may be better because of longer duration
of action and less sedation.
Continuous Prophylaxis
Phenobarbitone in a dose of 3 to 5 mg/kg/day was the
conventional practice. It reduced recurrence by 80 percent.
Side effects like learning disabilities and hyperactivity were
encountered in almost 20 percent making it an
unacceptable initial choice. Sodium valproate is equally
effective. Phenytoin and carbamazepine have no proven
benefit for febrile convulsion prophylaxis.
The optimal duration of treatment is at least one year
seizure-free or till the age of 5 years. Continuous
prophylaxis may be reserved for patients who do not
respond to intermittent prophylaxis, or have associated
mental retardation, presence of atypical complex febrile
seizures and family history of epilepsy. The choice of
intermittent or continuous prophylaxis should be
individualized on patient's risk factors and acceptance of
occasional febrile seizures.
INFANTILE SPASMS, WESTS SYNDROME
Infantile spasms (Salam seizures) refer to massive brief
flexion or extension spasms that occur usually in early
infancy. They occur in clusters either before sleeping or
during early waking hours. The contractions are often
severe and may be few to several hundreds in a day.
Neurodevelopmental retardation may be present before
or may follow. They occur in early infancy and are often
refractory to the standard anticonvulsant drugs. On follow-
up, the spasms either stop completely, continue to occur
or change their pattern and frequency. Most of the patients
have variable degrees of mental and developmental
retardation. The EEG has a chaotic background with spikes
and slow waves. The spikes often exceed 200 microvolts—
hypsarrhythmia. In certain variants, a definite slow wave
background is observed. The outcome in these categories
is often worse.

Etiology
It may be idiopathic, cytogenic or symptomatic. A wide
variety of pre-, peri- and postnatal insults are implicated.
The most frequent associations include hypoxic ischemic
encephalopathy (HIE), intrauterine infections, extreme low
birth weight, structural/migration defects and genetic
syndromes. Cardiorespiratory arrest and neurometabolic
defects have also been implicated. Neuroectodermatosis is
an important entity to exclude. The correlation between
infantile spasms and vaccines particularly do not indicate
any etiological role of the latter. It is probably an age coinci-
dence of two independent factors.
Management
Infantile spasms often respond to use of ACTH or corti-
costeroids. The dose and schedule of use is not
unanimously accepted. A course of 2 to 12 weeks is
recommended. ACTH gel, 40 units intramuscularly daily
for first two weeks followed by decreasing frequency of
injections up to 12 weeks appears a rational choice. Oral
corticosteroids produce almost similar benefit, at lesser
cost. Pyridoxine is found useful in a few selected patients.
Anticonvulsant drugs like phenobarbitone, carbama-
zepine, and phenytoin are usually ineffective. Valproic
acid and benzodiazepines including clonazepam,
clobazam, and nitrazepam are useful. Vigabatrine is
emerging as a good initial choice in intractable infantile
spasms and especially in spasms due to tuberous sclerosis.
Coexistence of other seizure types warrants use of other
antiepileptic drugs.
The outcome frequently depends upon etiology and
symptomatic cases have a worse prognosis. Some patients
are quite intractable. Delayed development and mental
retardation are commonly observed in children with
infantile spasms. On follow-up, other types of seizures
may be observed.
EPILEPSY IN CHILDHOOD
Epilepsy can be defined as recurrent seizures of neuro-
logical origin. It may be idiopathic, symptomatic or
cryptogenic. Epilepsy is essentially a clinical diagnosis; a
careful, detailed, sequential account of fits remains the
cornerstone of diagnosis. A clear witnessed account is
extremely useful. Clinical examination should include
detection of neurological signs, focal deficits, raised
intracranial pressure, stigmata of neurocutaneous syndro-
mes, neurometabolic disorders, systemic abnormalities
and dysmorphic features. Hyperventilation test should
be done if absence attacks are suspected.
Diseases of Central Nervous System 459
Childhood epilepsy is a frequently misdiagnosed
condition. It is confused with breath holding spells, night
terrors, syncopes, vasovagal attacks and cyanotic spells.
Childhood epilepsy can be classified as indicated in
Table 10.4.3 and may occur due to a variety of etiological
factors.
Almost all structural malformations, mental retar-
dation, delayed neurodevelopment, gray/white matter
diseases, neurometabolic disorders and some systemic
diseases may produce epileptic fits. Besides, neuroinfec-
tions, neuroinfestations (Taenia solium), migration
abnormalities also result in convulsions. Aftermath of
acute infections, hypoxic states and delayed neuro-
development states are frequent causes. Drugs, toxins, lead
poisoning and organ failures may all produce seizures.
Investigations
Investigations aim to confirm the occurrence of a con-
vulsion, distinguish it from nonconvulsive states and
establish the cause. Important investigations include the
following:
1. Electroencephalography: EEG helps to document
paroxysmal electrical dysrhythmias, to lateralize or
localize underlying structural lesions and determine the
background rhythm. It is also useful in classification of
epilepsy and epileptic syndromes in childhood.
2. Video EEG helps to correlate clinical ictus with EEG
and also record interictal events. It has utility in pre-
surgical work-up of epilepsy patients and also in dis-
tinguishing true from pseudoseizures.
3. Imaging techniques are indicated to identify a possible
underlying anatomical lesion especially in partial seizures,
seizures with focal neurological deficits and raised
intracranial pressure. Magnetic resonance imaging is
superior in identifying structural and migration defects.
Functional scans now available include PET, SPECT,
HmPAO, etc. These help in identifying hypo- and
hypermetabolic zones and correlate functional changes
with anatomic imaging.
4. Specific tests to exclude metabolic causes include blood
sugar, calcium, arterial pH, plasma amino acid screen,
and ammonia.
PRINCIPLES OF ANTICONVULSANT THERAPY
The ideal goal in the treatment of epilepsy is complete
control. If this is not attainable then a reduction in
frequency with minimal side effects is the desired goal.
The following broad principles are useful.
460 IAP Textbook of Pediatrics

• Identify the existence of seizures and its type accu-
rately so that proper drug can be selected.
• Initiate treatment with a single drug, which is least
toxic, easy to handle, acceptable and economically
affordable. Change to an alternate single drug before
trying polytherapy.
• Increase the dosage to maximum tolerated level or
optimal blood concentration before adding a second
drug.
• Achieve a steady state of the drug by using at least
4 to 5 times the half life of dose.
TABLE 10.4.4: Antiepileptic drugs in childhood epilepsy
Drug-preparation Indications Dose
Choice of drug in various types of seizures, are indi-
cated in Table 10.4.4. Drug doses and the number of daily
doses should be determined by the half life of the
drug.
Blood levels are not routinely required. They are useful
to check compliance, to determine change in doses of
drugs and to confirm suspected toxicity.
Regularity and compliance is the pillar of success of
epilepsy therapy.
Duration of therapy needs to be individualized as there
is no unanimity in literature. Seizures that are easily
Half-life Side effects

Carbamazepine (tab) 100, Partial, tonic- 10–30 mg/kg/day. 13–18 hr Relatively safe. Gastrointestinal
200, 400 mg (slow release clonic, atonic, Start with low doses symptoms, hepatitis, skin rash, bone
preparations) akinetic marrow depression (initial phase
only).
Sodium valproate 5 ml Broad spectrum 20–30 (up to 80) 7–10 hr Nausea, vomiting, sedation, weight
200 mg and 200, 500 mg mg/kg/day in 3 gain, and hair loss.
tablets. divided doses Idiosyncratic/toxic hepatic damage;
potentiates sedatives and,
barbiturates.

Phenobarbitone 15,30,60 mg Tonic-clonic, 5 mg/kg single 20–80 hr Drowsiness, hyperkinesia,

tablets akinetic, partial, daily dose dependency
febrile, seizures

Diphenylhydantoin Tonic-clonic, atonic- 5 mg/kg in one or up to 20 hr Hirsutism, gum hyperplasia. Skin

(Dilatin, Eptoin) akinetic two divided doses rash, rickets, megaloblastic anemia.
100 mg tablets Toxic symptoms—nystagmus,
ataxia, diplopia, drowsiness,
increased seizures.

Ethosuximide (Zarontin) Absence attacks 20–25 mg/kg in two 4–30 hr Photophobia, decreased
syrup, 250 mg/ml divided doses WBC, nephrosis, rarely
blood dyscrasia.

ACTH gel Inj. Myoclonus, West’s 20–40–100 units/ Hypercortisolism. Tendency to

(Synacthen) syndrome day for 4–6 weeks. infections.
Taper dose over 3
months.
Prednisolone Myoclonus 2 mg/kg/day – –

Nitrazepam 5,10 mg Myoclonus— 0.5 mg/kg/day in 2 – Excessive sleep, salivation,

tablets adjunctive therapy. divided doses hypotonia, ataxia

Clonazepam (Rivotril) Atonic, akinetic 0.03–0.1 mg/kg/day – Somnolence, hypotonia,

0.5, 1 and 2 mg tablets Mixed absence— in 3 divided doses hypersalivation
adjunctive

Clobazam (Frisium) Add-on drug for- 0.5 mg/kg/day Long. Single daily Less than other benzodiazepines.
5, 10 mg tablets Myoclonus, partial dose
seizures, genera-
lized seizures

controlled, without underlying structural lesion, neuro-
logical deficit or mental retardation generally need a 2 to 3
years seizure-free course. Seizures that are intractable,
juvenile myoclonic epilepsies, seizures in retarded
children and post-traumatic seizures merit long-term
anticonvulsants. Inflammatory granulomas (neuro-
cysticercosis) may not require long-term anticonvulsants.
Almost 80 percent of childhood epilepsies respond to
conventional antiepileptic drugs if the appropriate agent
is used optimally. Careful appraisal and re-evaluation is
necessary in the intractable patients.
In such patients, there is a role of newer antiepileptic
drugs. With greater precision in identification of anato-
mical sites and improved surgical techniques, epilepsy
surgery is gaining a more important place.
Guidelines regarding choice of antiepileptic drugs in
childhood epilepsy are depicted in Table 10.4.4.
Prognosis
Once the diagnosis is made and treatment initiated it is
imperative to stress regularity of treatment. Drug dosage
may be adjusted as per requirement. The possible need of
other anticonvulsants during course of therapy should be
explained. A seizure-free period of 2 to 3 years is considered
adequate and therapy may be gradually tapered over 3
months. Prolonged therapy more than 3 years is required
if seizures have tendency to recur. Recurrence risk is higher
if onset of epilepsy is early, seizures are difficult to control,
seizures are associated with mental retardation or neuro-
logical deficit, and certain specific types of epilepsies. The
prognosis of childhood epilepsy in the rest is good. A
normal lifestyle should be encouraged and optimism in
parental attitude fostered.
STATUS EPILEPTICUS
Status epilepticus is defined as persistence of a seizure for
more than 10 minutes or recurrent seizures without gain
of consciousness. It is a common neurologic emergency.
Prompt medical treatment is required to reduce mortality
and limit the morbidity that accompanies it as a result of
irreversible cerebral damage.
Status epilepticus may occur as a first presentation of
a seizure disorder in the lifespan of epilepsy or
neurologically ill patients, or due to intercurrent illnesses
like inflammatory, traumatic, hypoxic or metabolic causes.
Drug withdrawal is an important precipitant. The cause
may remain undiagnosed. Persistent and prolonged
Diseases of Central Nervous System 461
seizure activity causes cerebral edema, hypoxia,
hyperthermia, hypoglycemia and vasomotor instability.
Respiratory depression may ensue from involvement of
respiratory center, or from drugs used for seizure control.
Vomiting and aspiration of secretions also increase
morbidity. Treatment should take precedence over
investigation of cause.
Management
Patients should ideally be hospitalized, an intravenous
line established with 10 percent dextrose and diazepam
0.3 mg/kg given intravenously. It is lipophilic, crosses
the blood-brain barrier and has a quick onset of action by
potentiating the GABA pathways at the postsynaptic
cortical receptors. If seizures do not stop within 5 minutes,
a second dose may be repeated. The half-life is short and
seizures may recur. The more preferred benzodiazepines
include lorazepam 0.1 mg/kg and have added advantage
of prolonged duration of action. Midazolam can also be
used, and it causes lesser respiratory depression. The
benzodiazepines should be followed by intravenous
phenytoin in a dose of 20 mg/kg to maintain prolonged
seizure control. Rate of administration should not exceed
1 mg/kg/minute. If seizures remain uncontrolled,
phenobarbitone 20 mg/kg/intravenous may be used at a
rate of 1 mg/kg/minute.
Intravenous dextrose, mannitol to reduce brain edema,
care of body temperature and prevention of aspiration
and injury are additional measures that should be
attended to.
Noncontrol of seizures with the above regimen of
therapy necessitates other aggressive approaches. The
choice depends on availability of drugs, ventilatory
support and monitoring facilities. Diazepam infusion in
a dose of 0.01 mg/kg /minute may be used in gradually
increasing dose till a maximum of 0.03 mg/kg/minute or
till seizure control. Maintain a seizure-free state for 10–12
hours following which the dose may be tapered.
Midazolam infusion, may be used alternatively.
Thiopental 4 mg/kg intravenously or as a slow infusion
may be used till seizure control. Ventilatory
support, respiratory and hemodynamic monitoring are
essential.
Mortality and sequelae are determined by etiology of
status epilepticus, adequacy and promptness of therapy
and presence of secondary complications. Mortality ranges
from 10 to 18 percent and morbidity is even higher.
462 IAP Textbook of Pediatrics

10.5 Infections of the Central

Nervous System
Veena Kalra

Infections of the central nervous system are fairly common

TABLE 10.5.1: Etiology agents and initial empiric antimicrobial
in pediatric practice. The clinical profile is protean. A high regimens for bacterial meningitis in various age groups
index of suspicion of the treating physician is essential to
make an early diagnosis. The need for early diagnosis is Age group Common bacterial Initial antibiotic
pathogens regimens
imperative. Potent antibiotics have reduced mortality, but
do not prevent sequelae specially if therapy is delayed. Newborn Escherichia coli Ampicillin plus
The newer rapid diagnostic tests and imaging modalities Klebsiella pneumoniae aminoglycoside
Listeria monocytogenes or cefotaxime
have improved holistic management of children with Enterococcus sp.
neuroinfections. Salmonella sp.
Infections of the central nervous system can be broadly 4–12 weeks H. influenzae Ampicillin plus either
classified into: S. pneumoniae cefotaxime
• Meningitis—acute, subacute or chronic Group B Streptococcus or ceftriaxone
• Encephalitis and infective encephalopathy Listeria monocytogenes
• Cerebral abscess, granulomas, parasitic infestations 12 weeks H. influenzae Ceftriaxone or
• Miscellaneous and older S. pneumoniae cefotaxime or
N. meningitidis ampicillin plus
MENINGITIS chloramphenicol

Meningitis may be:

a. Acute—Bacterial, viral
b. Subacute or chronic—Tuberculosis, fungal, parasitic,
neoplastic, and chemical.
c. Partially treated
Etiology
Common etiologic agents of acute bacterial meningitis
vary with age (Table 10.5.1).
Acute bacterial meningitis, a major cause of morbidity
and mortality in young children, occurs both in epidemic
and sporadic pattern. It may follow septicemia, apparently
trivial illness such as upper respiratory tract infections,
otitis media, pyoderma and minor head trauma. Patients
with diminished host resistance as in diabetes mellitus,
malignancies and patients on immunosuppressive drugs
are more susceptible to develop meningitis.
The World Health Organization (WHO) has estimated
that annually bacterial meningilis causes at least 1.2
million cases worldwide and of those 135,000 deaths.
Neisseria meningitides, Hemophilus influenzae type b (Hib)
and Streptococcus pneumouiae are the triad responsisble for
more than 80 percent of all cases.
Bacterial Meningitis
Bacterial meningitis in the postneonatal age is commonly
caused by N. meningitidis, Streptococcus pneumoniae and H.
influenzae. However, any organism can produce
meningitis. Patients with VP shunt, prolonged hospital
stay, immunocompromised hosts, post-lumbar puncture
or post-trauma patients may have diverse etiology. While
most of the meningitis occurs in sporadic pattern,
epidemics are reported most frequently with H. influenzae
and N. meningitidis.
Bacterial meningitis may follow septicemia, or a septic
focus in the skin, lungs or bones. Trauma, pilonidal sinus,
fracture base of skull, neural tube defects, suppurative ear
and mastoid foci are recognized predisposing causes and
should always be examined for, specially in recurrent
meningitis.
Pathogenesis
The infections spread hematogenously to meninges from
the distant foci of sepsis such as pneumonia, empyema,
pyoderma and osteomyelitis or by contiguous spread.

Trivial head trauma and bacterial sepsis are impor-
tant causes.
The leptomeninges are inflammed, and exudation
occurs in the subarachnoid space and cisterns. Inflam-
matory cells are seen in the meninges over the cortex and
perivascularly. The exudates may obstruct CSF flow and
the vascular flow may be compromised by the perivascular
reaction. Cerebral edema may occur (Fig. 10.5.1).
Clinical Features
The onset is usually acute and characterized by irrita-
bility, excessive crying, vomiting, headache, neck pain or
stiffness in older children. Patients are usually febrile and
have constitutional symptoms. Alteration in sensorium is
usually not profound, and respiration may be altered. A
full anterior fontanel in a non-crying child is suggestive
of associated raised intracranial pressure. Fundus may
confirm optic disc congestion or papilledema. Seizures
are a common symptom and may occur in early or late
Figure 10.5.1: Pathophysiology of bacterial meningitis
Diseases of Central Nervous System 463
phase of the disease. This early seizures may be confused
with febrile seizures, particularly in infancy. Late seizures
usually imply secondary cerebral vascular or other
complications, specially if they are focal. Meningeal signs
include neck stiffness, Kernig's or Brudzinski sign.
Kernig's sign is elicited by flexing the hip of the patient to
90° and also flexing the knee and then extending the knee
beyond 135°, which evokes pain in the limb and limitation
of knee extension. Other features including cranial nerve
palsies, seizures, focal deficits, along with increased tone
and brisk reflexes may also be present.
Patients with meningitis should be examined for
evidence of septicemia, pneumonia, suppurative focus, or
septic foci of skin, suggestive of a Staphylococcus meningitis.
Hemorrhagic rash on the skin and hypotension or features
of shock are suggestive of meningococcal meningitis. In
meningococcal meningitis, the child develops an acute
fulminating illness, shock, hypotension, coma and even
death, unless aggressive therapy is given. Presence of
pneumonia or periotitic pathology points to a
pneumococcal etiology.
Clinical features of meningitis may remain masked in
certain situations like severe protein energy malnutrition,
immunocompromised states, malignancies and prolonged
corticosteroid therapy.
Meningitis in neonates: Bacterial meningitis in the
newborn is often asymptomatic or may have subtle clinical
features. It is a common accompaniment of septicemia and
should be suspected in every sick neonate. A lumbar
puncture is essential to rule out meningitis. The features
that should arouse suspicion are irritability, excessive
crying, vomiting, headache, neck pain or stiffness. Presence
of fever, or seizures are suggestive.
Investigations
A lumbar puncture is the single most informative test and is
mandatory where meningitis is a diagnostic possibility.
The contraindications include local skin sepsis and raised
intracranial pressure. In the event of raised intracranial
pressure, the lumbar puncture should be preceded by a
bolus of mannitol. Ideally, lumbar puncture should
evaluate opening pressure of the CSF. Cell count should
be performed within 30 minutes. Differential count of the
type of cells must be done on a stained slide and not on a
chamber while counting the cells in the CSF. Blood sugar
should be taken before performing lumbar puncture, as
the CSF sugar correlates best with blood sugar taken before
the LP. CSF biochemistry should include estimation of
464 IAP Textbook of Pediatrics
glucose and protein. Gram's and other appropriate stains,
and bacterial, viral or other appropriate cultures of CSF,
and blood should also be performed as early as possible.
In acute bacterial meningitis, grossly the CSF is often
turbid and has elevated cell counts, usually in 100's and
cells are mostly polymorphonuclear. Sugar is significantly
reduced and is often below 50 percent of the blood sugar.
Protein is elevated and Gram stain may be positive. Culture
yield can be increased by direct plating of the CSF on
culture media. Gram stain yield can be increased by
centrifuging the CSF.
The rapid diagnostic tests available to detect common
bacterial antigens include latex agglutination,
countercurrent immunoelectrophoresis or coagglutination
tests. These tests carry a sensitivity varying from 65 to 85
percent. The main advantages are that pre-treatment with
antibiotics does not alter the positivity of these and the
results are available quickly. Of these, latex agglutination
test is the most preferred. Another nonspecific test includes
C-reactive protein in CSF. This is raised in the acute phase
of acute bacterial meningitis to a greater extent, than in
viral or chronic meningitis. All these tests may help to
differentiate acute bacterial meningitis from other
etiologies. Polymerase chain reaction is being
increasingly used to detect the etiology of acute and
chronic meningitis.
Neuroimaging is useful in acute bacterial meningitis
to exclude complications like subdural effusion, brain
abscess, hydrocephalus, infarcts and identify presence
of meningeal exudates. It need not be performed in all
patients with bacterial meningitis. Ultrasound is useful
in neonates and infants with bacterial meningitis, for
determination of ventricular size and to serially
evaluate ventricular size and debris, if ventriculitis is
suspected.
Therapy
Therapy of meningitis should be prompt and be initiated
even before a definitive diagnosis is established. A lumbar
puncture with suggestive CSF cytology and Gram stain is
enough to initiate treatment.
General care It includes identification and management
of shock, cerebral edema, seizures and fluid imbalance.
Shock should be treated with fluids, and vasopressors;
respiratory resuscitation may be required. Electrolyte
imbalance may occur due to vomiting and inappropriate
secretion of anti-diuretic hormone (SIADH). Though
SIADH requires fluid restriction, management of shock
should take precedence in management, till circulatory
homeostasis is established. Increased intracranial pressure
should be treated with intravenous mannitol, given in a
dose of 1 g/kg as a 20 percent solution. The administration
should be rapid, within 20 minutes and may be repeated
every 4 to 6 hours. Therapy is usually not required beyond
24 to 48 hours. Anticonvulsant drugs are indicated, if
seizures are present. In the acute phase, diazepam 0.3
mg/kg may be given intravenously. Subsequently,
phenytoin may be given for its prolonged anticonvulsant
effect, and less influence on sensorium permitting better
evaluation of the patient. Prolonged anticonvulsant drug
use is not indicated, if seizures occurred in the early phase
of meningitis and were non-recurrent. In seizures that
occur late in the course of therapy, their causes may be
associated subdural effusion, infarct, abscess, etc.
requiring longer duration of anticonvulsant therapy.
Antimicrobial Therapy
Initial antimicrobial therapy has to be empiric, as early
treatment is essential in meningitis even before a
bacteriologic diagnosis is established. The choice of agents
depend upon the frequency of bacterial pathogen at a
particular age or in the peculiar setting, e.g. epidemic
meningitis. A rational choice based on frequency of
bacterial pathogens is indicated in Table 10.5.1.
Subsequent changes in antibiotic regime may be made
depending upon the bacterial pathogens identified or their
sensitivity patterns or clinical non-response as evidenced
by persistence of fever, meningeal signs, fresh neurological
signs, worsening sensorium or lack of CSF response.
Ampicillin is an important drug for regimes against
meningitis, specially in the first 3 months of life because
of its penetration across blood-brain barrier, and frequency
of gram-negative organisms. It should be given
intravenously in a dose of 200 to 300 mg/kg/day.
Ampicillin should be combined with an aminoglycoside
for neonatal meningitis or with third generation
cephalosporin like cefotaxime or ceftriaxone. Beyond 3
months of age, the conventionally used combination of
ampicillin and chloramphenicol is probably inferior to
the use of cefotaxime or ceftriaxone as a single drug for
meningitis. The latter should be preferred except, if
economic constraints prevent their use. Penicillin in a dose
of 3 mega units/kg/day given every 4 hours, is a good

choice for meningococcal meningitis and during its
epidemics. Meningitis with Staphylococcus, and
Pseudomonas may require specific agents like vancomycin,
and a combination of ceftazidime and aminoglycosides
respectively. Vancomycin has role in therapy of penicillin-
resistant and cephalosporin—resistant meningitis. It is
best used in combination with a third generation
cephalosporin.
The duration of therapy for meningitis is generally 10
to 14 days. Resistant gram-negative organisms, staphylo-
coccal meningitis may require longer course of treatment
up to 4 to 6 weeks. Meningococcal meningitis requires a
shorter regimen. Disappearance of clinical features,
defervescence and acceptable limits of cyto-biochemistry
of CSF should be attained before stopping the therapy.
Repeat lumbar punctures are indicated after 48 hours of
therapy, to look for cytobiochemical improvement and
bacteriological sterilization.
Dexamethasone Therapy
Studies have suggested benefit from dexamethasone in a
dose 0.15 mg/kg/6 hourly for 4 days in certain pyogenic
meningitis. The dose should be administered
intravenously 15 minutes, before the first parenteral
antibiotic dose. It results in reduction of hearing
impairment, specially after H. influenzae infections. The
benefit is mediated through reduction in cytokine mediated
inflammatory damage.
Patients with nonresponse of clinical signs, persistent
fever, recurrent seizures, focal deficits, persistent ICP rise
or vascular episodes merit detailed investigations
including CT imaging. The CT imaging helps to exclude
subdural effusion, cerebral abscess, infarct, ventriculo-
megaly and other complications.
Outcome
Acute complications include nonresolution of meningitis,
persistence of fever, subdural effusion, abscess, infarcts,
ventriculomegaly, hydrocephalus, ventriculitis, focal
neurological deficit or hearing impairment. A careful
examination including evaluation of hearing should be
conducted before discharge. Antibiotics have certainly
improved survival, but patients may have sequelae of the
disease in almost 30 percent. Common sequelae include
delayed development, mental retardation, hearing loss,
focal motor abnormalities like hemiplegia, cranial nerve
palsies and seizures.
Diseases of Central Nervous System 465
Differential Diagnosis
Differential diagnosis should include the following:
• Meningism
• Partially treated meningitis
• Acute viral and aseptic meningitis
• Acute encephalitis
• Subacute meningoencephalitis
PARTIALLY TREATED MENINGITIS
Antibiotic therapy, given to treat meningitis or inadver-
tently for other suspected infections, is known to alter the
clinical picture and cerebrospinal fluid parameters in
patients with meningitis. Adequate, intravenous
antibiotics render the CSF sterile in less than 24 hours,
alter the nature of cellular response from polymorpho-
nuclear to lymphocytic predominance, reduce the
hypoglycorrhachia within 1 to 2 days. This makes
differentiation of partially treated pyogenic meningitis
from tubercular or aseptic meningitis syndromes rather
difficult. Inadequate treatment, oral medication,
suboptimal dose of antibiotics or antibiotics that do not
permeate blood-brain barrier, may not significantly alter
the CSF cytobiochemical picture within the first 1 to 2
days. The CSF culture is often rendered sterile, even with
inadequate medication. However, if the duration of
antibiotic therapy has been longer, the CSF picture gets
altered and it becomes difficult to decipher the etiology of
meningitis, thereby creating the dilemma of partially
treated meningitis. The clinician has then to resort to other
diagnostic tests. Even after the CSF is rendered sterile, he
can resort to detection of specific bacterial antigens by
rapid antigen detection tests. Many tests are available,
e.g. latex particle agglutination test, countercurrent
immuno-electrophoresis, staphylococcal-A coaggluti-
nation test, and enzyme-linked immunosorbent assays.
A wide spectrum of bacterial antigens have to be tested
for. Latex particle agglutination is one of tests that is
sensitive, specific, easy to perform and provides results
within few hours. It can be performed on CSF, urine or
even blood. ELISA though useful, is not easy to perform at
various levels of health care. Detection of bacterial DNA
by polymerase chain reaction is extremely sensitive and
may be useful in culture negative cases.
The important differential diagnosis of partially
treated meningitis include aseptic and tuberculous
meningitis.
466 IAP Textbook of Pediatrics
Nonspecific tests like C-reactive protein, CSF lactate,
lactate dehydrogenase increase to a greater extent in
pyogenic meningitis, than viral or tubercular meningitis.
The sensitivity and specially the specificity of these tests
is limited. Despite all above tests, the clinician is often
faced with a diagnostic dilemma and difficulties in
deciding therapy options. In such situations if the onset
was acute and CSF picture supportive of acute bacterial
meningitis, antipyogenic, regime should be resorted to in
adequate dose and duration. Serial CSF cytobiochemical
changes should be monitored after 48 hours of therapy, to
observe the change in CSF cytobiochemistry. A repeat LP
is frequently informative and helps in decision-making.
In case of nonresponse clinically, and persistence of
lymphocytes in the CSF, the patient should be investigated
for other causes of subacute meningitis. Occasionally in
life-threatening situation a multipronged therapy shall
have to be given.
VIRAL MENINGITIS
Acute aseptic meningitis, is a relatively common illness
caused by a large variety of factors, often difficult to define
and identify except after exclusion of bacterial meningitis.
The precise diagnosis is often difficult as viral cultures
are not possible at most centers. The common viruses
implicated include:
• Enteroviruses—Echo, coxsackie, polio, rota
• Arboviruses
• Mumps, measles, rubella, Epstein-Barr, cytomegalo-
virus, Varicella zoster, influenza, parainfluenza
• Lymphocytic choriomeningitis
• Mycoplasma pneumoniae, leptospirosis, tuberculosis,
malignancy may also produce an aseptic meningitis
syndrome. Of these, the first two groups comprise the
major offenders.
Clinical Manifestations
The onset is usually sudden, preceded by fever of variable
degree and general prostation. Symptoms include
irritability, headache, vomiting, pain in the
neck and back and photophobia. A history of exanthems
or contact with an exanthematous patient is an important
clue. Sensorial loss is usually not severe, examination
reveals nuchal rigidity and variable neurological signs.
When there is an associated encephalitis, the clinical
features of seizures, sensorial loss, raised intracranial
pressure and focal deficits are more obvious.
Laboratory Findings
The cerebrospinal fluid contains variable (few to hundreds
cells/mm3). In the early stage, the cell response may be
polymorphonuclear but changes quickly to a lymphocyte
response. The CSF protein is slightly elevated and sugar
is usually not reduced, except occasionally in mumps
meningoencephalitis. Tuberculous meningitis may pose
a diagnostic problem. Gram’s stain and bacterial cultures
are negative. Viral cultures should be attempted on CSF,
throat and fecal specimens. Serological diagnosis is
possible, only if rising titers are demonstrated by serial
sampling at onset, and about three weeks after onset.
Treatment
Treatment includes management of symptoms, fluid
therapy and control of raised intracranial pressure.
Seizures and adequate hemodynamic and respiratory
support are indicated. The course is usually self-limited
with variable sequelae. No specific therapy is available.
Trials with corticosteroids, antiviral drugs and interferon
have not yielded satisfactory results.
ENCEPHALITIS
Encephalitis implies an inflammation of the brain and
often occurs in combination with meningitis. Cerebellar
or cord involvement may accompany encephalitis.
Involvement of the brain without a direct inflammatory
invasion is called encephalopathy and occurs in many
diverse states, e.g. typhoid, high fevers, Reye's syndrome,
exanthematous illnesses, Shigella, toxins and drug-
induced states.
Etiology
Table 10.5.2 identifies common biopathogens. Herpes
encephalitis is particularly important to diagnose, because
of therapeutic implications and severe complications, if
left untreated in the early stages of the disease. It usually
follows HSV-1 in older patients, and HSV-2 in the
newborn. The viral access is usually neurogenic in the
former and hematogenous in the latter, where it may be
associated with a severe, fulminant clinical profile.
Clinical Manifestations
Clinical features are variable in type, severity, clinical
course and eventual outcome. The onset is usually sudden
with high fever, headache, vomiting, altered sensorium
and seizures and variable neurological or motor

TABLE 10.5.2: Common pathogens for encephalitis
Viruses Nonviral
1. Inter human transmission 1. Rickettsia
Herpes—H simplex 1 and 2,
Varicella zoster, Mumps,
Measles, Pox-variola
2. Influenza 2. Mycoplasma pneumoniae
3. ARBO agents—Japanese B, 3. Bacterial—TB, others
eastern/western equine
encephalitis, etc.
4. Rabies, lymphocyte 4. Spirochetal
chorimeningitis
5. CMV 5. Fungal
6. Slow viruses 6. Protozoal
7. Dengue 7. Rare causes
Parainfectious: Typhoid, measles, mumps, Rubella, Pertussis
varicella, vaccinia, hepatitis, etc.
symptoms. The neurological deficits may reveal a static or
quickly progressive course and features of raised
intracranial pressure may supervene. Clinical picture is
variable and often difficult to distinguish from acute
bacterial meningitis. Hence, a very large number of
unexplained illnesses get clumped under this diagnosis.
Diagnosis
A carefully recorded history of the course of events, history
of exanthem, outbreaks in the community, toxic and
environmental factors is important. Recent illness may
provide clues to the possible causes. A carefully examined
CSF for exclusion of other causes listed earlier, is essential.
The CSF is generally under raised pressure, clear with a
cell count varying from zero to several hundred, with no
significant elevation of protein and normal sugar.
Virological work up is essential as in aseptic meningitis
on CSF, stool, blood and throat samples. Samples should
be referred to appropriate laboratories and should include
serological work-up. Sequential blood antibodies to
specific viral agents should be tested. ELISA for IgM on
CSF/serum should be done for arbo/enteroviruses. PCR
is an important test for viral encephalitis, specially herpes.
If skin lesions are present, scrapings should be examined
for multinuclear giant cells and brain biopsy may be
required for confirmation of herpes, identification of
specific features, and intranuclear inclusions. With the
advent of MR imaging, CT and EEG, the need for a brain
biopsy in suspected Herpes has diminished.
Diseases of Central Nervous System 467
Treatment
Symptomatic and supportive therapy is required by all
patients. Patients with severe illnesses and acutely
raised intracranial pressure, may require mannitol.
Dexamethasone in a dose of 0.4 mg/kg IV as initial dose,
followed by 0.1 mg/kg IV every 6 hours, is helpful in
reducing cerebral edema. Its potential hazard in permitting
quick viral replication has to be considered.
Specific therapy for herpes infection should be given
early, if the diagnosis is reasonably suspect. Herpes
should be identified and suspected in patients with
lateralizing clinical and EEG signs, imaging criteria
suggestive of lateralization, or if the CSF has RBC's. A
virological confirmation should not be awaited for, as early
therapy is mandatory. Treatment on suspicion of herpes
is justifiable in view of the sequelae that ensue from delay
in therapy. Acyclovir in a dose of 10 mg/kg/dose
intravenously, every 8 hourly for 10 days is preferable.
Adenine arabinoside can also be used. Corticosteroids
should be avoided in herpes.
Tuberculous meningitis: It is dealt with in chapter 9.11
on Neurotuberculosis.
BRAIN ABSCESS
A brain abscess implies a focal free or encapsulated
collection of pus within the brain substance. It may be
located anywhere, but is usually supratentorial. The source
of infection is hematogenous. Predisposing causes include
a remote septic focus, cardiac or pulmonary disease,
specially right to left shunts. Contiguous spread of
infection may result from fracture of skull bones, infections
of the middle ear, mastoid and paranasal sinuses. Abscess
may follow leptomeningitis. Immunocompromised
subjects may also be predisposed.
Etiology
The common organisms include streptococci, staphy-
lococci, bacteroides and pneumococci. Fungal infections
are less common causes. Rarely mycobacteria and
Pseudomonas pseudomallei may cause abscesses. Anaerobes
are frequent offenders.
The exact bacterial etiology is hard to define and choice
of therapy has to be based on circumstantial evidence and
common etiological pathogens. Brain abscess may be
single or multiple.
468 IAP Textbook of Pediatrics
Clinical Profile
Clinical picture can be nonspecific with fever, anorexia,
headache and vomiting. Specific symptoms include
papilledema, lateralizing signs, confusion, cranial nerve
palsies, symptoms of raised intracranial pressure, head
tilt, meningeal irritation, or alteration in sensorium. In
advanced undiagnosed cases, coma, herniation and death
may occur.
Diagnosis
Suspicion of brain abscess in a pyrexia of unknown origin
or in fever with neurological symptoms, may lead to timely
diagnosis. Peripheral blood counts have limited utility.
CSF shows a variable cytobiochemical profile ranging
from pleocytosis with elevated CSF protein to a normal
CSF with elevated pressure. Blood culture may be
noninformative. EEG may show lateralized slow waves.
Neuroimaging is the diagnostic modality of choice and
reveals a mass lesion with contrast enhancement and
perilesional edema. It is also useful for follow-up
evaluation. In cyanotic heart disease subjects, it helps to
distinguish a vascular complication from a brain abscess.
Vascular thromboses are more common below 2 years of
age, and abscess is more common beyond two years.
Treatment
The treatment includes symptomatic, supportive, and
appropriate antibiotics for an adequate period. Antibiotics
of choice include intravenous penicillin G,
chloramphenicol and metronidazole, to cover for
anaerobic infections. Specific agents like methicillin,
vancomycin may be required for resistant staphylococci,
aminoglycosides for pseudomonas; ceftriaxone can be
used. The duration of therapy varies from 4 to 6 weeks
and should be guided by radiologic resolution of the
lesion.
Surgical intervention of the abscess is indicated in case
of nonresponse to antibiotics and impending herniation
in a large abscess. Surgical approaches include aspiration
of the abscess and total excision.
NEUROCYSTICERCOSIS
Neurocysticercosis is the most common parasitic neuro-
infestation, common in developing countries, caused by
the larval stage of Taenia solium. Man is both an
intermediate and definitive host for this.
A significant increase in childhood neurocysticercosis
(NC) is clear from the abundance of reports in recent
literature.
Prevalence
One to two percent of hospital-based autopsies
reveal neurocysticercosis. CT scans on all consecutive
recent onset, unprovoked seizures in children more
than 3 years, reporting to our outpatient department for
one month period, revealed inflammatory granuloma in
approximately one-third of patients.
Clinical Varieties
NC can be classified into:
a. Parenchymal
b. Racemose
c. Meningoencephalitic
d. Disseminated
e. Rare intraventricular, throttled ventricles.
Parenchymal is the most common type, more than
95 percent , and consists of a single or few isolated lesions.
The image morphology depends on the stage of the larva.
The low attenuation cyst without perilesional edema
indicates a live parasite and may be missed, unless looked
for. A ring or disc lesion with or without perifocal edema
represents dying larvae and is the most common identified
lesion, as patients become symptomatic in this phase. Ring
lesions are characterized by enhancing margins with a
hypoisodense center. A scolex helps to identify the nature.
Perifocal edema may be variable depending upon larval
stage. While single lesions are most common in India,
multiple lesions are reported more frequently from America
and Thailand. The lesion may heal with no tell-tale evidence,
calcification or atrophy.
Clinical Profile
The disease generally occurs in a previously healthy and
neurologically normal child. Seizures are the most common
mode (more than 90%) of presentation, partial seizures
being more frequent than generalized. It is, however, not
uncommon for a single isolated granuloma to result in
generalized seizures.
Raised intracranial pressure is the other major
symptom (approx. 15%) and may result from multiple
lesions, single lesion with extensive perifocal edema,
obstructive hydrocephalus, throttled ventricles with

intense white matter edema or meningoencephalitis. The
frequency varies in different series. Neurological
examination is normal in the majority. Cranial nerve
paresis, hemiparesis or meningitis or hydrocephalus or
papilledema may be present. Less commonly associated
features include, fever before onset of symptoms, sub-
cutaneous nodules, ocular symptoms due to intraocular
cyst, and behavioral changes due to raised intracranial
pressure. Chance detection also occurs.
Diagnosis
The diagnosis is suspected from the image morphology of
the lesion. The profile, however, varies with the larval
stage and the host response. MRI imaging is more
sensitive. Important differential diagnosis include tuber-
culomas, chronic pyogenic abscess, localized encepha-
litis, seizure related vasogenic edema, vascular
malformations and rarely neoplastic cause. The real
practical difficulty in most cases is differentiating
tuberculoma from cysticercus granuloma. Evidence
supporting tuberculomas includes a size more than 20
mm, associated midline shift, irregular often thick walled
outline, absence of scolex and lack of early spontaneous
disappearance. Magnetic resonance imaging does
sharpen the diagnostic capability, by identifying live low
attenuating cyst, and by better resolution of the image
morphology. The characteristic hypointensity on T1 and
extreme hypointensity on T2W image in tuberculoma
contrasted with hypointensity on T1 and hyperintensity
on T2W in cysticercus may be useful. Despite this, the
gray zones in signal characteristics are not uncommon.
Multiple parenchymal lesions do occur and present a
severe diagnostic dilemma.
Supportive diagnostic features: The adult worm and Taenia
ova in stools are not commonly detected associations.
History of subcutaneous nodules were reported in 10
percent patients. Biopsy of the subcutaneous nodule is a
very simple and useful test.
The ELISA test (IgG/IgM) can be performed on the
serum and cerebrospinal fluid. The sensitivity and
specificity varies in different series and with the type of
lesion. In intraparenchymal solitary lesions, it has not
proven to be useful in our series.
Therapy
Treatment of seizures is recommended for at least 12 to 18
months, with a single antiepileptic drug (AED) or longer,
Diseases of Central Nervous System 469
if seizures continue. Carbamazepine or phenytoin are the
usual choices. Seizures are well controlled in the majo-
rity. The duration of AED required is under review, recent
observations suggest shorter courses may be sufficient.
Symptomatic treatment of raised intracranial pressure
with corticosteroids is recommended in the disseminated
and multiple parenchymal variety in the acute stage, 2
days preceding and 3 days concurrent with phase.
Corticosteroids are also recommended with cysticidal
drugs (5 days) to reduce side effects in single lesions with
extensive perilesional edema.
Role of Cysticidal Therapy
It has undergone considerable metamorphosis and a
categorical answer for its long-term benefit in the outcome
of NC, is awaited. Active lesions—parenchymal cysts
without inflammatory response merit therapy.
Spontaneous remission of such lesions is not expected.
Benefit in lesions with perifocal edema, and contrast
enhancement is controversial. Calcific lesions represent
inactive lesions and do not require cysticidal drugs.
Praziquantel and albendazole are the two commonly
used agents. Praziquantel is an isolated isoquinolone
pirazine which is active against the adult and larval form.
Usual therapeutic dose is 50 mg/kg/day for 15 days. A
strong inflammatory response may occur within a few
days of its administration, resulting in exacerbation of
cerebral edema and clinical symptoms. Corticosteroids
are recommended for the initial phase of therapy. The
radiological resolution was reported to be observed
partially in 73 percent and disappearance in 60 percent
after therapy.
Albendazole is an inidazol carbonic acid methyl ester,
used in a dose of 15 mg/kg/day. The duration schedule
varies from five day to a 28 days regime. A clinical
comparison between praziquantel and albendazole
reveals utility of albendazole as a better choice.
A big issue that has generated recently is, whether a
cysticidal drug is necessary at all for inflammatory
granulomas or not. Spontaneous resolution of the solitary
granulomas was observed in almost one-third. The
resolution rate was not statistically different amongst
patients who received albendazole vs controls in trials in
children.
Active forms require treatment. Presence of intraocular,
intraventricular cysts and meningoencephalitis should
be excluded before therapy.
470 IAP Textbook of Pediatrics
Long-term studies are needed to address the issue of
subsequent epilepsy, whether cysticidal treatment alters
the outcome in relation to subsequent epilepsy.
Environmental intervention is fundamental rather
than a mere treatment of patients. Eradication programs
are necessary and will result from socioeconomic
upliftment, and avoidance of open field defection. Public
education and mass treatment of human and porcine
reservoirs are necessary.
Outcome
Sequelae include seizures, mental retardation, focal
deficits, hydrocephalus, etc. Death may occur in the acute
phase, most often due to severe cerebral edema and
herniation.
For IAP- Infectious Diseases Chapter Protocol on
Pyogenic Meningitis, refer to Chapter 36.11.3, Page No.
1531.
BIBLIOGRAPHY
1. Chavez-Bueno S, McCracken GH Jr. Bacterial meningitis
in children Pediatr Clin North Am 2005;52:795-810.
2. John TJ, Cherian T, Raghupathy P. Haemophilus
influenzae disease in children in India: a hospital
10.6 Coma in Children
CR Banapurmath, Shobha Banapurmath, G Guruprasad
DEFINITION
Coma is a state from which a child cannot be aroused by
stimuli (verbal, physical, sensory, etc.) and no attempt is
made to avoid painful stimuli. It is a disorder of
arousability. The degree of response to an environmental
stimulus is reduced which is in contrast to that degree
found in sleep.
Stupor refers to a person who appears to be drowsy or in
light sleep, may be aroused by gentle stimulation and
responds to questions or commands but then lapses into
an apparent drowsy or sleep state when left undisturbed.
Neurological obtundation has similar meaning to
stupor and implies some blunting of cognition.
perspective. Pediatr Infect Dis J 1998; 179 (Suppl) S169-
S171.
3. Kanegay JT, Soliemanzadeh P, Bradley JS. Lumbar
puncture in pediatric bacterial meningitis: defining the
time interval for recovery of cerebrospinal fluid
pathogens after parental antibiotic pretreatment.
Pediatrics 2001;108:1169-74.
4. Organisation Mondiale de la Santé. Lutte contre les
épidémies de méningite á méningocoque. Guide pratique
OMS 2. WHO/EMC/BAC/98.3.1999.
5. Prober CG. Central nervous system infections. In:
Behrman RE, Kliegman RM, Jenson HB (Eds): Nelsons
Textbook of Pediatrics (17 edn) Saunders, Philadelphia:
Saimders 2004;2038-47.
6. Prospective multicentre hospital surveilance of
strepto-coccus pneumoniae disease in India. Invasive
Bacterial Infection Surveillance (IBIS) Group, International
Clincal Epidemiology Network (INCLEN). Lancet 1999;
353:1216-21.
7. Saez-LlorensX, McCracken JrGH. Antimicrobial andanti-
inflamatory treatment of bacterial meningitis. Infect Dis
Clin North Am 1999;13:619-36.
8. Tunkel AR, Hartman BJ, Kaplan SL. PRactice guideline
for the management of bacterial meningitis. Clin Infect
Dis 2004;39:1267-84.
9. Tunkel AR, Hartman BJ, Sheldon LK, Koufman BA, Ross
KL, Scheld WM, et al. Practice Guidelinse for the
Management of Bacterial Meningitis. Clini Infect Dis
2004;39:1267-124.
10. Tunkel AR, Sinner SW. Antimicrobial agents in the
treatment of bacterial meningitis. Infect Dis Clini North
Am 2004;18.
The condition is a medical emergency. The aim of
management should be to preserve life and to minimize
possibility of irreversible brain injury.
INCIDENCE
The incidence of coma in children under 16 years varies
from place to place. One recent study has recorded the
incidence to be 6 per 100,000 general population.
PATHOPHYSIOLOGY
Normal consciousness is maintained by the integrity of
certain areas in the cerebral cortex, thalamus and part of
reticular formation located in upper pons and midbrain.

Lesions affecting the brainstem, mass lesions in the
supratentorium or diffuse lesions of the cerebral cortex
may lead to disturbances of consciousness.
An alteration of consciousness could occur when there
is toxic or metabolic insult to brain; the toxin or an
alteration in homeostasis interferes with the function of
the brain. The encephalopathies occur when brain is
deprived of blood flow or oxygen or when there is infection
of the CNS.
Hypoglycemia occurs frequently as a manifestation of
metabolic and endocrine diseases and if left untreated, it
has deleterious long-term effects on the CNS.
Hypoglycemia should always be considered in the initial
evaluation of a comatose child.
Increased intracranial pressure in coma decreases the
effective cerebral perfusion pressure (CPP) of the brain.
Cerebral perfusion pressure (CPP) is measured clinically
as mean arterial pressure (MAP) minus mean intracranial
pressure (ICP) and obviously CPP tends to decrease with
systemic hypotension or intracranial hypertension with
consequent impairment in brain function.
CPP = MAP – ICP
Infants develop less intracranial hypertension (ICP)
because of sutural separation.
HISTORY
A careful history often provides clues to the diagnosis.
Acute deterioration is associated with ingestion of drugs,
cerebrovascular accidents, trauma, and metabolic
disturbance like diabetes and seizure disorders (Table
10.6.1). Previously well infants and young children dis-
covered comatose or convulsing may have suffered a
prolonged febrile convulsion and may be suffering from
early meningitis or encephalitis. In toddlers and small
children, intoxications are usually the result of accidental
ingestion, whereas in adolescents they are more frequently
deliberate.
Deterioration over days or weeks is more compatible
with CNS infection, chronic intoxication or raised
intracranial pressure. The past medical history may
provide vital clues. A family history of epilepsy or TB may
be discovered, or the report of previous stillbirths or deaths
in infancy may indicate inherited metabolic disease. An
altered state of consciousness in the newborn period
associated with vomiting, failure to thrive and seizures,
suggests an inborn error of metabolism.
Diseases of Central Nervous System 471
A child with chronic renal failure associated with
hypertensive encephalopathy, may present with coma. A
child with heart or pulmonary disease may develop coma
as a result of cerebral anoxia and ischemia. Acute
subarachnoid hemorrhage secondary to a bleed from an
arteriovenous malformation, causes sudden alteration in
consciousness.
PHYSICAL EXAMINATION
Physical examination may provide clues to diagnosis.
High fever may indicate infection. Increased respiratory
rate is often mistakenly attributed to pneumonia and may
indicate metabolic acidosis as seen in Reye’s syndrome.
The breath should be examined for odour of ketones and
for fetor hepaticus. High blood pressure is seen in
hypertensive encephalopathy associated with acute
nephritis or hemolytic uremic syndrome. The presence of
petechial skin rashes, lymphadenopathy or splenomegaly
usually indicates infection. The fundi should be examined
for papilledema and tubercle follicles. Presence of marked
pallor and bulging fontanel suggests intracranial
bleeding. Presence of petechial hemorrhages and shock
state along with coma should suggests possibility of
dengue shock syndrome. Neurocutaneous markers like
café-au-lait spots, hypo-and hyperpigmented spots should
suggest neurocutaneous syndromes like neurofibromato-
sis and, tuberous sclerosis. Presence of jaundice in a coma-
tose child should suggest fulminant hepatic failure and
hepatic encephalopathy.
Pyramidal tract signs like hemiparesis may indicate a
Todd’s paresis, focal encephalitis or localized hematoma
or abscess formation.
Paroxysmal nystagmus or conjugate deviation of the
eyes, sucking or chewing movements frequently represent
brainstem ‘release’ phenomena secondary to swelling
of the brain. Midbrain compression from cerebral shifts
causes ophthalmoplegia. It is important to note that
papilledema may be delayed or absent sign, even in
the presence of significantly raised intracranial
pressure. A bulging anterior fontanel, hypertension
and bradycardia may suggest raised intracranial
pressure.
Meningeal signs should be sought remembering that
nuchal rigidity and Kernig’s sign may be completely absent
in younger children, and in children pretreated with
antibiotics.
472 IAP Textbook of Pediatrics

ASSESSING THE DEGREE OF COMA INVESTIGATIONS

The Glasgow coma scale (GCS) is the most widely used
method for objectively grading the degree of consciousness,
although it has serious limitations in infants and young
children, since neither motor nor verbal responses to
commands and eye opening to speech can be assessed.
For young children, the modified children coma scale is
more useful (Table 10.6.2). Sequential charting of the coma
score helps the pediatrician to monitor the course of the
illness. It is more useful to record how the child actually
responds. The verbal response, ocular response and motor
response to each stimulus should be recorded.
The investigations of the child with coma should lead to
specific diagnosis and provide information which will
help to provide optimum supportive therapy.
Investigations must be tailored to the individual child’s
illness. The pediatrician should be guided by clues obtained
from the history and examination in the choice of investiga-
tions. Gastric aspirate may yield detectable drugs and
toxins. Urine may detect toxic metabolites and drugs
undetected on assay of serum (Tables 10.6.3 and 10.6.4).
In a suspected case of bacterial meningitis, a lumbar
puncture should be done. The contraindications for

TABLE 10.6.1: Causes of coma in children

Infections Trauma
Meningitis* Subdural hematoma*
Encephalitis* Chronic
Abscess Acute
Intracerebral Epidural hematoma
Subdural empyema Intracerebral hematoma
Epidural empyema Contusion and laceration
Systemic Infections Cerebral edema
Gram-negative septicemia* Electrolyte and acid-base abnormalities*
Septic shock Na+ ,Ca+, K+, Mg+, P+++
Shigella encephalopathy*
Dengue shock syndrome* Deficiency states
Thiamine
Hypoxia-Ischemia Niacin
Hypoxia* (normal cerebral blood flow) Pyridoxine
Hypoventilation Vitamin B12
Methemoglobinemia
Ischemia (decreased cerebral blood flow) Cardiac causes
Decreased cardiac output
Toxins Arrhythmias
Endogenous Valvular disease
Uremia * Generalized fall of blood pressure
Hepatic coma* Hypovolemic
CO2 narcosis Vasovagal
Porphyria Carotid sinus
Exogenous
Barbiturates* Vascular causes
Tranquilizers* Hypertensive encephalopathy*
Opiates Polycythemia
Hyperventilation Emboli
Anticholinergics Thrombosis
Vasculitis
Tumors Arteriovenous malformations
Cerebral
Posterior fossa
Others

* More frequently encountered causes of coma in children

 Diseases of Central Nervous System 473

TABLE 10.6.2: Glasgow coma scale

Response Form of occurrence Score
Eye opening Spontaneous 4
To speech 3
To pain 2
None 1
Verbal Oriented 5
Confused conversation 4
Inappropriate words 3
Incomprehensible sounds 2
None 1
Best motor Obeys commands 6
Localizes pain 5
Withdraws 4
Abnormal flexion 3
Extension response 2
None 1
Modified children’s coma scale for infants
Response Form of occurrence Score
Eye opening Spontaneous 4
To speech 3
To pain 2
None 1
Verbal Coos, babbles 5
Irritable cries 4
Cries to pain 3
Moans to pain 2
None 1
Motor Normal spontaneous movements 6
Withdraws to touch 5
Withdraws to pain 4
Abnormal flexion 3
Abnormal extension 2
None 1

Source: Trauner DA, James HE, 1985.

performing an LP are raised intracranial pressure where Ketone bodies—diabetic ketoacidosis

child may develop transtentorial herniations. Ferric chloride test, DNPH test—metabolic causes
Fundus examination for papilledema is mandatory 2. Blood investigation
before doing an LP. Decerebrate or decorticate posturing, Blood sugar
abnormalities of pupil size and reaction indicate Serum urea, creatinine
impending cerebral herniation, so LP should be withheld Serum electrolytes—Na, K, Ca and P
(Figs 10.6.1 and 10.6.2). Osmolality
Serum levels of anticonvulsants
Investigations which will facilitate supportive therapy Septic workup and complete blood counts
1. Urine examination: LFT
Color—frank hematuria in glomerulonephritis Coagulation profile
Smell—mousy odor in PKU Arterial blood gases
Microscopy—for cells, RBC casts 3. Imaging studies
pH of urine Chest X-ray and ECG
Sugar—reducing substances in diabetes CT scan, EEG, and evoked potentials
474 IAP Textbook of Pediatrics

Figure 10.6.1: A one-year-old child with TB meningitis

having decerebrate posturing and coma
Figure 10.6.2: Picture showing six years child with coma follo-
wing acute food poisoning receiving ventilatory support, eye
4. Virology studies care and clinical monitoring
Investigations which might provide a specific diagnosis
CSF examination Liver function tests
Toxicology screen Skeletal survey
Blood ammonia CT scan
Blood pyruvate, lactate MRI scan
Amino acid profile
Organic acid analysis An initial EEG provides valuable information about
Porphyrins cortical function. Focal slow waves may indicate a local

TABLE 10.6.3: Localizing the pathology

Signs and symptoms Cerebral Subcortical Midbrain Pons and medulla

Consciousness Normal or akinetic Lethargy and apathy Coma Coma

mutism (bilateral (thalamus); drowsiness
cingulate gyrus) (hypothalamus)

Respiration Normal or post- Cheyne-Stokes Central hyperventilation Apneustic or Atactic

hyperventilation apnea

Pupils Normal Small and reactive Nuclear: midposition Horner’s syndrome

and pinpoint fixed (lateral medulla)
3rd Nerve: unilateral
dilated and fixed
Pretectal: Large and
fixed

Eye movements Roving eye movements, Roving eye movements 3rd Nerve: eye down Look away from lesion
at rest or look toward or look toward and out and toward paretic side
destructive lesion and destructive lesion
away from paretic side

Doll”s eye and Present Present Absent or abnormal Absent or abnormal

Calorie stimulation response response

Motor Hemiparesis Decortication Decerebration Decerebration

(rostral pons)

lesion such as focal suppuration due to a pyogenic abscess.
Characteristic EEG findings include focal EEG signs in
Herpes simplex encephalitis.
CT scan is indicated when there are fundal changes or
other signs of raised intracranial pressure or when initial
investigations have failed to clarify the diagnosis. Real
time ultrasound can be done in infants with open fontanel.
In Reye’s syndrome, the most significant abnormalities
are elevated serum transaminases (SGOT and SGPT),
hypoprothrombinemia and hyperammonemia. If Japanese
encephalitis is suspected, a serologic diagnosis can be
made by demonstrating rising antibodies.
In dengue shock syndorme or dengue hemorrhagic
fever, 20 percent or greater increase in hemotocrit value,
thrombocytopenia and decreased prothrombin will be
seen. Definitive diagnosis is established by demonstrating
IgM and IgG antibodies.
In suspected poisoning toxicological analysis of blood
and urine is recommended. Diabetic ketoacidotic coma
must be differentiated from hypoglycemia, uremia and
metabolic acidosis. Diabetic ketoacidosis exists when
glucose is greater than 300 mg/dl.
MANAGEMENT
Sequential Management of the Comatose Child
1. A–Airway: Ensure adequate airway, place child in
lateral position gently with slight extension gently
get rid of all secretions by careful suctioning.
2. B–Breathing: Ensure patient is breathing well.
Provide oxygen. Get blood gases. Consider artificial
respiration.
3. C–Circulation: Record pulse rate, blood pressure
and assess the cardiac volume and output. Look for
signs of blood loss, shock and provide fluid bolus
followed by inotropic support, blood to be arranged.
Secure good IV access, draw blood for random blood
sugar (RBS) using glucometer, CBC, grouping and
cross- matching, electrolytes, and calcium. Reassess
every 10 to 15 minutes till cardiovascular stability
is achieved. Maintain cerebral perfusion pressure
above 50 mm Hg.
If hypotension take
(Dopamine drip, fluids)
Take Mean systolic BP
If hypertension-treat
Diseases of Central Nervous System 475
4. D–Dextrose, Drugs, Dysentery, DIC, Drug ingestion or
accidental.
5. E–Epilepsy and electrolyte disturbance: Observe for
seizures or stigmata of seizures like bitten tongue,
urinary and fecal incontinence. Control seizures.
Convulsions should be terminated as early as
possible by intravenous administration of diazepam.
The drug is given slowly in a dose of 0.3 mg/kg IV, or
diphenylhydantoin should be administered for
prolonged effect and if seizures recur.
6. F–Fever, and Febrile seizures: Check for fever, neck
stiffness, purpuric rash, look for meningococcemia.
Consider viral hemorrhagic fever and dengue fever.
7. G–Glasgow coma scale: Record response to each item
(Table 10.6.2).
8. H–Herniation: Is there evidence of coning? (Table
10.6.5). Look for hypertensive encephalopathy,
hepatic failure and Reye’s syndrome.
9. I-Increased ICP: Intracrainal BP (ICP monitoring) in
any case of coma put on ICP monitor.
Raised ICP: Treat with mannitol, frusemide, hyper-
ventilation, dexamethasone, phenobarbitone,
diazepam, pancuronium, drainage of CSF.
Infections, injury, inborn errors of metabolism,
Intussusception (early), Investigate.
10. J–Juggling with the Jigsaw puzzle, do not hesitate to
obtain second opinion.
PROGNOSIS
1. Depends on the etiology— for example, diabetic coma
(good), inborn errors of metabolism (bad)
2. Signs—Glasgow coma scale <5 (bad)
3. EEG—Reappearance of normal sleep spindles signals
recovery
4. Neurophysiological studies:
BEAR, BEVR, SEP (Somato-sensory evoked potential)
Most sensitive and reliable method
Normal SEP—Normal outcome in 93 percent of cases
Absent SEP—Bad prognosis in 100 percent of cases
Asymmetrical SEP—Associated with sequelae such
as hemiparesis.
5. Absent extraocular movements, nonreactive pupils
and hypothermia are poor prognostic signs.
476 IAP Textbook of Pediatrics

TABLE 10.6.4: Physical signs that provide clues

I. Examination of the Head:

a. Bulging fontanelle ICP, meningitis
b. Positive Macewen’s sign ICP, skull #
c. Small/large head Underlying structural CNS malformation.
d. Battle sign # base of skull.
II. Examination of the Eyes:
a. Jaundice Hepatic encephalopathy, FHF.
b. Retinal hemorrhages ICT, hypertensive encephalopathy.
c. Papilledema ICP, (Absence does not rule out CN pathology).
d. Ptosis III nerve involvement.

III. Pupils
a. Equal
Size Reaction Condition
Pinpoint Nil Opiate poisoning
Reactive Narcotic overdose
Small Reactive Metabolic encephalopathy
Midposition Fixed Midbrain lesion
Reactive Metabolic lesion
Large Fixed Atropine poisoning
Brain death
b. Pupils unequal
Dilated Unreactive III nerve palsy
Herniation
Small Reactive Horner’s syndrome

IV. Examination of face

Smell of breath
Tongue laceration

V. Examination of decubitus
Decerebrate posturing ICP
Coarse movements Brain swelling
Marked agitation Brain swelling
Petechial/Purpuric hemorrhages Meningoccemia
Hyperpigmentation Addison’s disease, hypoadrenalism

VI. Body secretions

Smell of breath Organophosphorus poisoning
Kerosene poisoning
Acetone breath Diabetic ketoacidosis
Ammoniacal odour Hepatic failure
Altered GI aspirate Stress ulcers, GI hemorrhage
Bilious aspirate Intestinal obstruction, septic ileus
Bloody urine Acute glomerulonephritis
Bloody stool Shigellosis, intussusception
Stains of blood on clothing Injury

Among children aged one year to 16 years sufferring up for one year, one-fourth of older children had a fatal
from non-traumatic pediatric coma who were followed outcome.
 Diseases of Central Nervous System 477

TABLE 10.6.5: Looking for danger signals in comatose children

Bradycardia, decerebrate posturing and periodic breathing are ominous clinical signs.
Most importantly, signs of coning should be sought.
Look for Coning:
Coning happens when brain substance is forced through a rigid hole.
i. Uncal herniation: The uncus and the temporal lobe of the midbrain is pressed against the bony tentorium.
Clinical signs:
Early: Ipsilateral pupillary changes with ptosis.
Later: Progressive IIIrd nerve palsy ipsilateral
Cheyne-Stokes respiration contralateral hemiparesis (Weber’s syndrome)
ii. Central herniation:
The cerebrum is pushed centrally through the tentorium. Initially the upper mid brain and later the pons and medulla are compressed.
Clinical signs
Early: Erratic respirations , small reactive pupils increased thumb tone, bilateral extensor plantors.
Later: Fixed dilated pupils, decerebrate posturing.
iii. Downward herniation:
Foraminal
—Cerebellar tonsils into foramen magmum (midbrain, pons, and medulla) gets compressed in same order from above
downwards

BIBLIOGRAPHY HE, Anas NG, Perkin RM (Eds). Brain insults in infants

1. Nayana Prabha PC, Nalini P, Tiroumourougene Serane
V. Role of glasgow coma scale in pediatric non traumatic
coma. Indian Pediatr 2003;40:620–25.
2. Trauner DA, James HE, Evaluation of coma. In: James
and children. Pathophysiology and management.
Orlando, Florida, Grune and Stratton 1985.
3. Wong CP, Forsyth RJ, Kely TP and Eyre JA. Incidence,
aetiology and outcome of nontraumatic coma; a popula-
tion based study. Arch Dis Child 2001;84:193–99.

10.7 Brain Tumors in Children

KS Rana

Primary brain tumors in children are a diverse group of
diseases. These are the most common solid tumors and
the second most common malignancy of childhood
following leukemia, accounting for almost 21 percent of
total childhood malignancies. Reported incidence in the
USA has varied from 20 to 50 per 1,000,000 children.
Almost 1500 new cases of brain tumors are diagnosed
annually in the United States. Incidence has increased
approximately 2 percent per year in the last 20 years. Even
the relative frequency of the type of the tumors has
changed. In the early part of 20th century, tuberculoma
was the most common intracranial tumor. Subsequent
survey stressed the preponderance of gliomas. In eighties
and early nineties, the incidence of primitive neuro-
ectodermal tumors (PNET/medulloblastoma) has
increased more than 4 percent per year. Outcome of these
tumors depends upon the histology, location, degree of
resectability, and response to adjuvant therapy. Advanced
surgical modalities like laser and microscopic operating
techniques and adjuvant therapy such as focused
radiotherapy and newer chemotherapeutic agents have
increased the life span and improved the quality of life of
these children.
PATHOGENESIS
Etiology of brain tumors is unknown. However, in the
recent years significant progress has been made in the
field of molecular genetics, implicating molecular
abnormalities in the pathogenesis of these tumors. Two
genetic abnormalities are believed to be responsible for
478 IAP Textbook of Pediatrics
the development of tumors. One is associated with the
activation or over- expression of growth- promoting factors
such as proto- oncogenes, and the other is the result of
loss or inactivation of genes that regulate or suppress cell
growth, the tumor suppressor genes.
Role of viruses in the etiology of brain tumors is
controversial. Choroids plexus tumors and ependymo-
mas express a segment of the gene related to monkey
polyoma virus (SV40) and JC virus.
Varieties of chromosomal abnormalities have been
observed in the cytogenetic analysis of brain tumors.
Astrocytomas and glioblastomas are associated with +7p,
-9p, -1p, and -17p chromosomal abnormalities and
medulloblastoma with -8p and -17p. Incidence of brain
tumors is higher in the relatives of children with these
cytogenetic abnormalities. Primary brain tumors have
increased association with genetic syndromes like
neurofibromatosis, Von-Hippel-Lindau disease, ataxia
telangiectasia and Wiskott- Aldrich syndrome. Primitive
cells have also been blamed for the origin of brain tumors
like craniopharyngiomas from the persistent remnants of
craniopharyngeal pouch and PNET/ medulloblastoma
from areas of maldevelopment. Environmental factors like
high dose radiations and immunodeficiency states like
human immunodeficiency virus infection have also been
implicated in the pathogenesis of CNS tumors.
PATHOPHYSIOLOGY
Neurological symptoms produced by brain tumors are
general and local. General symptoms are from increased
intracranial tension (ICT); that results from progressive
enlargement of tumor in the limited cranial vault,
obstruction of cerebrospinal fluid (CSF) and brain edema.
Local symptoms are due to the effects of the tumor on
contiguous areas of the brain. Small strategically located
tumor can be devastating by compressing the vital
structures. As the tumor enlarges, the intracranial contents,
primarily the ventricles are compressed compromising
CSF circulation. Compression of the large vascular
channels results in cerebral anoxia and in turn produces
vascular dilatation and a further increase in intracranial
volume and pressure. Increased intracranial pressure
further decreases cerebral blood flow when perfusion
pressure (difference between mean arterial and
intracranial pressure) falls to approximately 40 mm Hg.
Expanding mass also produces various herniations by
creating pressure gradient in different compartments.
Cerebellar tonsil herniates through foramen magnum,
uncal and diencephalons through tentorial opening and
cingulate gyrus under falx cerebri. These herniations
produce secondary brain dysfunction because of
overcrowding, stretching and rupturing of blood vessels,
edema and pressure over vital structures, notably cranial
nerves and vital centers in the brainstem.
CLASSIFICATION OF BRAIN TUMORS
Histological Classification
The WHO classification of brain tumors based on
histological criteria is depicted in Table 10.7.1.
Anatomical Classification (Table 10.7.2)
Approximately two thirds of brain tumors are infratentorial
in children between ages of 2 and 12 years, with three
fourths of these located in the cerebellum or fourth
ventricle. Supratentorial tumors seen in adolescents and
children less than two years of age include those tumors
that occur in the sellar or suprasellar region and/or in the
cerebrum or diencephalons.
Classification based on Degree of
Malignancy (Table 10.7.3)
The terms “benign” and “malignant” often are misleading
when applied to brain tumors. Malignant tumors are
usually aggressive neoplasms that have the capacity to
disseminate within and occasionally outside the nervous
system, whereas benign tumors grow more indolently.
Malignant tumors such as medulloblastomas may be
curable in up to 80 percent of children who are older than
3 years if radically removed and are not disseminated at
diagnosis. Conversely, some benign tumors can
disseminate (up to 4% of cases in low-grade astrocyto-
mas), and may be quite difficult to eradicate.
CLINICAL FEATURES
Clinical signs and symptoms depend upon tumor’s
location, size, child’s age and obstruction of CSF.
Aggressively growing tumors are associated with early
and severe symptoms, whereas initial signs and
symptoms of slow-growing tumors are subtle. Sub-
tentorial tumors, obstructing CSF pathway present with
features of raised ICT. Intra-axial masses like pontine
gliomas present with features of multiple cranial nerves
palsy. Supratentorial tumors present with seizures and
focal neurological deficit. Brain tumors in younger
 Diseases of Central Nervous System 479

TABLE 10.7.1: Histological classification of brain tumors TABLE 10.7.2: Anatomical classification of brain tumors

A. Tumors of neuroepithelial tissue Location Tumors

Astrocytic tumors:
Astrocytoma, Anaplastic astrocytoma, Glioblastoma,
Pilocytic astrocytoma, Peomorphic xanthoastrocytoma,
Subependymal giant cell astrocytoma
Oligodendroglial tumors:
Oligodendroglioma, Anaplastic oligodendroglioma
Ependymal tumors:
Ependymoma, Anaplastic ependymoma, Myxopapillary
ependymoma, Subependymoma
Mixed gliomas:
Oligoastrocytoma, Anaplastic oligoastrocytoma
Choroids plexus tumors:
Choroid plexus papilloma, Choroid plexus carcinoma
Neuroepithelial tumors of uncertain origin:
Astroblastoma, Polar spongioblastoma, Gliomatosis
cerebri
Neuronal and mixed neuronal glial tumors:
Gangliocytoma, Dysplastic gangliocytoma of cerebellum
(Lhermitte-Duclos), Desmoplastic ganglioglioma,
Ganglioglioma, Centralneurocytoma
Pineal parenchymal tumors:
Pineocytoma, Pineoblastoma, Mixed transitional tumors
Embryonal tumors:
Medulloepithelioma, Neuroblastoma, Ependymoblastoma,
PNET, Medulloblastoma.
B. Tumors of meninges
Tumors of meningothelial cells:
Meningioma, Atypical meningioma, Papillary meningioma,
Anaplastic meningioma.
C. Germ cell tumors
Germinoma, Embryonal carcinoma, Yolk sac tumor,
Choriocarcinoma, Teratoma, Mixed
Infratentorial Cerebellar astrocytoma, Medulloblastoma,
Brainstem gliomas, Ependymomas,
Choroids plexus papilloma, Dermoids,
Epidermoids, Chordomas, Teratomas
Supratentorial Craniopharyngioma, Gliomas, Choroids
plexus papilloma, Germ cell tumors,
Teratomas, Pineoblastoma, Pinealomas,
Astrocytomas Ependymomas, Oligodendro
gliomas, PNET, Gangliogliomas, and leukemia
infiltrates
children before sutures are closed manifest as progres-
sively enlarging head size.
Headache
Headache in children with brain tumors result from either
direct or transmitted pressure on cerebral arteries, venous
sinuses, dura, cranial nerves, or from hydrocephalus. Brain
parenchyma is insensitive to pain. About 60 to 65 percent
of children with brain tumors have headache. This may be
the earliest (less than 4 months in 95%) or may be the only
symptom in majority of the children. Headache is mainly
diffuse. Mostly transient, occurring in the morning or
awakening the child at night. Headache of more than 4
months duration with normal ophthalmic and
neurological examination is unlikely to be associated with
brain tumor.

TABLE 10.7.3: Brain tumors based on degree of malignancy

Grade Prognosis Intracerebral Extracerebral

Grade 1: Benign Favorable with removal only Gangliocytoma, Plexus papilloma, Neurinomas, Meningiomas,
Cerebellar astrocytoma, Craniopharyngiomas, Pituitary
Hemangioblastoma, Isomorphic adenomas, Ventricular
pinealomas ependymomas

Grade 2: Semi benign Favorable, additional Extraventricular ependymomas Polymorphic pituitary

therapy required Isomorphic astrocytomas adenomas
Anisomorphic pinealomas

Grade 3: Semi malignant Guarded, additional Polymorphic gangliocytoma Polymitotic meningioma

therapy required
Polymorphic ependymoma Polymitotic neurinoma
Polymorphic plexus papilloma
Polymorphic astrocytoma
Polymorphic oligodendroglioma
Polymorphic pinealoma

Grade 4: Malignant Poor Glioblastoma, Medulloblastoma Meningeal sarcoma

480 IAP Textbook of Pediatrics
Vomiting
It is one of the most constant sign of raised ICT, occurring
in 84 percent of patients. It can result from raised ICT or
irritation of the brain stem chemo receptors. Vomiting
usually relieves the headache. It may be associated with
nausea and may not be projectile. It is prominent in the
morning and not related to eating.
Hypertension and Bradycardia
When intracranial pressure approaches or equals the
systemic arterial pressure, it causes the systemic arterial
pressure to rise; this is associated with bradycardia and
irregular respiration (Cushing triad).
Ataxia
It is characteristically observed in cerebellar tumors.
Cerebellar vermial tumors produce truncal ataxia that
enhances with sitting, standing and walking. Tumors
arising from cerebellar hemisphere produce ipsilateral
ataxia and dysdiadochokinesia.
Head Tilt and Neck Rigidity
This may indicate tonsillar herniation through foramen
magnum.
Mental Status Changes
Changes in behavior and personality are uncommon in
children. Progressive depression of consciousness
suggests raised intracranial pressure and compression of
ascending reticular activating system.
Papilledema
This is absent in almost half the children with brain tumors,
especially those with a rapid course such as medullo-
blastoma, supratentorial tumors and in young children
with open anterior fontanel. Separation of cranial sutures
and bulging of fontanel may decompress the intracranial
contents. Trend of decreasing prevalence of papilledema
at the time of diagnosis reflects readily available
neuroimaging modalities to evaluate headache at the
onset. Presence of papilledema makes an intracranial mass
highly probable but its absence in no way excludes such a
diagnosis.
Visual Symptoms
Visual problems are seen in around 40 percent of children
with brain tumors. Diplopia usually results from unilateral
or bilateral paralysis of lateral recti muscles and is a
common symptom of posterior fossa tumors. Small
children usually don’t complaint of double vision, they
compensate by tilting the head in an attempt to align the
two images. Other symptoms those may suggest diplopia
in small children are frequent falls, scare of walking or
playing use of one eye. Strabismus is most striking in
posterior fossa masses and is prominent in the end of the
day. Blurring of vision is a serious symptom and may
indicate vasoconstriction of cerebral vessels impending
cerebellar herniation. Progressive visual loss and
nystagmus may suggest optic nerve glioma of pituitary
mass.
Seizures
Seizures as initial symptoms are seen in less than 15 percent of
supratentorial tumors. Complex partial seizures are the most
common type of seizures seen in intracranial
malignancies. Temporal lobe is the most common site for
tumors producing seizures early in the course of disease.
Focal Neurological Deficits
Focal neurological deficits in the form of hemiparesis are
seen in less than 15 percent of patients as an early
presenting feature of supratentorial brain tumors.
Enlargement of the Head
Progressive enlarging head size is characteristic of long
standing increase in intracranial pressure in infants and
young children and is observed in 76 percent of infants
younger than 2 years of age.
DIAGNOSIS
Neuroimaging modalities have superseded the old
evaluation techniques in the diagnostic evaluation of the
child suspected of brain tumor. CT is the imaging modality
of choice in emergency. Intravenous contrast material assists
in tumor identification. Most tumors demonstrate
enhancement with contrast material. Tumors may appear
hypodense, isodense, or hyperdense or may have mixed
density. CT is effective for imaging the skull base, where
natural contrast of bone, paranasal sinuses, fat and CSF

provides inherent contrast resolution. However tumors
in the posterior fossa and temporal lobe can be missed by
CT imaging.
MRI is better in delineation of benign masses from
malignant growths, inflammatory and infectious
conditions and normal brain tissue. Tumors in the
posterior fossa, temporal lobe, sellar and chiasmatic
regions are best visualized with MRI. An understanding
of the nature of the tumor and its location requires
knowledge of T1, T2, FLAIR and gadolinium –enhanced
sequences. It is also sensitive to pick up acute, subacute,
and chronic presence of blood products within tumor
mass. MR angiography and conventional arteriography
using digital subtraction techniques, helps delineate the
blood supply to the tumor and exclude the presence of
vascular malformation.
EEG is less useful in the localization of brain tumors.
Persistent slow wave activity usually associated with
seizures suggests temporal lobe mass in children with
complex partial seizures.
Positron–emission tomography (PET) has considerable
potential in delineating brain tumors. Primary tumors
show good correlation between the uptake of labeled
fluorodeoxyglucose (FDG) and the malignancy of tumor.
MR spectroscopy has a role in characterization of brain
tumors, in follow-up and differentiation from other non
malignant conditions.
Plain X-ray skull can suggest an intracranial mass if
there is separation of sutures, erosion or enlargement of
sella turcica and calcification (15-20% of brain tumors).
CT and MRI guided stereotactic biopsy is preferred to
open biopsy in childhood brain tumors involving basal
ganglia, thalamus and midbrain. Accurate diagnosis with
this is possible in 95 percent of cases with morbidity in
the 2 to 5 percent range.
DIFFERENTIAL DIAGNOSIS
Increased intracranial pressure is also observed in other
masses like intracranial hemorrhage, brain abscess,
vascular malformations and, inflammatory granulomas.
In infants brain tumors cause increased intracranial
pressure less commonly than hydrocephalus. In pseudo-
tumor cerebri, raised ICT is elevated in the absence of mass
lesion, but there are no localizing signs and the CSF is
normal. Neuroimaging studies show normal or pinched
ventricles. Lead poisoning can also present like posterior
fossa mass but generalized seizures and encephalopathy
are more common.
Diseases of Central Nervous System 481
Treatment
Surgery
Surgery remains the mainstay of treatment for brain
tumors. Total resection cannot be accomplished in many
cases, but partial resection is useful to reduce the bulk of
tumor thus permitting destruction of remaining malignant
cells by irradiation and chemotherapy. Perioperative
administration of dexamethasone at a 0.1 to 0.5 mg per kg
per dose reduces increased intracranial pressure and
perilesional edema. Other medications such as phenytoin
can also be used prophylactically. Goal of neurosurgery
is maximum resection while preserving function. Gross
total resection of both malignant and benign tumors has
been correlated with prolonged survival rates. Advent of
operating microscope, laser beam, and ulterasonographic
methods have made it possible to do safe and complete
resections. Establishing the correct neuropathological
diagnosis of the tumor is critical for subsequent therapy.
This often requires immunohistochemistry, flowcytometry
and electron microscopy. Post-operative serial imaging
studies are important to assess the extent of any residual
tumor/recurrence and to follow-up post operative
abnormalities like edema and bleed.
Radiation Therapy
Radiotherapy can be used either as an adjuvant to surgery
or for definitive therapy. Many pediatric brain tumors are
radiosensitive, but because of radiation’s toxicity to the
developing brain, delivery methods have been modified
to target the area treated more precisely and, when
possible, to decrease the total volume of the brain that is
irradiated. Volume and radiation dosage vary with
different histological diagnoses. Children with
medulloblastomas, for example, receive radiation to the
entire brain and spine, with a booster dose to the original
tumor area, whereas children with brain stem gliomas
receive radiation only to the tumor area. Limited field
radiotherapy and craniospinal radiotherapy have offered
curative therapy for low grade gliomas, PNET and
germinomas. Some of the most intriguing new methods in
brain tumor treatment are conformal therapy and
stereotactic radiosurgery involving a radiation procedure
called Gamma Knife surgery. This treatment precisely
focuses radiation beams to the tumor, delivering radiation
beams in the exact size and shape of the tumor with the
aid of brain imaging techniques. Advantage of stereotactic
radiosurgery is that the surrounding, healthy tissue
482 IAP Textbook of Pediatrics
receives only a very small dose of radiation compared to
the tumor. Pathophysiology of radiation induced injury
results from damage to vascular endothelium that is more
radiosensitive than neurons, injury to glia and axons and
autoimmune vasculitis. Side effects of radiation can be
acute with in 2 to 6 hours in the form of nausea, vomiting
or develop several weeks later in the form of hair lose,
erythema, sore throat, thrombocytopenia, leucopenia and
anemia. Late effects include impaired cognition, defective
endocrinal function and development of secondary
neoplasia.
Chemotherapy
Chemotherapy is increasingly being used to treat both
malignant and benign tumors, especially in infants, where
it has replaced radiation therapy in the postoperative
period. The addition of chemotherapy to the treatment
regimen has increased median survival rates for high-
risk medulloblastoma and high-grade astrocytoma. The
use of low-intensity chemotherapy for low-grade gliomas
(optic/hypothalamic gliomas) has shrunk or stabilized
tumors in up to 70 percent of patients. Newer strategies
have been designed to concentrate chemotherapy agents
directly in to the tumor. One of the proposed strategies is
to implant a self contained delivery pump that
administered the drug. Another approach is the use of
polymer matrix to improve local therapy of malignant brain
tumors. The new plastics enable the drugs to diffuse more
uniformly and continuous in to the tumor. Recent advances
in chemotherapy include primarily supportive-care
measures such as the use of haematopoietic growth factors
and autologous stem-cell harvesting and reinfusion. These
measures shorten the duration of myelosuppression,
allowing administration of higher and more frequent doses
of chemotherapy.
Newer Modalities
These include blocking tumor cell surface receptors, inhibit
transduction, inhibit tumor infiltration, metastasis and
angiogenesis that is essential for tumor survival. Gene
therapy is one of the most promising approaches involving
replacement of defective gene.
SPECIAL ISSUES RELATED TO
THE TREATMENT OF BRAIN TUMORS
Endocrinal Dysfunctions
Endocrine dysfunctions can develop after removing
midline tumor, after craniospinal radiation or chemo-
therapy. Diabetes insipidus is common after resection of a
craniopharyngioma, a germ-cell tumor, or a hypothala-
mic glioma. CNS radiation is associated with
hypothalamic and pituitary dysfunction. Signs and
symptoms include fatigue and cold intolerance (caused
by hypothyroidism), amenorrhea, decreased libido,
hypotension, coma (Addisonian crisis), and retarded bone
age. Decreased growth velocity has been noted in 30 to
100 percent of children treated with cranial irradiation.
Most common hormonal deficiency is growth hormone.
Children may require steroids, thyroid hormone, and or
growth hormone replacement. Several chemotherapeutic
agents, for example, cyclophosphamide can cause gonadal
dysfunction and later on sterility.
Behavioral and Educational Issues
Immature brain of infants and young children is more
susceptible to ionizing radiation. Children who survive
have a high incidence of intellectual impairment as well
as emotional and behavioral problems. Cognitive deficits
include distractibility, memory impairment, confusion,
personality changes, and lowered IQ. Causes for these
deficits are likely a combination of prolonged hydro-
cephalus, direct damage by tumors, surgical morbidity,
chemotherapy, and whole brain irradiation. Younger the
child, the greater is the effect. More-affected children often
require special education and supportive services, such
as physical and occupational therapy, speech therapy,
and psychological counseling.
Posterior Fossa Syndrome (Cerebellar Mutism)
This unusual entity can follow posterior fossa surgery.
Child is mute, apraxic, unable to execute complex motor
commands, emotionally labile and has difficulty in
swallowing. Most children lose their speech 12 to 72 hours
after surgery. Parents can be reassured that neurological
function and speech generally return in from 2 to 20 weeks
in most children.
INDIVIDUAL TUMORS
Astrocytoma
These tumors are derived from astrocytic neuroglial cells,
commonly from the vermis or lateral cerebellar lobes. They
are cystic with the neoplasm confined to a small intramural
nodule. It is the most common brain tumor, accounting for
more than half of all primary CNS malignancies. Association
with NF1 is present in 50 to 80 percent of patients with
 Diseases of Central Nervous System 483

isolated optic nerve astrocytomas and in as many as 20

percent of those with chiasmal or optic tract tumors.
Ionizing radiation to the head for prior malignancies
causes secondary supratentorial malignant astrocytomas
in a small number of patients. Peak age of presentation is
5 to 9 years.
Histologically astrocytomas can be classified in to four
different subtypes. Pilocytic astrocytomas (WHO
grade I) arise throughout the neuraxis, but preferred sites
include the optic nerve, optic chiasma/hypothalamus,
thalamus and basal ganglia, cerebral hemispheres,
cerebellum, and brain stem. These tumors show low
cellularity, low proliferative and mitotic activity, and
rarely metastasize or undergo malignant transformation.
Most common variety seen in children and constitute two
thirds of cerebellar astrocytomas.
Diffuse astrocytomas (WHO grade II) may arise in any
area of the CNS but most commonly develop in the Figure 10.7.1: Post gadolinium T1 weighted transverse MRI
cerebrum, particularly the frontal and temporal lobes. The image of brain showing a well defined heterogeneously
enhancing mass lesion in the right cerebellar hemisphere.
brain stem and spinal cord are the next most frequently
Biopsy proven case of cerebellar astrocytoma.
affected sites, while the cerebellum is a distinctly
uncommon site. These tumors are moderately cellular and
infiltrative, often enlarging, that distorts, but does not possible. Total resection depends upon the location and
destroy neighboring anatomical structures. They arise from grade of the tumor. Patients who develop significant
the white matter and extensively infiltrate the adjoining obstructive hydrocephalus may require ventriculoperi-
grey matter. These are difficult to eradicate surgically. toneal shunt. Post-operative radiotherapy is indicated in
Anaplastic astrocytoma (WHO grade III) arises in the recurrence. Chemotherapy has a limited role. High-grade
same locations as diffuse astrocytomas, with a preference astrocytoma and diffuse pontine lesions are treated with
for the cerebral hemispheres. These tumors show radiation.
increased cellularity, marked mitotic activity, and a
tendency to infiltrate through neighboring tissue. Medulloblastoma
Glioblastoma multiforme (WHO grade IV) tumors Medulloblastoma accounts for 10-20 percent of primary
occur most often in the subcortical white matter of the CNS tumors and approximately 40 percent of all posterior
cerebral hemispheres. Combined fronto-temporal location fossa tumors. It is a highly invasive embryonic
with infiltration into the adjacent cortex, basal ganglia, neuroepithelial tumor derived from primitive neurons and
and contra lateral hemisphere is typical. Glioblastoma is neuroblasts present in the fetal granular layer, a superficial
the most frequent tumor of the brain stem in children, while layer of cerebellar cortex presents at birth. It has the
the cerebellum and spinal cord are rare sites. These tumors tendency to disseminate throughout the CNS early in its
are highly cellular, with high proliferative and mitotic course. Morphologically similar tumors arising in the
activity. Although rapid and extensive invasion of pineal region are termed pinealoblastomas, and those
surrounding tissue is common, distant metastasis within arising in other CNS locations are called PNETs. Ataxia-
or outside the CNS is rare. telangiectasia is a known common association. The most
Cytogenetic abnormalities of childhood astrocytomas frequent cytogenetic abnormality in sporadic
are seen in chromosomal 9,13 and 17. MRI with DTPA medulloblastoma and PNETs is loss of heterozygosity for
enhancement is generally preferred diagnostic mean. the short arm of chromosome 17 [i (17q)]. Other common
Pilocytic astrocytomas are hypointense and enhance on losses of heterozygositiy involve 8p, 11p, 10p, 11q, 16q,
T1 (Fig. 10.7.1) and hyperintense on T2 weighted images. 20q and 20p. Gains have been found at 7q, 17q, 18q, 7p,
Principal treatment is gross total resection, whenever 13q and 18p. Several biological markers has been studied
484 IAP Textbook of Pediatrics

as prognostic factors in these primitive tumors, of these,

TrkC mRNA, MYC mRNA expression seems to be the most
prognostic factors. Male to female ratio is 2:1 and the peak
age is two to four years.
As the tumor grows, obstruction of CSF generally
occurs, resulting in hydrocephalus. Tumor may spread
contiguously to the cerebellar peduncle, floor of the fourth
ventricle; brainstem, cervical spine, or above the tentorium.
It can also spread to the leptomeninges and spinal cord
through the CSF. Of all the pediatric CNS tumors,
medulloblastoma has the greatest propensity for extra
neural spread, especially to bone and bone marrow. Early
clinical features include unsteadiness and features of
raised ICT.
Macroscopically, these tumors are soft, friable and well
demarcated from remainder of the cerebellum.
Histologically, these are highly cellular. These tumors
express a variety of neuronal and neuro endocrine
Figure 10.7.2: Post gadolinium T1 weighted sagittal MRI image
markers, including synaptophysin and neurofilament of brain showing a well defined intensely enhancing mass
proteins. Photoreceptor differentiation is identified in 27 lesion expanding the fourth ventricle and dispalcing the brain
to 50 percent of these tumors and glial fibrillary acidic in stem anteriorly—Biopsy proven case of medulloblastoma.
13 to 62 percent.
MRI with gadolinium-diethylenethriaminepentaacetic weighted images. Total resection of the infratentorial
acid (DTPA) enhancement is generally preferable tumor is a favorable prognostic factor, though it is difficult
diagnostic mean (Fig. 10.7.2). Medulloblastoma is and dangerous. Complete resection should be followed
isointense to grey matter on T2-weighted images. The goal by radiation. For incomplete resections, radiochemo-
of treatment is to achieve a gross near total resection with therapy is advised. For supratentorial ependymomas,
reduced dose posterior fossa radiotherapy followed by limited field radiotherapy and chemotherapy are
chemotherapy. The overall event free 5 year’s survival is recommended.
60 to 70 percent. After recurrence, less than 25 percent
children survive for 5 years. Brainstem Gliomas
They account for 10 percent of childhood brain tumors.
Ependymomas
All brainstem gliomas are malignant by virtue of their
Ependymomas are the third most common brain tumor location. Morphologically these are nonhomogeneous
after astrocytoma and medulloblastoma. They account for group, ranging from the benign well differentiated
6 to 15 percent of childhood brain tumors. These can arise astrocytoma to the highly malignant glioblastoma. Mostly
from any part of the ventricular system, the roof and floor arise from pons, 80 percent are diffusely infiltrative and
of fourth ventricle are the most common sites. These tumors 50 percent are histologically malignant. The four cardinal
are less infiltrative than astrocytomas. Microscopically, presenting features are cranial nerve palsies, pyramidal
the tumor is composed of uniform looking cells. tracts signs, cerebellar signs and usually with out features
Ependymomas with increased cellularity, pleomorphism, of raised ICT. Tumors appear hypointense on T1 (Fig.
mitosis and necrosis are termed anaplastic. Paradoxically 10.7.4) and hyperintense on T2. Common differential
calcification in the tumor has poor prognosis. diagnosis include, brain abscess, granulomas, dermoid
Chromosomal abnormalities noted are deletion of and epidermoid cysts. Treatment depends upon the
chromosome 22, trisomy of chromosome 7 and loss of sex tumor’s resectability. If resectable then complete resection
chromosome. Most of these tumors are hypointense and with radiotherapy and for infiltrative tumors, radiotherapy
enhance on T1 (Fig. 10.7.3) and are hyperintense on T2 and chemotherapy are the treatment options.

Figure 10.7.3: Post gadolinium T1 weighted coronal MRI image
of Brain showing a well defined rim enhancing lesion in the
3rd ventricle—Biopsy proven case of 3rd ventricle
ependymoma.
Craniopharyngioma
It is located in the sellar region and arises from the
remnants of the embryonal Rathke’s pouch. Chromosomal
Figure 10.7.4: FLAIR Coronal MRI images of brain showing
an ill defined mass lesion expanding the the pons—biopsy
proven case of pontine glioma.
Diseases of Central Nervous System 485
imbalances are rare. As it expands forward, it compresses
the optic chiasma, with downward expansion, the
pituitary gland and upward expansion the third ventricle
is compressed. Macroscopically, they are partially or
completely cystic and microscopic picture can vary greatly.
Dystrophic calcification is characteristic. Main clinical
features include, vision defects, endocrine abnormalities,
raised ICT, ataxia and intracranial calcification.
The tumor is readily demonstrated by imaging studies.
Other common space occupying lesions in sellar and
suprasellar areas are optic glioma, chondroma, arachnoid
cyst and meningioma. With microscopic surgical
techniques, total resection of the mass with minimal
neurological, endocrine and visual dysfunction is possible
in 70 to 90 percent of patients. But the resective role of
radical surgery and limited surgery with radiotherapy
continue to be debatable. Therapeutic options include total
resection, subtotal resection with observation, subtotal
resection with radiotherapy, cyst aspiration and
instillation of intracavitary radiation or bleomycin.
Endocrine disturbances are generally exacerbated after
surgery. Most common deficiency (almost 100%) is growth
hormone followed by gonadotropins (93%). Diabetes
insipidus develops in two third cases. Post-operative
obesity and psychological deficits are common and
include, visual perception defects and lack of inhibitory
control.
CONCLUSIONS
Progress in treating brain tumors creates a challenge: As
more and more children survive longer, the quality of life
after treatment becomes an increasingly important issue.
The late effects of brain tumor therapy include neurological
and neuropsychological, endocrine, and, rarely, secondary
neoplasm. These conditions create a lasting medical,
emotional, and financial burden, which has a significant
impact on the patient, his family, and society. The present
goal is to continue to improve cure rates and lower death
rates and also to reduce the long-term side effects of
therapeutic interventions. Technical advances in surgical
procedures will allow for safer tumor resections, and new
targeting techniques will permit safer irradiation. Increased
delivery of chemotherapeutic agents by disruption of the
blood-brain barrier also is being studied. The future of
oncological therapy probably lies in a better understanding
of the basic mechanisms of oncogenesis, however, allowing
for more specific and less toxic medications. The combi-
486 IAP Textbook of Pediatrics
nation of immunology and cytogenetics, including
antitumor gene therapy and monoclonal antibodies, are
promising alternatives to standard therapy. An aggressive
approach to supportive care has been instrumental in
decreasing perioperative morbidity and mortality in
children with brain tumors, and pediatricians can play a
crucial role in perioperative care, appropriate management
of infection, nutrition, and overall health maintenance.
BIBLIOGRAPHY
1. Agamanolis DP, Malone JM. Chromosomal abnormalities
in 47 pediatric brain tumors. Cancer Genet Cytogenet
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2. Aicardi J. Tumors of the central nervous system and other
space – occupying lesions. In Diseases of the nervous
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3. Albright AL. Pediatric brain tumors. CA Cancer J Clin
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10.8 Raised Intracranial Pressure
Intracranial pressure (ICP) is defined as pressure within
vault that results from interaction of the brain (80-85%),
cerebrospinal fluid (CSF 10-15%) and the cerebral blood
volume (CBV-5-10%). Monro (1783) and Kellie (1824)
doctrine states that, the alteration in the volume of one
compartment must be compensated for opposite change
in another compartment to keep ICP same. Normal ICP in
children varies with (newborn 3.5, toddler 6.5 and older
6-13 mm Hg). Raised ICP if not treated, results in ischemia,
dysfunction of autoregulation, herniation and death. ICP
cannot rise beyond arterial blood pressure.
Etiopathogenesis
Intracranial pressure fluctuates during day, and is greater
in supine position. Coughing and sneezing are also
known to increase the ICP. Normal brain is capable of
dealing these transient changes. The initial increase in
volume of intracranial contents is compensated by
displacement of CSF in spinal canal, decrease in CSF
production, increase in CSF absorption and displacement
4. Bernald L Maria, John H Menkes. Tumors of nervous
system. In: John H menkes, Harvey B Sarnat, Bernald L
Maria, (Eds). Child Neurology, 7th edn. Lippincott
Williams and Wilkins, Philadelphia; 2006;729-802.
5. Cohen ME, Duffner PK. Tumors of the brain and spinal
cord including leukemic involvement. In Pediatric
Neurology principles and practice. 3rd edn. Mosby Inc
volume two; 1999;1049-98.
6. D Rocco C, Massimi L, Caldarelli M, et al. Cerebral tumors
in children less than one year of age. Neuro-Oncology
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7. Dyer S, Prebble E, Brundler M, et al. Genomic imbalance
in high and low grade astrocytomas. Neuro-Oncology
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8. Mickle JP. Neurosurgery for pediatric brain tumors.
Semin Pediatr Neurol 1997;4:273-81.
9. Pomeroy SL, Tamayo P, Gaasenbeek M, et al. Prediction
of CNS embyonal tumors outcome based og gene
expression. Nature 2002;415:436-42.
10. Richmond IL, Wilson CB. Parasellar tumors in children,
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differential diagnosis. Childs Brain1980; 7:73.
AD Tewari, Kundan Kumar Mittal
of blood in dural sinuses. The cerebral blood flow (CBF)
must be kept constant to provide oxygen and nutrients to
the brain. The major adaptive mechanisms available to
relieve pressure are compressibility of the brain and rapid
reabsorption of CSF by arachnoid villi. In children the
cranial bones are unfused and hence provide an extra-
adaptive defence mechanism. Whenever intracranial
volume exceeds the capacity of vault to expand, ICP rises
dramatically. The raised ICP will result in failure of
autoregulation thus increasing CBF (normal 50-60 ml/
min/100 gm of brain). Cerebral blood flow is under
neurogenic control (5-10%) and is also affected by
hypercarbia, hypoxia, CPP, CMRO2, SjO2, MAP and
dividing by Cerebrovascular Resistance (CVR). Once
autoregulation is lost, cerebral perfusion pressure falls
(normal more than 60 mmHg). Cerebral Perfusion Pressure
(CPP) is the difference between MAP and ICP. The mean
arterial pressure (MAP) can be calculated by multiplying
diastolic blood pressure by 2, adding systolic blood pres-
sure and then divide by 3. Under such condition raised

ICP become detrimental to nerve cells. There are three
grades of ICP, mild (15-22.5 mmHg), moderate (22.5-30
mmHg) and severe (37.5 mmHg).
Various etiological factors and mechanisms involved
in raised ICP are:
1. Increased intracranial volume Subdural hematoma,
hemorrhage, tumor and infarction.
2. Acute brain swelling Anoxia, acute hepatic failure,
birth asphyxia, hypertensive encephalopathy, Reye’s
syndrome.
3. High venous pressure Cardiac failure, superior
mediastinal obstruction, cerebral vein thrombosis.
4. Obstruction in CSF flow and absorption Hydrocephalus,
meningitis.
5. Increase in CSF production Choroid plexus tumor
6. Benign intracranial hypertension Discussed in chapter
10.9.
7. Causes of raised ICP in PICU Fever, agitation, emotions,
noxious stimulus, head turning, REM sleep, electrolyte
disturbances, volume overload, seizure, hypoxia,
PEEP, hypertension, vasodilator drugs, DKA, free
radical production, encephalitis and expanding
lesions of skull.
Clinical Features
Symptoms and signs of raised ICP are due to secondary
pressure effects and tissue shift and often depend upon
rate of rise in ICP and underlying disease. Various clinical
features of raised ICP are:
a. Headache Persistent headache especially in early
morning often bioccipital or bifrontal is a result of
stretching of dura, venous sinuses and sensory nerves.
b. Vomiting Usually projectile and often present early
in the morning.
c. Increase in head size Seen in children below 2 years of
age.
d. Visual changes It includes enlargement of blind spot,
decrease in visual acuity, diplopia, squint and
papilledema (a reliable sign of increased ICP).
e. Personality changes Irritable, lethargy, apathy and
disturbance in speech.
f. Shrill cry, sunset sign.
g. Herniation syndrome Severe brain edema and pressure
difference in various tissues of brain lead to herniation
during which part of brain get impacted in abnormal
location (transtentorial, central, tonssilar, and angular
herniation).
Diseases of Central Nervous System 487
Following features of herniation may be present:
• Impaired consciousness
• Abnormality of pupil
• Irregular respiration
• Hypertonicity
• Paresis
• Decerebrate or decorticate posture
• Altered body temperature
• Cardiovascular collapse.
h. Systemic effects Cushing’s triad (irregular respiration,
bradycardia and hypertension due to brain-stem
compression), pulmonary edema, myocardial
dysfunction, GI and urogenital hemorrhage.
Diagnosis
A detailed history and physical examination should be
carried out. Laboratory workup includes acid-blood-gases
(ABG), blood sugar, complete blood counts (CBC), LFT,
serum osmolality, electrolytes, cultures and toxic screen.
Skull radiogram may reveal separation of sutures and
erosion of sellae. CT and MRI studies are done to establish
the etiology. Lumbar puncture is relatively contra-
indicated.
ICP Monitoring
Various indications of ICP monitoring are GCS less than
8, decerebrate/decorticate posturing, bilateral or unilateral
pupil dilation, CT showing edema and midline shift, head
injury, CNS infections, and intraoperative management.
The relative contraindications of ICP monitoring are awake
patients and coagulopathy. Accurate assessment of ICP
and monitoring is essential. The purpose of ICP monitoring
is to maintain cerebral perfusion, detection of changes in
ICP and to prevent ischemia and herniation of brain.
Monitoring will also help in different therapeutic modalities
and efficacy of treatment of ICP. Various methods of ICP
monitoring are:
a. Invasive methods: Subdural, parenchymal and intra-
ventricular catheters, cerebral oxygen monitoring,
PbCO 2, screw and bolt devices, Ladd devices,
cardiosearch pneumatic sensor, etc.
b. Noninvasive methods: Scalp blood flow monitoring,
pneumoelectronic switch, CT, MRI, tympanic
membrane displacement, transcranial Doppler
ultrasonography, ultrasonic transducers.
488 IAP Textbook of Pediatrics

TABLE 10.8.1: Modalities of treatment

Basic Therapies
1. Maintain ABC’s (Airways, breathing and circulation), keep SaO2 100%, PaCO2 30-35, SjVO2 55-75%, MAP (appropriate
for age), Temperature 36-37°C, CVP 5-10 mm. Keep ICP less than 20 mmHg. Determine optimal CPP (NB >30, 1mo-1yr > 40, 1-
10yr > 50 and 10-15yr > 60).
2. Head position: CPP will be maximum if head is raised between 15 and 30° to provide venous drainage from brain (there is no
valve) and kept in midline in evolumic patients by putting towel rolls or cervical collor (to avoid distention of jugular veins which
impedes venous outflow thus leading to ↑ CBV and ICP). While turning the patient keep hip joint flexed less than 30°.
3. Temperature control: Keep normothermic (36-37°C) as rise in temperature will increase the metabolic rate, thus result in ↑
CBF, ↑ CBV and ↑ ICP.
4. Blood pressure: Maintain mean arterial blood pressure in the normal range for age.
5. Seizure control: Seizure increases cerebral oxygen consumption and diminishes the capacity to maintain ICP. Midazolam 0.1-
0.2 mg/kg/IV given every 5 minutes till seizures are controlled, load the patient with phenytoin.
6 Fluid: Keep patient normovolemic, give isotonic fluids (Normal saline). Do not use D5W. Hypotension, if present should be
treated aggressively.
7. Ventilation: Maintain PaO2 more than 80 mmHg and PaCO2 of 30-35 mmHg.
8. Paralysis and sedation: Sedation decreases the sympathetic activity thus reduces hypertension and plays a key role in
management. Paralysis is used during controlled ventilation.
9. Lidocaine: It helps in acute reduction of pressure (1.5 mg/kg). It should also be instilled locally before endotracheal tube
suctioning to avoid coughing.
10. Osmotherapy:
a. Both osmotic and loop diuretics are used. Mannitol in low-dose 0.25-0.5 mg/kg of 20% solution given as bolus
and may be repeated 4-6 hourly. It helps by decreasing CSF production, stabilizing membrane, opens BBB,
decreases blood viscosity thus increasing CBF, increased brain compliance, cerebral vasoconstriction and as an
antioxidant.
b. Furosemide: 0.5-1.0 mg/kg/IV may be given alone or with osmotic diuretics.
c. Oncodiuretic therapy.
11. Steroids: Steroids are used in vasogenic edema (tumor, abscess and organized subdural hematoma). Dexamethasone:
Loading dose 1 mg/kg, then 0.25 mg/kg/IV 6 hourly.
12. Hyperventilation: Maintain mild hyperventilation if required, the effect will start within 30 sec and peak in 8 minutes. This will
lead to vasoconstriction and decrease in cerebral blood flow thus resulting in acute reduction of raised ICP.
13. Prevent external stimulus, monitor signs of over stimulation, keep noise level less than 90 db.
Advanced therapies (ICP monitoring is required)
• Barbiturate coma.
• Moderate hypothermia (32-36°).
• Decompressive craniotomy/durotomy/lobectomy.
• Operative treatment of mass lesions.
• Ventricular drainage/VP shunt.
• Neuromuscular blocking agents.

Treatment
It should be started when there is clinical evidence of raised
ICP or sudden increase in ICP, i.e. more than
20 mm Hg for more than 3 minutes or 16 to 20 mm Hg for
more than 30 minutes. Various modalities of treatment
described in brief are shown in Table 10.8.1. Gradual
reduction of therapeutic modalities should be done.
Pupillary response should be assessed periodically.
BIBLIOGRAPHY
1. Dean JM, Roger’s MC, Traystaman RJ. Pathophysiology
and clinical management of the intracranial vault. In
Roger’s MC (Ed): Textbook of Pediatric Intensive Care.
Baltimore, Williams and Wilkins, 1987;527-55.
2. Emily L, Dobyn S, Anthony G et al. Current Pediatric
Diagnosis and Treatment. Lange Medical Book, 2003;321.
3. ICP monitoring and treatment—Orland Health Care and
Education-2000.
4. Krishnamoorthy KS, Todres DT. Management of
cerebral edema and intracranial hypertension. The Indian
Journal of Pediatrics 1994;61:27-32.

10.9 Benign Intracranial Hypertension
Benign intracranial hypertension or idiopathic intra-
cranial hypertension (IIH) also known as pseudotumor
cerebri (PTC) is characterized by headache, papilledema,
raised intracranial pressure without any cause, normal
CSF components and normal or small ventricle size of
brain on imaging studies. Historically, another term used
for this order is otitic hydrocephalus. However, there are
causes bearing close relationship to PTC but failing to
comply with one or more of the accepted criteria. There-
fore, Johnston et al, proposed the term pseudotumor synd-
rome, to broaden the concept of PTC, to include cases
showing intracranial hypertension without ventri-
culomegaly and being secondary to a presumed disorder
of CSF circulation. The annual incidence of IIH is 1 per
100,000 population and varies from country to country.
Specific etiology may be found in children below 6 years
of age, while cases seen above 11 years are usually of
idiopathic in nature.
Classification of PTC in children according to Brodsky,
Baker and Hamed is given in Table 10.9.1.
Etiology
Following are the possible causes of pseudotumor cerebri
in children.
a. Drugs: Nalidixic acid, tetracycline, steroid, lead
toxicity, nitrofurantoin, fluroquinolones, lithium,
phenothiazines.
b. Infections: GB syndrome, Roseola infantum, lateral
sinus thrombosis.
c. Metabolic and endocrinal: Hypervitaminosis A, vitamin
A and D deficiency, galactosemia, Addison’s
disease, obesity, menarche, hypoparathyroidism,
pseudohypoparathyroidism, hypocalcemia, growth
hormone therapy, chronic CO2 retention, catch-up
growth in nutritionally deprived infants and diabetic
ketoacidosis (treatment).
d. Hematological: Polycythemia, iron deficiency anemia,
hemolytic anemia, leukemia, non- Hodgkin’s
lymphoma, Wiskott-Aldrich syndrome.
e. Vascular: Obstruction of intracranial venous drainage
and superior vena cava.
f. Traumatic: Minor head injury
Diseases of Central Nervous System 489
AD Tewari, Kundan Kumar Mittal
g. Miscellaneous: Sydenham’s chorea, Lyme’s disease.
Bell’s palsy and SLE, DPT immunization, cystic
fibrosis, chronic otitis media, systemic infections.
Pathogenesis
The mechanism of raised intracranial pressure in
pseudotumor cerebri is controversial. Various theories
have been put forth on the basis of CSF dynamics:
• Alteration in CSF absorption or production and it may
be due to edema of arachnoid villi and venous
obstruction.
• Cerebral edema which is interstitial and cytogenic type
may be due to increase in cerebral blood volume and
impaired CSF absorption.
• Decrease cerebral flow and venous obstruction which
result in venous engorgement, elevated venous
pressure and associated elevation of intracranial
pressure.
Why the CSF spaces do not dilate is still unclear?
Clinical Features
Symptoms may be acute or gradual in onset and both sexes
are equally affected. Obesity may be associated with many
cases. Infants and young children may present with
irritability and somnolesence. Headache followed closely
by diplopia are principal symptoms as a result of raised
intracranial pressure. Less common symptoms are transient
visual obstruction, nystagmus, neck stiffness, tinnitus,
ataxia, pulsatile intracranial noise, seizures, movement
disorders, paresthesia and rarely facial paresis.
Neurological examination is normal except for
papilledema with enlargement of blind spot, early optic
nerve atrophy and abducens nerve palsy. Consciousness
is preserved and no focal neurological signs are present.
The anterior fontanel is full in infants and Macewen sign
may be positive in older children. There is no risk of
herniation. Mortality rate associated with PTC is no more
than in general population.
Diagnosis
The diagnosis of pseudotumor cerebri is by exclusion and
usually established when the following modified Dandy
criteria is met:
490 IAP Textbook of Pediatrics
a. Signs and symptoms of raised intracranial pressure,
i.e. headache, nausea, vomiting, transient obscuration
of vision and papilledema.
b. Absence of localized findings on neurological exa-
mination except 6th cranial nerve paresis.
c. Absence of deformity displacement, or obstruction of
the ventricular system in otherwise normal
neurodiagnostic studies, except for increased CSF
pressure (> 250 mmH2O), and
d. Alert and oriented patient, no other cause of increased
intracranial pressure present.
The condition should be differentiated from migraine,
AV malformation, aneurysms, cavernous sinus malfor-
mation, encephalopathy (toxic or metabolic) and
infectious, inflammatory disease of brain. Laboratory
workup should be based on detailed history and physical
examination.
CT with contrast enhancement should be done prior
to lumbar puncture to rule out other causes. The results of
CT scan and MRI are normal or may demonstrate small
ventricular size and obliteration of normal sulcal marking
due to increased cerebral volume. LP may reveal raised
pressure (0-2 yr 75 mm H2O, 2-5 yr 135 mmH2O and above
5 yr 200 mmH2O). It may be raised falsely in a crying child
thus sedation may be required prior to LP. CSF composition
is normal. The protein contents are usually low. Skull
radiogram may show separation of sutures and erosion
of the dorsum sellae. Electroencephalography shows
excessive slow wave activity of theta range with occasional
paroxysmal burst of high voltage slowing. Visual system
must be assessed.
Treatment
Pseudotumor cerebri is usually self-limiting benign
condition, but optic atrophy and blindness are most
important complications. The goals of therapy are to:
• Identify and treat underlying cause.
• Relieve neurological symptoms, and
• Avoid permanent visual loss.
The initial lumbar puncture is both diagnostic and
therapeutic in the management of raised intracranial
TABLE 10.9.1: Classification of pseudotumor cerebri
1. Primary pseudotumor cerebri
A. No recognized cause (idiopathic or benign)
2. Secondary pseudotumor cerebri
A. Pseudotumor cerebri associated with neurological
cause
B. Pseudotumor cerebri secondary to systemic diseases
C. Pseudotumor cerebri secondary to ingestion or
withdrawal of exogenous agents.
3. Atypical pseudotumor cerebri
A. Occult pseudotumor cerebri (no papilledema)
B. Normal pressure pseudotumor cerebri
C. Infantile pseudotumor cerebri.
pressure. This may be sufficient to reverse the process in
many cases. Children with raised intracranial pressure
are usually treated with acetazolamide (5 mg/kg/24 hr
or 150 mg/m2/qd) following lumbar puncture. The dose
may be titrated on the basis of clinical response. The risk
of hypokalemia, acidosis and renal calculi (if used above
6 months) must be monitored. In spite of above measures,
if patient still have raised pressure then a course of
prednisolone 2 mg/kg may be given and depending upon
the response the duration is adjusted. Low salt diet and
weight reduction may be tried in adolescents. Digoxin,
glycerol and topiramate have also been tried in
management of IIH.
Lumboperitoneal shunting (LPS) and optic nerve
sheath fenestration (ONSF) are recommended if above
measures fail to relieve symptoms or optic nerve atrophy
supervenes. Visual monitoring is required during follow-
up. In general, the prognosis is very good.
BIBLIOGRAPHY
1. Bergman I. Increased intracranial pressure. Pediatr Rev
1994;15:241.
2. Roberto Warman, MD. Management of pseudotumor
cerebri in children. International pediatrics. 2000;15:3.
3. Soler D, Cox T, Bullock P et al. Diagnosis and manage-
ment of benign intracranial hypertension. Arch Dis Child
1998;78:89.

10.10 Motor Weakness in Infancy and
Childhood—Clinical Approach
The clinical evaluation of motor symptoms in the pediatric
patient is often a challenge. The neurological examination
of an irritable, crying, uncooperative infant can be quite
tiring. The physician has to rely on the parents, who if not
observant, may confuse things further.
A brief outline of the important motor pathways, salient
features on neurological examination and clinical patterns
of motor weakness are discussed.
A description of the upper motor neuron (UMN—
supraspinal and spinal motor pathways) and lower motor
neuron (LMN—the motor unit) follows:
Corticospinal Tract (CST)
It has its origin in the motor cortex (MC) situated on the
side of the rolandic fissure. There are contributions from
the premolar and sensory cortices. Lesions in only the
motor cortex result in unilateral weakness mainly in the distal
hand, leg or lower half of the face. The proximal muscles
may become transiently weak, recover fairly quickly due
to supplementary motor area, subcortical and basal
ganglia influences. If area 8 (anterior to the MC) is involved
a transient contralateral gaze paresis is seen. Cranial
musculature is mostly bilaterally represented except for
the lower half of the face. However, there is a lot of variation
in corticospinal tract (CST) when it traverses the
subcortical white matter—the so-called corona radiata and
occupies the posterior limb of the internal capsule where
it lies in close proximity to the basal ganglia. A lesion here
causes dense hemiplegia often associated with dystonia.
The CST when winds its way down in the anterior cerebral
peduncle of the midbrain, close to the IIIrd nerve. Lesions
in the brainstem cause 'crossed hemiplegias' with ipsilateral
cranial neuropathies (IIIrd in the midbrain, VI and VII in
the pons, XII in medulla). Ipsilateral cerebellar
dysfunction may be associated.
When the ascending reticular activating formation is
involved, disturbances of consciousness may result.
Diseases of Central Nervous System 491
Vrajesh Udani
Spinal Cord
Anatomically, this has the gray matter in the center
arranged in an “H” and the white matter surrounds this
in anterior, lateral and posterior columns. The central gray
matter has the anterior horn with the alpha and gamma
motor neurons and the posterior horn has several masses
of nuclei, concerned with sensory input coming through
the dorsal root ganglia. The alpha motor neurons receive
input from major descending tracts and project to the
corresponding myotome.
In clinical practice, lesions involve both systems and
lead to a combination of signs. Hence in complete spinal
cord lesions, one gets lower motor neuron signs at the level of
the lesion in the form of wasting, weakness, hypotonia and
decreased reflexes. Below the lesion, there are signs of
spasticity, weakness, increased deep tendon reflexes,
absent superficial reflexes and bilateral Babinski signs. If
the lesion is acute, there is initial hypotonia with
diminished reflexes. Bladder/bowel involvement is more
common with intrinsic lesions.
The other spinal cord syndrome is the poliomyelo-
pathy syndrome, where only the anteior horn cells are
involved, either segmentally or diffusely with only lower
motor neuron signs without sensory involvement.
Motor Unit
The cranial and spinal motor neurons receive direct or
indirect input from the CST as well as other tracts
(reticulospinal, rubrospinal, vestibulospinal, etc.), which
originate in the brainstem. The alpha motor neurons project
their axons through the ventral roots and the motor nerves
and via the neuromuscular junction to the extrafusal fibers,
which are primarily responsible for muscle contraction.
The gamma motor neurons receive their afferent inputs from
the muscle spindle and regulate tone and length of muscle
with the help of supraspinal influences.
Disorders of the motor unit have varying combinations
of weakness, hypotonia and decreased/absent deep
492 IAP Textbook of Pediatrics
tendon reflexes. Anterior horn cell and ventral root/plexus
diseases cause weakness in specific myotomes, peripheral
nerve diseases generally cause distal more than proximal
weakness and muscle diseases cause more proximal
weakness.
Neuromuscular junction disorders have a predilection for
ocular, pharyngeal and proximal limb muscles. Anterior
horn cell diseases and peripheral nerve diseases have early
loss of reflexes with little correlation with muscle
weakness, while in muscle and neuromuscular junction
diseases, reflexes are lost late and more so in weaker
muscles. Fasciculations indicate anterior horn cell or
peripheral nerve involvement while myotonia is seen
exclusively in muscle disease.
HEMIPLEGIA
Approach
In children, the first step is to make sure that the hemi-
plegia is due to a corticospinal deficit: It must be
distinguished from hemichorea or hemiataxia.
The acuteness of onset in hemiplegias help in
determining etiology. Hyperacute onset, sometimes asso-
ciated with seizures, indicate cerebrovascular disease. If
the hemiplegia occurs after seizures the other
consideration is a post-ictal Todd’s paresis which can
sometimes be prolonged. Status epilepticus can cause a
permanent focal deficit. Onset over a couple of days is
seen with demyelinating disorders while gradual onset
over a few weeks is seen with tumors. Common etiological
factors are listed in Table 10.10.1.
The examination should determine associated deficits.
Aphasia and hemianopias indicate cortical or subcortical
lesions—more often the latter. Seizures are more often in
cortical lesions. Associated dystonia which usually
develops later, suggests concomitant basal ganglia
involvement. Brainstem lesions have either associated
ipsilateral cranial neuropathies, ataxia or subtle
corticospinal deficits on the opposite side.
Hemiplegic Cerebral Palsy
This is usually secondary to prenatal or perinatal
cerebrovascular disease (CVAs) or cortical malformations—
usually disturbances in neuronal migration. Causes of
perinatal ischemic CVAs are different in term and preterm
infants. In the latter, periventricular leucomalacia (PVL)—
an ischemic white matter lesion associated with sepsis/
maternal chorioamnionitis is the most common cause of
TABLE 10.10.1: Common causes of acquired hemiplegia
Acute onset
1. Stroke
— Arterial ischemic
— Venous
— Hemorrhagic
2. Acute postconvulsive hemiplegia
3. Traumatic brain injury
4. Infectious — Meningoencephalitis
— Bacterial, TB, viral, fungal
— Acute disseminated encephalomyelitis
— Brain abscess
— Subdural empyema
Metabolic disease — MELAS, homocysticuria
Insidious onset
1. Tumors—Brainstem or supratentorial
2. Infections—SSPE
3. Cervicomedullary junction lesions (spinal hemiplegia)
— Atlantoaxial dislocation
— Tumors, cysts
4. Metabolic diseases—Leukodystrophies
5. Rasmussen’s encephalitis
spastic cerebral palsy. Periventricular and intraventricular
hemorrhage occurs often in very preterm babies from the
immature germinal matrix and can cause hemiplegic
cerebral palsy. In the term baby, cerebral infarction due to
cardiac or placental emboli, trauma, thrombosis due to
sepsis and associated disseminated intravascular
coagualtion may be causal. This is usually prenatal.
Hemorrhagic disease of the newborn (Vitamin K deficiency)
can lead to intracranial hemorrhage in the 3rd to 8th week
of life, specially in breastfed infants receiving antibiotics.
Diagnosis rests on demonstration of prolonged PT and often
PTT, and treatment consists of fresh frozen plasma and IV
vitamin K.
Cerebrovascular Diseases (CVAs)—Stroke
CVAs are infrequent in children with an incidence of 2.5
in 100,000 in western countries. They may be higher in
developing countries because of infections and rheumatic
heart disease.
Infections Any meningitis can cause stroke either by
involvement of the arteries (tuberculosis, syphilis and
fungal infections), or by involvement of the veins-
thrombophlebitis as occurs in bacterial meningitis and
subdural empyemas. Treatment primarily aims at specific
antimicrobial drugs, use of steroids—short term for
bacterial and longer term for TBM, and management of
complications like hydrocephalus.

Hematologic diseases Sickle cell disease is a major cause
of stroke in western countries with large black populations.
It is seen specially in tribals from central India. Immediate
treatment consists of exchange transfusion to remove the
sickled RBCs and sickle hemoglobin. Recurrence may be
seen in 60 to 70 percent. Transfusions are given
periodically to suppress the marrow and keep the HbSS
below 30 percent. This can be instituted even before clinical
stroke using transcranial doppler. Chelation therapy is
needed to obviate iron overload.
Hypercoagulable states Inherited or acquired deficiencies
of natural anticoagulants are probably common causes of
stroke. Heterozygosity for deficiency of protein C, protein
S, antithrombin III, etc. should always be looked for, as
they may need long-term anticoagulation. Factor V laden
mutation causing resistance to activated protein C is an
important cause. Antiphospholipid antibodies are also
commonly associated with ischemic strokes. Tissue
plasminogen activator (tPA) has not been adequately
evaluated in children so far. Thrombosis is usually venous
and is precipitated by dehydration, surgery, infections
and drugs.
Vasculopathies Moya-moya is an important cause and is
characterized by supraclinoid internal carotid artery (ICA)
occlusion bilateraly. Vasculitis associated with varicella
is increasingly being recognized.
Acute Paraplegia/Quadriplegia
The causes of both are similar. Legs are involved more
often and earlier than the arms. Causes include spinal
cord disorders and disorders of the motor unit. Non-
neurological painful disorders with apparent weakness
(pseudoparalysis) are seen in conditions like scurvy,
osteomyelitis and fractures. Acute myositis can also mimic
paralysis. Evaluation of the spine—for deformity (e.g.
gibbus in Pott’s spine), scoliosis (spinal cord tumor) and
tenderness is critical. Involvement of bladder and bowel
suggests spinal cord lesion. Sensory abnormalities are
difficult to confirm in small children but if present, are
suggestive.
Spinal Cord Disorders
Compressive myelopathy This usually causes subacute or
chronic symptoms. The important causes include
infections, congenital lesions, malignancies, vascular and
other lesions. Important amongst these is tuberculosis,
Diseases of Central Nervous System 493
which can cause spinal meningitis, extension of TB spine,
and damage the cord by direct compression, vasculitis,
and ischemic damage. Spinal meningitis is sudden while
TB spine is slowly progressive.
Congenital
This is mostly due to occult spinal dysraphism or
craniovertebral abnormalities. Tethered cord and diasto-
matomyelia are often associated with scoliosis and
abnormalities on the overlying skin, e.g. tuft of hair and
lipoma. Dermal sinuses might also be present and provide
an avenue for CNS infections. Craniovertebral junction
abnormalities are usually congenital, or caused by trauma,
and include atlantoaxial dislocation, basilar invagination
etc. These may be associated with a short neck, low hairline,
mucopolysaccharidosis or Down syndrome. They usually
come with a more indolent quadriparesis, but can present
acutely with minor neck trauma. Spinal cord tumors can
be causal.
Diagnosis of spinal cord compression rests on plain
radiology of the appropriate spinal level followed by an
urgent MRI of the spine with contrast. A CT myelography
is the next best option. Vascular malformations would
need spinal angiography.
Treatment Initial treatment of even suspected cord
compression should start with intravenous high-dose
methylprednisolone as an antiedema measure. In tumors,
surgical decompression is required for a tissue diagnosis
and therapy. Specific treatment if possible, should also be
given, e.g. appropriate antimicrobials, local radiation and
chemotherapy.
Transverse Myelitis
This is often a misnomer as several segments may be
involved. It may occur alone or as part of a more diffuse
process, e.g. encephalomyelitis. The pathogenesis is
presumed to be immune mediated, precipitated by an
infectious insult. The child gets back pain followed by a
rapidly evolving paraplegia with early onset of bladder
dysfunction. Sensory levels are noted, posterior column
sensations, i.e position and vibration are uniformly
affected. MRI depicts swelling and hyperintensity of the
cord on T2 weighted images, the edema may be severe.
Ischemic myelopathies should be excluded. These usually
have dissociated sensory loss with preservation of
position/vibration sense and loss of pain/temperature
below the level of the lesion. Treatment basically consists
of limiting the damage and supportive care. Pulse
494 IAP Textbook of Pediatrics
intravenous methylprednisolone is the mainstay of
treatment, and is often associated with dramatic
improvement. IVIG is another option.
Motor Unit Disorders
These are more common causes of flaccid para/
quadriplegia than the spinal cord disorders. They may
affect the anterior horn cell as in the polio and enteroviral
infections, the peripheral nerves and roots as occurs in
the Guillain-Barré syndrome (GBS) and its variants, e.g.
acute motor axonal neuropathy (AMAN), neuromuscular
transmission defects as in acute botulism, periodic
paralysis and myasthenic crisis and finally in muscle
disease as in acute infectious myositis and dermato-
myositis.
Guillain-Barré Syndrome
This is probably the commonest cause of acute flaccid
paralysis. It is an immune antibody mediated attack on
the peripheral nerve myelin with a predilection for the
proximal root. It is associated with several anti-ganglioside
antibodies.
Clinically, it presents acutely with leg pains and
stiffness. The child often refuses to walk or starts limping.
Weakness progresses rapidly for about 2 to 4 weeks. There
is symmetric involvement of the legs, trunk, arms and often
cranial nerve involvement of the VII and lower cranial
nerves, giving rise to dysphagia and nasal twang.
Respiratory muscles are invariably affected in severe cases
and are the most common cause of mortality. Autonomic
manifestations include cardiac arrhythmias and fluctua-
tions of blood pressure. The clinical picture along with
characteristic slowing of nerve conduction velocities and
increased CSF protein without a cellular response, suggest
the diagnosis.
Treatment is supportive with prevention of aspiration,
frequent checks on respiratory status and intervening with
intubation and ventilation at the first sign of fatigue.
Specific treatment consists of either plasma exchange (PE)
to remove the circulating immune complexes, or IVIG—a
total of 2 g/kg over two days, or 400 mg/kg daily for 5
days. IVIG is as effective as PE, if not more and is much
easier to administer. The illness is usually benign. Majority
of children recover on their own. The rapidity of improve-
ment and the persistence of deficit is clearly affected by
the use of the above therapies.
Acute Motor Axial Neuropathy (AMAN)
AMAN is similar to GBS, with the major difference being
that only axons are involved and the myelin is spared.
There is a relation to Campylobacter jejuni infection and
recovery is good despite a prolonged course.
Enteroviral Infections
With the pulse polio program, poliomyelitis is rapidly
diminishing. Clinically, the child has high fever, meningis-
mus, back spasms, leg pain and tenderness. Preparalytic
form is more frequent. The paralysis is usually asymmetric
in the lower limbs, though any muscle can be affected.
Paralysis may be preciptated by the use of intramuscular
injections or by exertion. Respiratory and bulbar
involvement is possible.
CSF shows cells and mildly increased protein.
Pleocytosis is initially polymorphonuclear and later
mononuclear. Stool cultures are positive and an essential
part of acute flaccid surveillance. Paired sera help in
diagnosis.
Treatment is supportive with rest to the muscles and
relief of pain. Respiration may need support.
Coxsackie and ECHO viruses give rise to milder
disease. CPK is elevated. The natural history is one of
rapid improvement and only supportive treatment is
enough.
Vaccine associated poliomyelitis (VAP) is a rare
complication of the live vaccine and gives rise to a milder
disease sometimes in contacts of those given the vaccine.
 Diseases of Central Nervous System 495

10.11 Floppy Infant Syndrome

R Anandam, D Kalpana

Floppy infant syndrome is the term used to denote infantile b. Down syndrome
hypotonia. The infant is limp, immobile and is often c. Prader-Willi syndrome
compared to a rag doll. Three main clinical features of 2. Infection
hypotonia are: a. Sepsis
• Maintenance of unusual postures b. Meningitis
• Increased resistance of joints to passive movements c. Encephalitis
• Increase in the range of movements of joints. 3. Metabolic/Endocrine
Thus the baby assumes a pithed frog appearance with a. Hypocalcemia
the hips abducted and externally rotated with loss of b. Hyponatremia
postural tone. When the infant is examined in ventral c. Hypoglycemia
suspension, the floppy infant will have marked head lag d. Hypothyroidism
and floppiness of the trunk arms and legs, whereas a normal e. Aminoaciduria
infant will have straight back, arms flexed at elbows and 4. Perinatal trauma
partially extended at the shoulder and partially flexed a. Perinatal asphyxia (HIE)
knees. In the supine position, traction on the hands to b. Hemorrhage
raise the shoulders off the couch will show marked head
lag. Pectus excavatum is present when the infant has long- 2. Lower Motor Neuron Causes
standing weakness in the chest wall muscles. Newborns
1. Anterior horn cell
that are hypotonic in utero may be born with hip
a. Spinal muscular atrophy
dislocation, multiple joint contractures (arthrogryposis),
b. Poliomyelitis
or both. Hip dislocation is a common feature of
2. Peripheral nerve
intrauterine hypotonia.
a. Congenital hypomyelinating neuropathy
The maintenance of normal tone requires intact central
b. Demyelinating neuropathies
and peripheral nervous systems. Not surprisingly,
3. Neuromuscular junction
hypotonia is a common symptom of neurological
a. Transient neonatal myasthenia gravis
dysfunction and occurs in diseases of the brain, spinal
b. Congenital myasthenia
cord, anterior horn cells, peripheral nerves, neuromuscu-
lar junction and muscles. One anterior horn cell and all c. Infantile botulism
the muscle fibers that it innervates make up a motor unit. 4. Muscle
The term cerebral hypotonia encompasses all causes of a. Congenital myopathy
postural hypotonia caused by a cerebral disease or defect. b. Congenital myotonic dystrophy
All motor unit disorders (lower motor neuron disorders) c. Congenital muscular dystrophy
producing floppiness are characterized by significant muscle d. Metabolic and endocrine myopathies
weakness; in contrast to cerebral hypotonia where the weakness
is minimal compared to hypotonia. The baby will be able to lift APPROACH TO DIAGNOSIS
the limb off the couch in upper motor neuron disorders. In
infancy and childhood, cerebral disorders far outnumber The first step in diagnosis is to determine whether the
motor unit disorders. disease location is in the brain, spine, or motor unit. More
than one site may be involved.
Differential Diagnosis of Floppy Infant Cerebral hypotonia in newborns usually does not pose
diagnostic difficulty. The history and physical
1. Upper Motor Neuron Causes
examination identify the problem. Many clues to the
1. Chromosomal diagnosis of cerebral hypotonia exist. Most important is
a. Turner syndrome the presence of other abnormal brain functions: decreased
496 IAP Textbook of Pediatrics
consciousness and seizures. Cerebral malformation is the
likely explanation for hypotonia in an infant with
dysmorphic features or with malformations in other organs.
A tightly fisted hand in which the thumb is constantly
enclosed by the other fingers and does not open
spontaneously (fisting) and adduction of the thigh so that
the legs are crossed when the infant is suspended
vertically (scissoring) are precursors of spasticity and
indicate cerebral dysfunction. The tonic neck reflex is an
important indicator of cerebral abnormality if the
responses are excessive, obligatory, or persist beyond age
6 months. When hemispheric damage is severe but the
brainstem is intact, turning the head produces full
extension of both ipsilateral limbs and tight flexion on the
contralateral side. An obligatory reflex is one in which
these postures are maintained as long as the head is kept
rotated. Tendon reflexes are generally normal or brisk,
and clonus may be present.
FEATURES OF CEREBRAL HYPOTONIA
• History of birth asphyxia
• Seizures
• Dysmorphic features
• Persistent fisting of the hands
• Malformations of other organs
• Normal or brisk tendon reflexes
• Scissoring on vertical suspension.
Chromosome Disorders
Despite considerable syndrome diversity, common
characteristics of autosomal chromosome aberrations in
the newborn are dysmorphic features of the hands and
face and profound hypotonia. Eg. Down, Turner, Prader-
Willi syndromes.
Cerebral Dysgenesis
This may be due to known or unknown noxious
environmental agents, chromosomal disorders, or genetic
defects. In the absence of an acute encephalopathy,
hypotonia may be the only symptom at birth or during
early infancy. Hypotonia is usually worse at birth and
gets better with time. Cerebral dysgenesis should be
suspected when hypotonia is present along with
malformations in other organs or abnormalities in head
size and shape. Magnetic resonance imaging (MRI) of the
head is advisable when cerebral malformation is suspected.
Brain injuries occur in the perinatal period and, less
commonly, throughout infancy secondary to anoxia,
hemorrhage, infection, and trauma. The premature
newborn showing a decline in spontaneous movement
and tone may have an intraventricular hemorrhage.
Hypotonia is an early feature of meningitis in full-term
and premature newborns. Tendon reflexes may be
diminished or absent during the acute phase.
Genetic Disorders
Several genetic disorders cause infantile hypotonia. Many
are syndromic and can be diagnosed by the associated
features. Infantile hypotonia is rarely the only
manifestation of inborn errors of metabolism. Acid maltase
deficiency(Pompe’s disease) causes a severe myopathy.
The doll like facies and associated cardiomyopathy
clinches the diagnosis. The initial features of pyruvate
carboxylase deficiency are neonatal hypotonia, tachypnea,
and movement disorders. Hypotonia may be the only
initial feature of generalized GM1 gangliosidosis.
Diseases of Spinal Cord
Hypoxic-ischemic myelopathy is an expected outcome in
severe perinatal asphyxia. Affected newborns are
hypotonic and areflexic. Because the injuries are always
associated with a difficult and prolonged delivery,
decreased consciousness is common and hypotonia is
falsely attributed to asphyxia or cerebral trauma. However,
the presence of impaired sphincter function and loss of
sensation below the chest should suggest myelopathy.
MOTOR UNIT DISORDERS
Disorders of the motor unit are not associated with
malformations of other organs except for joint deformities
(Fig. 10.11.1). Tendon reflexes are absent or depressed. In
neuropathy loss of tendon reflexes is early. Depression of
reflexes is proportionate to muscle weakness in myopathy
and the ankle jerk is retained till late in the course of
disease. Muscle atrophy suggests motor unit disease but
does not exclude the possibility of cerebral hypotonia.
Failure of growth and even atrophy can be considerable
in brain-damaged infants. The combination of atrophy
and fasciculations is strong evidence of denervation.
However, the observation of fasciculations in newborns
and infants is often restricted to the tongue, and
distinguishing fasciculations from normal random
movements of an infant’s tongue is difficult unless atrophy
is present.

Figure 10.11.1: Motor unit disorders
Features of Motor Unit Disorders
• Absent or depressed tendon reflexes
• Failure of movement on postural reflexes
• Fasciculations
• Muscle atrophy
• No abnormalities of other organs
Evaluation of Motor Unit Disorders
As the DNA based diagnosis is commercially available
for many disorders e.g. Spinal muscular atrophy (SMA), it
is preferred to electrodiagnosis or muscle biopsy. Such
investigations are done only when results of DNA
diagnoses are inconclusive or unavailable.
Serum creatine kinase is elevated in muscular
dystrophies. But can be seen elevated in asphyxiated
newborns.The values may be mildly elevated in congenital
myopathies.
Electrodiagnosis
Needle EMG studies help to differentiate myopathies from
neuropathies.The appearance of brief, small-amplitude,
polyphasic potentials characterizes myopathies; the
presence of denervation potentials at rest (fibrillations,
fasciculations and sharp waves) and motor unit potentials
that are large, prolonged, and polyphasic characterize
denervation.
Diseases of Central Nervous System 497
Congenital myotonic dystrophy is often diagnosed by
demonstrating myotonic potentials in the mother of the
baby.
Studies of nerve conduction velocity are useful in
distinguishing axonal from demyelinating neuropathies;
demyelinating neuropathies cause greater slowing of
conduction velocity.
Repetitive nerve stimulation studies demonstrate
disturbances in neuromuscular transmission.
Muscle biopsy can clinch the diagnosis in congenital
myopathies, spinal muscular atrophy and muscular
dystrophies.
Investigations
• DNA-based testing
• Serum creatine kinase
• Electrodiagnosis
Electromyography
Nerve conduction studies
Repetitive stimulation
• Muscle biopsy
• Serum electrolytes, glucose
• Renal function tests
Spinal Muscular Atrophy (SMA)
SMA constitutes a major group of floppy babies. SMA is
classified into 3 types, (1-3) depending on the age of onset
and progression. SMA type 1 is the most severe form and
presents as floppy infant. The symptoms start in utero
with history of decreased foetal movements, marked
hypotonia, poor feeding, difficulty in swallowing and
labored breathing due to involvement of intercostal
muscles. The weakness is more proximal than distal. The
infant is very alert with good cognitive development.
Fasciculations are seen on the tongue. Tendon reflexes
are completely absent. The infants do not survive beyond
2 years and death is by respiratory failure.
Most SMA cases are associated with deletions or
mutations in exons 7 and 8 of the telomeric copy of spinal
musculat atrophy gene (SMN1- survival motor neurone1)
in chromosome 5q11.2-13.3.
DNA diagnosis is now widely available which helps
in prenatal diagnosis. The disease are inherited in an
autosomal recessive fashion.
The diagnosis is often clinical which can be confirmed
by DNA diagnosis. EMG and muscle biopsy are used
when these facilities are unavailable or results
inconclusive.
498 IAP Textbook of Pediatrics
Polyneuropathies
Polyneuropathies are uncommon in early infancy as a
cause of floppy infant syndrome. These neuropathies
present with distal muscle weakness with wasting and
sensory disturbances. Only with congenital hypomyeli-
nating neuropathy is infantile hypotonia the initial feature.
The others are more likely to start as progressive gait
disturbance or psychomotor retardation. Rarely Guillian
Barré syndrome can present in infancy.
Disorders of Neuromuscular Transmission
Familial Infantile Myasthenia
Several genetic defects in the neuromuscular transmission
can cause congenital myasthenic syndrome. All are
autosomal recessive except for the slow channel syndrome,
which is an autosomal dominant trait. Among the
autosomal recessive forms, the causative mutation in one
is in the choline acetyltransferase gene on chromosome
10q; another maps to chromosome 17. All genetic
myasthenic syndromes are seronegative for antibodies that
bind the acetylcholine receptor (AChR). Both the genetic
and clinical features are the basis for classifying
congenital myasthenic syndromes. Neostigmine test is
often negative.
These infants present as floppy infants with ocular,
bulbar or respiratory weakness which is worsened by
excessive crying, after feeding or activity. The tendon
reflexes are preserved. Some may partially respond to
anticholinesterase drugs.
Transient Neonatal Myasthenia
It occurs in about 10 percent of babies born to myasthenic
mothers and is due to transfer of acetyl choline receptor
antibodies from the mother. The affected infants have weak
cry, difficulty in sucking and swallowing, hypotonia and
muscle weakness. Some may need ventilation and
parenteral neostigmine. The symptoms resolve
spontaneously within a few days.
Muscle Diseases
Congenital Muscular Dystrophies
They are a group of muscle disorders appearing
sporadically, or transmitted as an autosomal recessive
trait. These infants are hypotonic at birth, with proximal
or generalized motor weakness involving face, trunk and
proximal muscles. Tendon reflexes are depressed.
Contractures occur in about 50 percent of infants. Variants
of the disease are associated with mental retardations
seizures, joint contractures or visual impairment.
Diagnosis is confirmed by markedly elevated CPK values
and findings of dystrophy in muscle biopsy.
Congenital muscular dystrophy with cerebral and
cerebellar involvement has been recognized in Japan and
later in many countries and is called Fukuyama type of
muscular dystrophy. MRI brain reveals periventricular
white matter changes and cysts in cerebellar white matter.
Congenital Myotonic Dystrophy
The newborns present with myopathic facies, hypotonia,
and feeding difficulties. CPK is moderately elevated. The
disease is transmitted in an autosomal dominant fashion,
but in majority of children presents in newborn period,
mother is the affected parent. History of difficulty in
releasing the hand grip of mother clinches the diagnosis.
Myotonia may be demonstrated in needle EMG of mother.
Myotonia is not detectable in the baby, it may develop
later.
Congenital Myopathies
A variety of congenital myopathies have been recognized
and they present at birth. Inheritance follows autosomal
recessive pattern. Clinical features include hypotonia,
muscle wasting and developmental delay.
Some children have a myopathic facies. CPK is normal
or mildly elevated. Diagnosis is confirmed by muscle histo-
chemistry and electron microscopy. Disease are named
from the appearance of muscle biopsy, e.g. central core
disease, nemaline myopathy, mini core disease and
congenital fiber type disproportion.
Metabolic Myopathies
Glycogenosis type 2 is called Pompe’s disease. It is
characterized by severe hypotonia, hepatomegaly and
cardiac involvement. Muscle weakness is due to primary
involvement of muscle and anterior horn cell due to
denervation.
BIBLIOGRAPHY
1. Bradley. Neurology in clinical practice. 5th edn. 394-400.
2. Fenichel GM. Clinical Pediatric Neurology: A Signs and
Symptoms Approach, 5th edn. Elsevier, 2005.

10.12 Muscular Disorders in Children
Muscle disorders in childhood present a wide spectrum
of handicap and distress in childhood. Most of the
difficulties are insidious in onset and are noted when the
child starts walking or as late as when child goes to school.
Unfortunately, most of the disorders are crippling and are
associated with a shortened life-span. Muscle weaknesses
may be acute or chronic. The chronic disorders comprising
the dystrophies are discussed in this chapter.
Presenting Features of Muscular Weakness in Children
Presenting symptoms
General
Weakness
Fatigability
Frequent falls
Slower than peers
Lower Limb
Abnormal gait
Waddling-hip weakness
Steppage gait-weak dorsiflexors
Toe walking-weak peroneal
Difficulty in climbing up/downstairs
Difficulty in getting up from squatting—Gowers sign
Upper Limb-difficulty in
Elevation of arm
Grooming hair
Dressing undressing
Weakness of hand grip
Change in handwriting
Head and Neck
Double vision
Difficulty in swallowing chewing, sucking, whistling,
blowing
Alteration of voice
Floppy neck.
Children may appear normal at birth. Most of them
have normal motor milestones. But in retrospect some
children have definitive history of delayed motor
milestones. The weakness starts in the proximal muscles
and more in the lower limbs. Frequent tripping, stumbling
and falling may be the presenting complaints due to
weakness of evertors and dorsi-flexors of the foot.
Abnormal gait such as steppage gait, toe walking and
waddling appear in established weakness. Child has
difficulty in climbing stairs which is due to weakness of
hip extensors and descending stairs due to quadriceps
Diseases of Central Nervous System 499
K Pandian
weakness. Has difficulty in keeping up to the speed of his
classmates and has considerable difficulty in crossing
obstacles. Later there is difficulty in getting up from a
squatting posture to standing up and the child typically
climbs up on his legs, the “Gowers” sign. Walk becomes
waddling due to weak hip muscles and unstable pelvis.
Weakness of proximal muscles of upper limbs is
manifested as difficulty in reaching up a cupboard,
combing hair, reaching behind to remove dress and later
on, weakness of hands and fingers.
Weakness of muscles of head and neck may present as
difficulty in vision, drooping of eyelids, difficulty in
chewing, sucking, whistling and alteration of speech.
Examination
It is always better to observe the child sit, stand and walk
in any suspected muscle disease with under-garments
only. Prominence of muscles, wasting, atrophy and
contractures are easily made out. Child is made to walk
on toes and heels to make out weakness of gastrocnemius
and anterior compartment muscles respectively. Always
examine neck and ocular muscles for weakness. Look for
contractures, myotonia, strength and tendon reflexes.
MUSCULAR DYSTROPHIES
Muscular dystrophies are a group of progressive
genetically determined disorders predominantly affecting
skeletal muscles resulting in wasting and weakness.
Molecular studies help in establishing accurate diagnosis, detect
preclinical cases, identify carriers and defects. Classification
is mostly by clinical and immunochemistry and gene
typing are useful for sub-typing (Table 10.12.1).
Classification of Muscular Dystrophies
1. Duchenne and Becker muscular dystrophy (DMD,
BMD)
2. Emery-Dreifuss muscular dystrophy (EDMD)
3. Limb girdle muscular dystrophy (LGMD)
4. Congenital muscular dystrophies (CMD)
5. Facioscapulohumeral dystrophy (FSHD)
6. Oculopharyngeal dystrophy
7. Distal myopathies
8. Myotonic dystrophy
500 IAP Textbook of Pediatrics

TABLE 10.12.1: Genetic basis of Muscular Dystrophics

Disease gene locus Protein/gene

product

X-linked recessive
1. DMD/BDM Xp21 Dystrophin
2. EDMD Xq28 Emerin

Autosomal dominant
3. LGMD 1A 5q22-31 Myotilin
4. Myotonic dystrophy 1 19q13.2 DM/ZFN9
5. FSHD 4q35 ?not identified
6. Oculopharyngeal 14q Polyalanine
dystrophy Binding protein
Figure 10.12.1: DMD with calf muscle hypertrophy
Autosomal recessive
7. LGMD 2A 15q15 Calpain3
8. Congenital muscular show hypertrophy. Muscle mass tends to decrease in later
dystrophy type 1 6q21-22 Merosin[laminin-2] stages especially in leg muscles, and distal muscles of
arms and legs also exhibit weakness as disease progresses.
DUCHENNE (DMD) AND BECKER (BMD) Most children have prominent calf muscles with toe
MUSCULAR DYSTROPHY walking as classical presentation with increased lordosis
(Fig. 10.12.1).
DMD has X-linked recessive inheritance with a
Knee jerks tend to diminish early in contrast to ankle
prevalence of 1/3,500 male births. About one-third of cases
jerk which may be elicited for many years. They have
are from spontaneous mutation in dystrophin gene
progression of muscular weakness and loss of ambula-
located in chromosome xp21.
tion and are confined to wheelchair by 12 years of age.
BMD is a milder form of dystrophinopathy than the
Patients without calf hypertrophy can be identified by
more severe DMD phenotype with which it is allelic.
presence of valley sign visible behind shoulders (Pradhan
sign).
Pathology
Cardiac dysrhythmias, progressive cardiomyopathy
Dystrophin, a large cytoskeletal protein is intimately bound [especially the non-steroid treated group] and cardiac
to sarcolemma and provides structural integrity to muscle failure occur late. Gastroparesis and pseudo-obstruction
membrane. High mutation rate is due to the large size of can occur. The average IQ of these patients is also below
the gene. Large deletions or duplications in the gene mean. Joint contractures, scoliosis and respiratory
account for about 70 percent of cases of DMD. Size of impairment are common in the non-ambulatory stage of
deletion or its location does not correlate with severity of illness. Death occurs mostly from respiratory and cardiac
lesion. Screening of 19 exons by multiplex polymerase complications. The mean age of death in untreated group
chain reaction identifies about 98 percent of all deletions. is around 19-20 years .
The severity of BMD is variable. They are ambulatory
Clinical Features past 15 years of age and slowly progressive with a lifespan
even up to 40 years. This may manifest with myalgias,
Most children appear normal at birth and achieve
cardiomyopathy and asymptomatic elevation of CK.
satisfactory milestones with slight delay. Frequent falls
are noted as the first manifestation at about 3 to 6 years of
age along with clumsy walk. Proximal weakness is more Investigations
than distal and lower limbs are more weaker and involved Genetic studies have largely replaced the need for painful
earlier. Weakness is present in neck flexors, hip girdle biopsies and ENMG. Serum creatine kinase is markedly
muscles and then the shoulder girdle. Hypertrophy of calf elevated 50 to 100 times normal but can drop in late stages
muscles is prominent by 3-4 years of age. Vastus lateralis of disease. [Do not depend on CPK values alone for diagnosis].
infraspinatus, deltoid and occasionally gluteus maximus Muscle biopsy shows fiber degeneration and regeneration.

Immunochemistry shows absent dystrophin staining on
the muscle membrane. Western blot analysis of quantity
and size of dystrophin present is possible and is presently
the investigation of choice.
Management
Gene therapy and stem cell therapy holds much promise
for children with DMD in the near future.
Obesity can become a issue in ambulation and proper
diet management is necessary especially when started on
steroids.
Medical Management
Drugs
Steroids have been tested widely. They improve the
weakness and the quality of life. They are of no use once
the patient is confined to wheel-chair or bed and
preferably stopped at that stage. Prednisolone 0.75 mg/
kg/day to a maximum of 40 mg/day, is effective in
increasing the function and strength, improves pulmonary
function and helps slowing of the rate of deterioration.
Effects can be seen in two weeks and probably last for 3
years. An alternative high-dose treatment with 10 mg/kg
per week in two divided dose on 2 consecutive days each
week has been tried with effectiveness. Side effects of
prednisolone are risk of infections, cataract, hypertension,
osteoporosis, weight gain and irritability.
Deflazacort an analog of prednisolone at a dose of
0.9 mg/kg/day has been tried with equal effectiveness
and less side effects.
Emerging therapies—These include creatine, useful in
increasing muscle supply of phosphocreatine 0.1g/kg/
day and glutamine 0.6 g/kg/day; Coenzyme q10;
Myostatin inhibitor which acts on myostatin, a negative
regulator of muscle growth have been tried.
Supportive Therapy and Appliances
A group involving neurologist, psychiatrist, physio-
therapist, genetic counsellors and the whole family is more
helpful. The aim is to avoid contractures and
physiotherapy to be started as early as possible around 3
to 5 years.
Assistive devices: Ankle foot orthroses [AFO] at night
combined with day time stretching are useful in ambulatory
stage. They should be applied in daytime also once
ambulation is lost to keep gastrocnemius –soleus tendons
stretched.
Diseases of Central Nervous System 501
Braces are helpful in delaying the eventuality of
wheelchair.
Long leg brace/knee ankle-foot orthroses[KAFO]—stabilizes
the knee. Disadvantages include stiff legged gait, useful
on level ground. Standing frames can be used when the
child is no longer able to walk. High top boot with upright
double braces gives excellent stability.
Wheel chairs/hoist- both manual and powered wheel
chairs are now available tailored to suit individual needs
and help in activities indoor and outdoor. Proper wheel
chair sizing, solid back support, and solid seating are
important to prevent spinal deformities.
Surgery Spinal instrumentation and fusion may be
necessary to correct scoliosis. Percutaneous tenotomy of
tendo-achilles, knee flexors, hip flexors and iliotibial
bands helps to a certain extent. Patient should be
monitored during and after surgery watching for cardio
respiratory depression. Avoid depolarizing muscle
relaxants.
Genetic Counseling
Daughters of males with BMD and mothers of affected
children are obligate carriers of mutant gene. Serum CK
can be elevated in female carriers (50%) but not always.
DNA analysis is most reliable method.
Prenatal diagnosis can be made with DNA analysis of
chorionic villi or amniotic fluid cells.
LIMB GIRDLE MUSCULAR DYSTROPHIES (LGMD)
It has equal occurrence in males and females. Autosomal
dominant varieties are classified as type 1 and recessive
forms as type 2. Manifestations can be either like DMD or
BMD. Investigations are non-specific. Immunochemistry
shows normal dystrophin. Staining for sarcoglycans,
merosin and dysferlin are useful to know subtypes.
CONGENITAL MUSCULAR DYSTROPHY (CMD)
They are a autosomal recessive disorders. Mostly present
with hypotonia, proximal weakness and joint contractures.
Several subtypes are described.
They show absence or marked deficiency of
extra-cellular matrix protein merosin. They are classified
as merosin positive or negative. They are based on clinical,
ophthalmological, radiologic and pathological features.
Serum CK is elevated. Fukuyama type presents with severe
mental retardation, contractures, microcephaly and
seizures.
502 IAP Textbook of Pediatrics
FACIOSCAPULOHUMERAL
MUSCULAR DYSTROPHY (FSHMD)
It is inherited as autosomal dominant linked to
chromososme 4q35.
Age of onset is usually 3 years to adult age. Initial
involvement of facial muscles, shoulder girdle and humeral
muscles is an early sign. Scapular winging occurs due to
weakness of muscles which stabilize the scapula.
Asymmetry of motor deficits, sparing of deltoid, neck flexor
and calf muscles, retinal vasculopathy with telangiectasia,
hearing loss involving high frequencies are added
supportive findings. Wasting of upper arm when
compared to forearm gives the typical appearance. Lower
limbs also develop weakness especially anterior
compartment muscles. CK is moderately elevated.
EMERY DREIFUSS MUSCULAR DYSTROPHY (EDMD)
It is caused by mutation in gene xq28 which encodes for
protein emerin.
Three forms X-linked, autosomal recessive, autosomal
dominant are recognized. Features are slowly progressive
muscular atrophy and weakness mostly of
humeroperoneal distribution, contractures at tendo-
achilles, elbows, posterior cervical muscles, and
cardiomyopathy with conduction defects. Deltoids are
spared and hypertrophy of muscles and facial weakness
do not occur. Contractures [upper extremity precedes
lower extremity] are disproportionate to the degree of
weakness. The disease is slowly progressive till third
decade. Female carriers have cardiomyopathy.
Serum CK may be normal or raised. ECG are useful to
pickup bradycardia and conduction defects.
MYOTONIC DYSTROPHY (DM)
It has an autosomal dominant inheritance. It presents at
any age from infancy. Limb weakness begins distally and
progresses very slowly to proximal muscles. Myotonia is
prominant in hands. Frontal balding, cataracts, wasting
of facial and masseter muscles are characteristic. Cardiac
abnormalities are common, usually conduction defects.
Involvement of diaphragm and intercostal muscles
common. EMG demonstrates myotonic discharges.
Congenital form is severe and presents with hypotonia,
facial weakness, respiratory and feeding difficulties.
If myotonia is severe phenytoin/mexiletine can be tried.
Cardiac complications need treatment and periodic
pulmonary functions need to be done. Type 2 has later
onset and less cardiac complications.
At present most patients can be accurately labelled as
gene localization and immunochemistry are available.
There is no definitive treatment to alter the mortality and
morbidity. The future of these patients lies in realization
of gene therapy.
BIBLIOGRAPHY
1. Emery AEH. Muscular Dystrophy; the facts. Oxford
University Press, 2000.
2. Emma Ciafaloni. Treatment options for DMD. Current
treatment options in neurology 2008;23.
3. Gerald M Fenichell. Clinical paediatric neurology. 5th
edn, 2005.
4. Kenneth F. Swaiman Paediatric Neurology principles and
practice 4th ed, 2006.
5. Panigrahi I, Mittal B. Carrier Detection and Prenatal
Diagnosis in Duchenne/Becker Muscular Dystrophy,
Indian Pediatrics 2001;38:631-9.
6. Martin A Samuel. Manual of neurological therapeutics.
7th edn, 2004.
7. Mukherjee M, Mittal B. Muscular dystrophies. Indian J
Paed 2004;71:161-8.
8. Neuromuscular disease—Neurology in practice. spl-
supplement 2003.
9. Pradhan S. Valley sign in DMD. Neurol India 2002;50(2):
184-6.
10. Gupte S. Recent advances in paediatrics; spl vol 9;
Neurology 2001.
11.1 Congenital Heart Disease: General Aspects: NC Joshi .................................................................................................................. 504
11.2 Common Congenital Heart Diseases in Children: Anita Khalil, M Zulfikar Ahamed ...................................................................... 509
11.3 Medical Management of Congenital Heart Diseases: Anita Khalil, Bharat Dalvi ............................................................................ 518
11.4 Surgery for Congenital Heart Diseases: KS Dagar, KS Iyer, Srikanta Basu ................................................................................... 521
11.5 Rheumatic Fever and Rheumatic Heart Disease: Anita Khalil ......................................................................................................... 526
11.6 Congestive Heart Failure in Children: Anita Khalil ............................................................................................................................ 534
11.7 Systemic Arterial Hypertension in Children: Srikanta Basu, S Srinivasan .................................................................................... 538
11.8 Pericardial Diseases and Disorders: S Srinivasan, Srikanta Basu ................................................................................................... 548
11.9 Cardiac Arrhythmias in Children: S Srinivasan, Srikanta Basu ....................................................................................................... 551
504 IAP Textbook of Pediatrics
11.1 Congenital Heart Disease:
General Aspects
Congenital heart disease is one of the most common birth
defects accounting for 30 percent of total congenital
malformations. The heart is developed during the period
of embryogenesis from a primitive muscles wrapped tube
to a four chambered muscular organ with septa, valves,
conduction system and major vessels originating and
terminating in the heart. Any defect in the orderly and
sequential development leads to structural or functional
malformation.
Congenital heart disease is defined as the structural,
functional or positional defect of the heart in isolation or
in combination, present at birth but may manifest at any
time after birth or may not manifest at all.
Incidence—6 to 8 per 1000 live borns have significant
structural cardiac malformation.
• About 1 in 10 stillborn infants have a cardiac ano-
maly.
• The eight most common anomalies account for over
80 percent of all lesions (Table 11.1.1) and about 10 to
15 percent have complex lesions with more than one
cardiac anomaly.
Previously diagnosis of the defect involved physical
examination, radiography of chest and electrocardiogram
(ECG), later invasive catheter studies. With the
introduction of ultrasound, echocardiography,
interventional cardiology, and intensive care facilities,
now:
1. Antenatal ultrasound increasingly offers early diag-
nosis.
2. Most structural heart defects are diagnosed non-
invasively by echocardiography.
TABLE 11.1.1: The eight common congenital heart lesions
Acyanotic — VSD 32%
— PDA 12%
— Pulmonic stenosis 8%
— ASD 6%
— Coarctation of aorta 6%
— Aortic stenosis 5%
Cyanotic Tetralogy of Fallot 6%
Transportation of great arteries 5%
NC Joshi
3. An increasing number of defects are treated non-
surgically, e.g. patent ductus arteriosus.
4. Even complex defects can be corrected completely at
initial operation, e.g. transposition of great vessels at
least in major cities in India.
5. The overall infant cardiac surgical mortality is on the
decline.
In adults a heart disease is mostly acquired in origin,
in children it is mostly congenital. The exception is
rheumatic heart disease.
Etiology
There is a major change in the understanding of etiology
of heart malformations. The prevailing dogma has been
that 8 percent of defects are due to chromosomal defects,
2 percent secondary to environmental teratogens
(intrauterine infections, cytotoxic drugs, radiation during
1st trimester) and the remaining 90 percent are multi-
factorial that is secondary to combined environmental
and genetic factors.
Based on indirect evidence (animal models) and
studies on human familiar patterns of inheritance, much
greater percentage has been attributed to single gene
mutation (Table 11.1.2).
Classification of Congenital Heart Diseases
There are various elaborate classifications. A simple
classification is into:
i. Acyanotic defect with left to right shunts
ii. Cyanotic defects with bidirectional shunts
iii. Defects that do not have shunt but have obstruc-
tive element (Table 11.1.3).
Some cardiac malformations are complex and can-
not be described using Table 11.1.1. To simplify the
description of these defects, the sequential segmental
analysis has been developed. The heart is divided into
four segments, the great vein, the atria, the ventricles and
the arterial trunks. Abnormalities are described in each of
these segments and in the connections between them
(Table 11.1.4).
 Diseases of Cardiovascular System 505

TABLE 11.1.2: Etiology of congenital heart disease TABLE 11.1.4: Sequential segmental analysis of the heart
I. Chromosomal abnormalities 8% Segment Examples
Incidence Type of defect
Atrial situs • Solitus
21 Trisomy-Down 60% A-V canal
• Inversus
syndrome defect
• Left isomerism
18 Trisomy- 90% VSD, PDA,
• Right isomerism
DORV
Venous • Total or partial anomalous
13 Trisomy- 90% Dextrocardia
connections of pulmonary venous
X0-Turner’s 15% Coarctation of
aorta connection
syndrome aorta
• Anomalous systemic venous
connections
II. Environmental Teratogen 2%
Atrioventricular • Concordant
Types of defect
connections • Discordant
I/U infection Rubella PDA, VSD, ASD
• Absent left connection (mitral
Mumps Endocardial fibroelastosis
atresia)
Maternal drugs
• Absent right connection
Phenytoin Variable
(tricuspid atresia)
Vitamin D Supravalvular aortic
• Double inlet left ventricle
stenosis
Ventriculoarterial • Concordant
Alcohol ASD, VSD
connection • Discordant
Maternal disease
• Double outlet right ventricle
Diabetes Transposition of great
Associated • VSD
vessels
anomalies • ASD
Systematic Lupus Congenital heart block
• PDA
• Coarctation
III. Single gene mutation 90%

TABLE 11.1. 3: Classification and incidence of congenital Clinical Presentation

heart defects
Despite a large number of cardiac defects that exist, there
Acyanotic defects with left to right Relative are only limited numbers of hemodynamic alterations
shunt incidence caused by cardiac malformations and symptoms.
Ventricular septal defect 32%
i. Mixing of systemic and pulmonary circulation lea-
Patent/Persistent ductus arteriosus 12%
Atrial septal defect 7% ding to cyanosis.
Acyanotic defects without shunt (with obstruction) ii. Inadequate blood reaching the lungs for oxygena-
Aortic stenosis 5%
tion leading to cyanosis.
Pulmonary stenosis 5% iii. Inadequate blood reaching the body: growth is
Coarctation of aorta 5% affected.
Cyanotic defects with bidirectional shunt iv. Increase in volume and pressure load over ventri-
Transposition of the great arteries 6% cles leading to congestive heart failure.
Tetralogy of Fallot 5% v. Abnormal situs leading to positional malformation
Double outlet right ventricle 1% dextrocardia.
Truncus arteriosus 1%
vi. Dysfunction of intrinsic conduction system leading
Pulmonary atresia 2%
Mitral atresia 1% to arrhythmias.
Tricuspid atresia 1%
Total anomalous pulmonary venous 1% Cyanosis
drainage
Cyanosis is blue discoloration of the skin, mucous
membranes, nails due to presence of desaturated
It is important to learn this segmental approach hemoglobin more than 5 gm/dl percent in arterial blood.
because universally echocardiography analysis is Those cardiac anomalies in which systemic venous return
reported according to this sequential segmental analysis. reaches systemic circulation without passage through
506 IAP Textbook of Pediatrics
lungs, presents with central cyanosis and clubbing of
fingers.
Cyanosis occurs under following circumstances:
i. Reduced pulmonary blood flow in defects with right
ventricular outflow tract obstruction
ii. Right to left shunts as in tetralogy of Fallot
iii. Discordant ventriculoarterial connections as in
transposition of great arteries, and
iv. Mixing of venous and arterial blood as in truncus
arteriosus or single ventricle.
Heart Failure
When heart cannot supply the blood flow demanded by
tissues, a clinical syndrome of symptoms and signs
manifest from elevated atrial pressure. It manifests with
rapid and labored breathing due to pulmonary edema,
pallor with peripheral cyanosis due to poor cardiac
output, tachycardia and excessive sweating due to
increased sympathetic activity and feeding difficulties.
Heart failure occurs in following situations:
1. Volume overload In all defects, with left to right shunt
like ventricular, atrial septal defect, patent ductus
arteriosus
2. Pressure overload In pulmonary and aortic, valve-
stenosis
3. Intrinsic myocardial diseases In cardiomyopathies, and
myocarditis
4. Decreased or increased diastolic filling In tachyarrhy-
thmias and bradyarrhythmias.
Heart Murmurs
In older children and in infants, congenital heart disease
presents as a heart murmur detected on routine
examination. The murmurs are produced due to
abnormal pressure gradient across laminar or non-
laminar pathways. The murmur is continuous in patent
ductus arteriosus, pansystolic in ventricular septal
defects, midsystolic in atrial septal defect and pulmonary
stenosis, diastolic in atrioventricular valve stenosis and
to and fro continuous murmur in congenital absence of
pulmonary valve.
Shock
Cardiac malformations resulting in a hypoplastic
ascending aorta, aortic atresia results in low cardiac
output. Child appears extremely ill with cold extremi-
ties, diminished pulses, low blood pressure, peripheral
cyanosis and in a semicomatose state.
Hypercyanotic Spells
In cardiac malformations with pulmonary infundibular
stenosis the obstruction is of dynamic variety. Whenever
the muscular outflow tract contracts, blood flow to
pulmonary circuit diminishes and patient gets intense
cyanosis. It occurs in Fallot’s tetralogy and defects with
Fallot’s physiology.
Stridor
Malformations leading to compression of trachea and
bronchi obstructing airways, presents with stridor as seen
in vascular rings and in dilated pulmonary artery due to
increased pulmonary blood flow.
Chest Pain
Malformation like anomalous origin of left coronary
artery, severe aortic stenosis leads to myocardial ische-
mia and patient presents with episodes of screaming,
pallor and chest pain.
Recurrent respiratory tract infections In cardiac defects
with left to right shunt, as seen with ventricular septal
defect and patent ductus arteriosus, there is a decreased
lung compliance which leads to frequent respiratory tract
infections.
Growth Failure
Growth failure is a very common manifestation of heart
defects due to poor oxygen saturation in the growing
tissues, persistent heart failure, and frequent respiratory
infections with undernutrition.
Diagnostic Investigations
The investigative tools that are available for diagnosis of
congenital heart diseases include chest radiography,
electrocardiography, echocardiography, cardiac cathe-
terization, cineangiography and cardiac MRI. All tests
except ECG and radiography are expensive.
Radiography of Chest
If there is a suspicion of heart disease on the basis of
history and physical examination, radiography which
complements clinical findings should be obtained.
Interpretation of chest radiograph involves evaluation
of cardiac size and classical cardiac contours, lung
vasculature, individual cardiac chambers, aortic arch and
abdominal situs (Fig. 11.1.1).
 Diseases of Cardiovascular System 507

Figure 11.1.1: The position of transducer and orientation of

the scanning for parasternal long axis image of the heart Figure 11.1.2: Position of transducer for subcostal four
chamber image of the heart
Electrocardiogram
Like radiography, electrocardiogram also complements
clinical findings. The electrocardiogram gives valuable
information about
1. Hemodynamic status of the defect
2. Severity of the defect
3. A few electrocardiographic patterns are suggestive
of certain lesions.
Normal values of the various ECG parameters are
available and for interpretation age of the child should
be kept in mind. In newborns, normal ECG and radio-
graph do not rule out serious cardiac defect as it takes
few days to evolve.

Echocardiography (Figs 11.1.1 to 11.1.5)

With the advent of real-time echocardiography imaging,
an elegant elaboration of intracardiac anatomy of all
structural defects of heart became possible. Doppler Figure 11.1.3: Normal pressures and oxygen
echocardiography can evaluate hemodynamic data saturation in heart and big vessels
regarding pressure differences across the aortic and
pulmonary valves, detection of shunt flows, semi-
Cardiac Catheterization
quantification of valve insufficiency. It has almost replaced
invasive cardiac catheterization and at some centers The classical invasive tool pertaining to pediatric
surgical correction of lesions like PDA, ASD (ostium cardiology remains cardiac catheterization. As men-
secundum) is possible without catheterization. tioned above, echocardiography has reduced diagnostic
508 IAP Textbook of Pediatrics
Figure 11.1.4: Normal X-ray chest showing structures that
form right and left side of the heart
Figure 11.1.5: Position of transducer for imaging aortic arch
value of cardiac catheterization but interventional
therapeutic catheterization procedures have increased its
therapeutic value (Fig. 11.1.6).
Indications
• Preoperative anatomical definition of the lesion
• Preoperative physiological assessment of pulmonary
artery pressures, pressure gradients, etc.
• Therapeutic interventional procedures
i. Balloon dilatation of stenotic valves and coarcta-
tion of aorta
Figure 11.1.6: Position of transducer for apical four chamber
ii. Blade and balloon atrial septostomy
iii. Nonsurgical closure of PDA and ASD
iv. Catheter ablation of arrhythmogenic focus,
pacemaker implantation.
Management of Congenital Heart Defects
Management is divided into medical management,
interventional management and surgical management.
Medical management is mainly concerned with pre-
vention and treatment of medical problems.
i. Nutritional support including treatment of anemia
ii. Antibiotic treatment for
1. Frequent pulmonary infections in lesion with
L → R shunt.
2. Infective endocarditis prophylaxis and treatment
3. Cerebral abscess commonly seen in cyanotic
heart diseases.
iii. Treatment of stroke seen in cyanotic heart defects
iv. Prevention and treatment of hypercyanotic spells
v. Antiarrhythmic treatment in arrhythmias
— complete congenital heart block
— paroxysmal SVT
vi. Use of prostaglandin E1 in shunt dependent con-
genital heart defects.
Surgical Strategies
1. Palliative surgeries mitigates symptoms or extends life
without addressing basic pathophysiology of cardiac
lesion.
 Diseases of Cardiovascular System 509

Examples
1. Systemic and pulmonary artery shunt
2. Pulmonary artery banding.
Corrective surgery when they are intended to
completely or nearly completely
1. Separate pulmonary and systemic circulation
2. Restore adequate quantities of appropriately oxy-
genated blood to capillary beds
3. Reduce volume and pressure overloads towards
normal.
BIBLIOGRAPHY
1. HO SV Baker EJ, Rigby ML, Anderson RH. Color Atlas
of CHD. London, Mosby Wolfe 1995.
2. Jordan SC, Scott O: Heart Disease in Pediatrics (2nd edn)
1981;3:7.
3. Nora JJ. Causes of congenital heart disease: Old and new
modes. Am Heart J 1993;125:1409–19.
4. Skinner J, Alverson D, Hunter S. Echocardiography for
neonatologist. London, Churchill Livingstone 2000.
5. Walters HL. Congenital cardiac surgical strategies and
outcome: Hearts, Pediatric Annals 2000;29(8):489–98.

11.2 Common Congenital Heart

Diseases in Children
Anita Khalil, M Zulfikar Ahamed

ACYANOTIC CONGENITAL HEART DISEASE 1. Ostium secundum defect—It is the most common
defect, accounting for 50 to 70 percent of all ASDs.
ATRIAL SEPTAI DEFECT (ASD) This defect is present at the site of fossa ovalis,
Prevalence allowing left to right shunting of blood from LA to
RA.
ASD (ostium secundum defect) occurs as an isolated defect 2. Ostium primum defects—30 percent of all ASDs.
in 6 to 10 percent of all congenital heart diseases. It occurs
3. Sinus venosus defect—occurs in about 10 percent of
twice as commonly in females than males. ASDs occur in
all ASDs, most commonly located at the entry SVC
1 child/1000 live births.
into RA.
Pathology
Clinical Manifestations
Three types of ASDs exist; secundum, primum and sinus
venosus defects (Fig. 11.2.1). Infants and children with ASD are usually asymptomatic.
Rarely, ASDs in infants are associated with poor growth,
recurrent lower respiratory tract infection and heart
failure.

Physical Examination

On auscultation (Fig. 11.2.2) A widely split and fixed S2

Figure 11.2.1: Unlabeled arrow right superior
pulmonary vein
and grade 2 to 3/6 ejection systolic murmur are
characteristic findings of ASD in older infants and
children with a large L-R shunt, a mid-diastolic rumble,
resulting from relative tricuspid stenosis (TS), may be
audible at left lower sternal border.
These typical auscultatory findings may be absent in
an infant.
510 IAP Textbook of Pediatrics

Figure 11.2.2: Cardiac findings of ASD. Heart murmurs with solid borders are the primary murmurs, and those without solid
borders are transmitted murmurs or those occurring occasionally.. Exp—expiration, lnsp—inspiration

Figure 11.2.3: Tracing from a 5-year-old girl with secundum-type ASD

Electrocardiography (Fig. 11.2.3)

Right axis deviation (RAD) of + 90 to + 180 degrees. Right
ventricular hypertrophy (RVH) and right bundle branch
block (RBBB) with rSR pattern in VI are typical.

X-ray Studies (Fig. 11.2.4)

1. Cardiomegaly with right atrial and right ventricular
enlargement. (cardiothoracic ratio> 0.5).
2. Prominent main pulmonary artery may be seen in
large shunts.
3. Prominent pulmonary vascular markings.
Echocardiography (Fig. 11.2.5)
1. Two-dimensional echo-study is diagnostic. The study
shows the position as well as size of defect, which
can be seen best in subcostal four chamber view.
Figure 11.2.4: PA and lateral views of chest roentgenogram
from a 10-year-old child with ASD. The heart is mildly enlarged
with involvement of the RA (best seen in PA view) and the RV
(best seen in the lateral view with obliteration of the retrosternal
space). Pulmonary vascularity is increased and the
MPA segment is slightly prominent
In ASD secundum—A dropout can be seen in mid atrial
septum.

Figure 11.2.5: Diagram of two-dimensional echo of the three types of ASD. The subcostal transducer position provides the most
diagnostic view. (A) Sinus venosus defect. Defect is located in the posterosuperior atrial septum, usually just beneath the orifice
of the SVC. This defect is often associated with partial anomalous return of the right upper pulmonary vein, (B) Secundum ASD.
Defect is located in the middle portion of the atrial septum. (C) Primum ASD. Defect is located in the anterointerior atrial septum,
just over the inflow portion of each AV valve
In ASD primum—It is a defect in lower atrial septum.
Sinus venosus defect (SVC type)—Defect in postero-
superior atrial septum.
Coronary sinus ASD- communication at level of
coronary sinus.
2. Flow velocity is increased depending upon the shunt
which brings about dilatation of pulmonary artery and
enlargement of right atrium and right ventricle.
3. Pulsed Doppler examination—A characteristic flow
pattern with the maximum left to right shunt occurring
in diastole.
Color flow mapping—It evaluates the hemodynamic
status of ASD.
Doppler examination—It estimates ressures in right
ventricle and pulmonary artery.
5. M-mode Echo may show increased right ventricular
dimension and paradoxical motion of the inter-
ventricular septum—It signifies RV volume. In older
children and adolescents transesophageal echo (TEE)
may be necessary to visualize the defect. Associated
Partial anomalous pulmonary venous connection may
be picked up by this method.
Natural History
i. In ASD less than 3 mm—Spontaneous closure occurs
in 100 percent before one and half years of age. But if
the defect is more than 8 mm or age is more than 2
years it rarely closes spontaneously
ii. Most of the children remain active and asympto-
matic, though CHF may rarely develop during
infancy
iii. If untreated, pulmonary vascular disease leads to
hypertension and subsequent CHF develops in the
3rd and 4th decades.
Diseases of Cardiovascular System 511
iv. Infective endocarditis does not occur in isolated
ASDs; therefore, prophylaxis against subacute
bacterial endocarditis (SBE) is unnecessary.
v. Onset of atrial fibrillation may occur and less
commonly atrial flutter occurs with increasing age.
Management
Medical
1. No exercise restriction is indicated.
2. In infants—CHF should be treated urgently because
of possibility of spontaneous closure.
3. Nonsurgical closure indicated nowadays by
“clamshell” or “buttoned” devices in uncomplicated
and smaller defects. But now Amplatzer Septal
occluder (ASO) is the only FDA approved device for
ASD closure.
Surgical Indications
1. Left to right shunt with a QP/QS ratio of more than 1.5
2. Some consider a smaller shunt to be an indication,
because of danger of paradoxical embolization and
cerebrovascular accident. High pulmonary vascular
resistance (PVR) (i.e. more than 10 units/rn2) is a
contraindication to surgery.
3. Device closure is not feasible or has failed
Timing and procedure Surgery is usually delayed till 2 to 4
years, because of the possibility of spontaneous closure.
But if CHF in infancy does not respond to medical
management, then surgery is indicated. The defect is
repaired under cardiopulmonary bypass with either a
simple suture or a pericardial or a teflon patch.
512 IAP Textbook of Pediatrics
Complications and mortality: In the immediate postoperative
period, arrhythmias and cerebrovascular accidents may
develop. Fewer than 1 percent of patients die; however,
there is a greater risk for small infants or those with high
PVR.
Postoperative follow-up: Atrial or nodal arrhythmias occur
in 7 to 20 percent of the postoperative patients.
Occasionally, sick sinus syndrome may supervene,
especially when a sinus venosus defect is repaired. This
eventuality may require antiarrhythmic drugs or
pacemaker implantation.
Patent Ductus Arteriosus (PDA) patent ductus arterio-
sus (PDA) is the persistence of the duct which connects
the pulmonary artery to aorta during foetal life.
Prevalence
PDA occurs in 5 to 10 percent of all CHDs accounting
for 1 in 2000 live births excluding premature infants. It is
more common in females than males (M:F1:3).
Pathology
1. There is persistence of patency of a normal fetal
structure, between the left pulmonary artery (PA) and
the descending aorta (i.e. 5-10 mm distal to the origin
of the left subclavian artery).
2. The ductus is usually cone shaped, with a small orifice
to the PA, which is restrictive to blood flow.
Clinical Manifestations
Patients are usually asymptomatic when the ductus is
small. A large shunt PDA—is accompanied by tachy-
pnea, hyperdynamic circulation and poor weight gain.
It might be associated with repeated chest infections, and
CHF.
Physical Examination
1. Hyperactive precordium with a systolic thrill at the
upper left sternal border. Bounding peripheral pulses
with wide pulse pressure are other characteristic
feature of hyperdynamic circulation. On auscultation,
P2 may be loud in presence of pulmonary hyper-
tension.
2. Aloud and harsh 4/6 continuous machinery murmur
is best heard at the left infraclavicular area.
Electrocardiography
In small to moderate sized PDA—Normal or left
ventricular hypertrophy (LVH), large PDA combined
ventricular hypertrophy. In reversal of shunt-RVH
develops.
X-ray Studies
1. Small shunt PDA—normal X-ray.
2. Cardiomegaly of varying degrees occurs with
enlargement of left atrium (LA), left ventricle (LV) and
ascending aorta.
Echocardiography
1. PDA can be imaged in most of the patients by 2-D echo
in a high-parasternal or a suprasternal notch view.
2. The dimensions of LA and LV provide an indirect
assessment of the magnitude of the left to right shunt.
Natural History
1. Unlike PDA in preterms, spontaneous closure of the
PDA does not occur; PDA in term infants, results
because of structural abnormality of the ductal smooth
muscle.
2. If the shunt is large, recurrent chest infection and CHF
develop.
3. Reversal of shunt takes place, if a large PDA remains
untreated and pulmonary hypertension develops.
4. SBE may supervene, more frequent with small PDA
than large ones.
Management
Medical
1. No exercise restriction in absence of pulmonary
hypertension.
2. Indomethacin oribuprofen is ineffective in term infants.
3. SBE prophylaxis indicated in presence of small PDA.
4. Catheter closure of ductus with different devices –
Infants more than a few months of age – with ductus
< 3 mm in diameter – occluding coils, one or two.
Treatment of choice for larger PDAs, < 12 mm in
diameter. Amplatzer duct occluder is device of choice.
For PDAS > 12 mm, septal closure devices are indicated.

Surgical
Anatomic existence of PDA, regardless of size is an
indication for surgery, but before that reversal of shunt
has to be ruled out. Surgical procedure is performed any
time between 6 months to 2 years, or any time in an older
child. Surgery remains the treatment of choice for
premature infants and children with very large PDAs.
Procedure Ligation and division through left postero-
lateral thoracotomy, without cardiopulmonary bypass.
This is a safe procedure; death occurs in less than
1 percent of patients.
Ventricular Septal Defect (VSD) (Fig. 11.2.6) VSD is
the most common form of CHD and accounts for 20
percent of all CHDs. Incidence is 1.5-3.5 per 100 term
infants and 4.5-7 per 1000 premature infants.
Pathology
1. The ventricular septum may be divided into a small
membranous portion and a large muscular portion.
The muscular septum has three components—the
inlet, the trabecular septum and the outlet (infundi-
bular) septum. The trabecular septum has three
components: central, marginal and apical.
A VSD may be classified into: perimembranous,
inlet, outlet (infundibular), central muscular, marginal
muscular and, apical muscular defect
Figures 11.2.6A and B: (A) The four major components of the ventricular septum seen from the right ventricular aspect. The
membranous septum is contiguous with portions of the outlet septum, the trabecular septum and the inlet septum (B) Possible
sites of ventricular septal defect
Diseases of Cardiovascular System 513
2. Defects vary in size ranging from a tiny defect to a
large defect with accompanying CHF.
3. ‘Bundle of His’, is related to posteroinferior quadrant
of perimembranous defect and superoarterior
quadrant of inlet muscular defect.
VSD Classification
1. Perimembranous: most common -80% of surgical or
autopsy series.
2. Outlet -5-7% of surgical and autopsy series. Situated
just beneath the pulmonary valve (supracristal,
infundibular etc).
3. Inlet – 5-8%. Posterior and inferior to perimembra-
nous defect.
4. Muscular: 5-20%
a. Central – mid muscular- may have multiple
apparent channels on RV side and coalesce to a
single defect on LV side.
b. Apical- multiple apparent channels on RV side
and single defect on LV side – as in central defect.
c. Marginal – along RV septal junction.
d. “Swiss cheese” septum – large number of
muscular defects.
Clinical Manifestations
History
1. Small VSD—The patient is asymptomatic and growth
is normal.
514 IAP Textbook of Pediatrics

Figure 11.2.7: Tracing from a 3-month-old infant with large VSD, PDA, and pulmonary hypertension.
The tracing shows CVH with left dominance. Note that V2 and V4 are in standardization

2. Moderate to large VSD—repeated pulmonary

infections, easy fatiguability, decreased exercise
tolerance, failure to thrive, pulmonary hypertension.
3. If VSD not operated—pulmonary hypertension
develops cyanosis appears and level of activity is
decreased.

Physical Examination
1. Small VSD—The child is well-developed and
acyanotic.
2. Large VSD—tachypneic child, repeated chest infec-
tion, poor weight gain, and CHF, prominent
precordial bulge.
3. Reversal of shunt—cyanosis, clubbing (Eisenmenger’s
complex) respiratory distress. SI and S2 are well-heard.
P2 may be single and loud in presence of PAH.
Pansystolic murmur, i.e. 3 to 5/6 is heard at left sternal Figure 11.2.8: PA view of chest roentgenogram in VSD with
border. large shunt and pulmonary hypertension. The heart size is
moderately increased, with enlargement on both sides. PVMs
Electrocardiography (Fig. 11.2.7) are increased, with a prominent MPA segment
1. Moderate sized VSD volume overload LVH with or
without LAH. Echocardiography (Fig. 11.2.9)
2. Large VSD-combined ventricular hypertrophy (CVH)
Two dimensional and Doppler echo can identify the
3. Eisenmenger’s Complex-RVH.
number, size and exact location of defect, estimate PA
pressure by using modified Bernoulli equation, identify
X-ray Studies (Fig. 11.2.8)
other associated defects and estimate the magnitude of
1. Cardiomegaly of varying degrees depending on the the shunt.
size of VSD and magnitude of L-R shunt. The
pulmonary vascular markings are increased in central Natural History
and peripheral fields. 1. Spontaneous closure in 30 to 40 percent of cases with
2. When reversal of shunt takes place, hilar PA enlarges membranous and muscular VSDs, especially when
and peripheral lung fields become oligemic. they are small.
 Diseases of Cardiovascular System 515

Figure 11.2.9: Diagrammatic representation of different parts of the ventricular septum seen a various two-dimensional views.
(A) parasternal long-axis view. (B), (C) and (D) Different levels of the parasternal short-axis view. (E) and (F) a’ subcostal four-
chamber views, respectively (G) and (H) apical and subcostal five-chamber views, respectively

2. CHF develops in large VSD, after 8 weeks of age.
3. In a large VSD, the shunt may reverse as early as 6 to
12 months of age, but Eisenmengers syndrome does
not get established till the teenage years.
4. Infective endocarditis more common compared to other
lesions.
5. In large VSDs, infundibular stenosis may develop
which decreases the magnitude of L-R shunt
(acyanotic TOF).
Management
Medical
1. No exercise restriction in the absence of pulmonary
hypertension.
2. Maintenance of good dental hygiene, antibiotic
prophylaxis against infective endocarditis is very
important.
3. Treatment of CHF—when poor feeding, sweating
easy fatiguability, tachypnea- leading on to failure to
thrive. It has to be treated with decongestive therapy
(digoxin and diuretics) and ACE-inhibitors indicated.
4. Frequent feeding of high calorie formula—Anemia has
to be corrected by iron therapy or blood transfusion
5. “Umbrella” closure of selected muscular defects is
possible but, has still not been established.
Surgical lesions
1. Small defects need not be operated.
2. Large VSDs—If CHF responds to decongestive
therapy, then surgery is delayed. If CHF does not
respond—then the VSD should be closed within the
first 6 months of life.
3. After one year of age, significant L-R shunt with QP/
QS of at least 2:1 indicates surgical closure.
4. Older infants with large VSDs and increased
pulmonary resistance should be operated imme-
diately
5. Small VSD with no CHF and QP/QS less than 1.5:1,
should not be operated.
6. Surgery is contraindicated in presence of predomi-
nant R-L shunt or PVR-SVR is more than 0.5.
7. VSD with aortic crisp prolapse should be operated
immediately to prevent further aortic regurgitation.
516 IAP Textbook of Pediatrics
Mortality Surgical mortality 2 to 5 percent after the age of 6
months. It is higher in smaller infants, less than
2 months or with associated defects.
Complications
1. Incomplete closure.
2. Different degrees of heart blocks—RBBB, left anterior
hemiblock or even complete heart block.
3. Aortic regurgitation.
Postoperative follow-up
1. Activity not to be restricted, unless postoperative-
complications are present.
2. SBE prophylaxis may be discontinued 6 months after
surgery, if no complications occur.
3. In presence of heart blocks, pacemaker implantation
may be indicated.
CYANOTIC CONGENITAL HEART DISEASE
Tetralogy of Fallot (TOF)
Prevalence
Prevalence of TOF ranges between 0.48-0.8 per 1000 live
births.
TOF occurs in 3.5-9 percent of all CHDs. This is the
most common cyanotic CHD, seen beyond infancy.
Pathology (Fig. 11.2.10)
The four components of tetralogy of Fallot include:
1. RV outflow tract obstruction—Infundibular pulmonic
stenosis.
Figure 11.2.10: Apical four-chamber view with LV outflow tract
(apical five chamber view) in a patient with perimembranous
VSD (arrow), AV – arotic
2. Perimembranous ventricular septal defect.
3. Dextroposed and overriding of aorta.
4. Right ventricular hypertrophy.
Other associated features are:
1. Right aortic arch in 25 percent of cases.
2. Pulmonic annulus and main pulmonary artery are
hypoplastic in some patients.
3. In about 5 percent of patient abnormal coronary
arteries are also present.
Clinical Manifestations
Symptoms vary widely depending on severity of
pulmonary stenosis.
1. Most cases of TOF are mildly cyanosed at birth.
Exertional dyspnea, squatting and hypoxic (cyanotic)
spells develop later on in life.
2. Acyanotic TOF with a large VSD will present with
CHF.
3. Presence of severe cyanosis at birth signifies
pulmonary atresia with VSD.
4. Squatting – characteristic Symptom of TOF. Typical
posture after exertion to get relief from dyspnoea.
5. Hypoxic (cyanotic) spell- episode characterized by
paroxysmal, tachypnoea, deepening cyanosis,
limpness, syncope, occasional convulsion or death,
feeding, crying or defecation precipitates the episode.
Physical Examination
1. Varying degrees of cyanosis, clubbing and tachypnea
are present.
2. S2 is usually single in pulmonary area because aortic
component is heard due to dextroposed and overrid-
ing of aorta. A loud 3 to 5/6 ejection systolic murmur
is heard at the upper left sternal border. The more
severe is the PS, softer and shorter is the murmur.
3. The only indirect evidence of VSD is the presence of
cyanosis.
4. In acyanotic TOF (VSD with mild P.S.)—Long pan-
systolic murmur resulting from VSD and ejection
systolic murmur due to inendibular stenosis is heard
in pulmonary area. Cyanosis is absent.
Electrocardiography
1. RAD (+120 -+ 180 degrees) in cyanotic form. In
acyanotic cases QRS axis is normal.
2. RVH – tall R in v1 and prominent S in V5 and V6.

Figure 11.2.11: A posteroanterior view of chest roentgenogram
in TOE The heart size is normal, and pulmonary vascular mark-
ings are decreased. A hypoplastic MPA segment contributes
to the formation of the boot-shaped heart
X-ray Study (Fig. 11.2.11)
1. Normal sized heart with oligemic lung fields
2. Typical presentation-concave MPA segment with
upturned apex giving “boot shaped heart” or “coeur
en sabot” appearance.
3. Right atrial enlargment and right sided aortic arch
may be present in 25 percent of cases.
4. Acyanotic TOF X-ray findings are no different from
that of a VSD, but patients with TOF have RVH rather
than LVH on ECG.
Echocardiography (Fig. 11.2.12)
Two-dimensional echo and Doppler studies can make the
diagnosis and quantitate the severity of TOF
1. A large perimembranous infundibular VSD and
overriding of the aorta are visualized in long
parasternal view.
2. RV outflow tract (RVOT) obstruction with pulmonary
valve and annulus, MPA and the branches are smaller
than normal.
3. Doppler studies estimate the pressure gradient across
RVOT.
4. Anomalous coronary artery distribution can be
imaged or suspected.
Natural History
Infants who are acyanotic at birth, become cyanosed by 8
to 12 weeks of life.
Diseases of Cardiovascular System 517
Figure 11.2.12: Parasternal long-axis view in a patient with
TOF Note a large subaortic VSD (arrow) and a relatively large
(AO) overriding the interventricular septum (IVS) AV—aortic
valve, MV—mitral valve
1. Hypoxic spells may develop, depending upon severity
of RVOT and thereby growth retardation may
supervene in future.
2. Brain abscess, cerebrovascular accidents and SBE are
occasional complications.
3. Since central cyanosis predisposes to polycythemia,
iron deficiency anemia and coagulopathy should be
remembered as potent complications.
Management
Medical
1. Physician should recognize and treat the hypoxic
spell. Parents have to be educated to recognize it and
palliative procedures to be carried out.
2. Oral propranolol therapy 1-4 mg/kg 4 times a day
given in hypoxic patients to prevent hypoxic spells
3. Balloon dilatation of RV outflow tract and pulmonary
valve has been attempted to delay surgical repair
4. Relative iron deficiency anemia should be detected
and treated since it is very common in polycythemic
children.
Surgical
Palliative shunt procedures (Fig. 11.2.13) Shunt proce-
dures are performed to increase pulmonary blood flow.
Indication are the following, especially in the poorer
nations where primary repair is difficult.
1. Neonates with TOF and pulmonary atresia.
2. Infants with hypoplastic pulmonary annulus and
hypoplastic PAS.
518 IAP Textbook of Pediatrics
Figure 11.2.13: Palliative procedures that can be used in
patients with cyanotic cardiac defects with decreased PBF.
The Glenn procedure (anastomosis between the superior
vena cava and right PA) may be performed in older infants
with hypoplastic RV, such as is seen with tricuspid atresia
3. Severely cyanotic infants—younger than 3 months and
those who have medically unmanageable hypoxic
spells.
The Shunt Procedures
1. Classic Blalock-Taussig shunt—Anastomosis between
subclavian artery and ipsilateral pulmonary artery -
11.3 Medical Management of
Congenital Heart Diseases
Advances in perinatal management has resulted in
identifying a large number of babies with congenital heart
disease. With the improvements in surgical techniques and
understanding of cardiopulmonary bypass, more and
more babies with congenital heart disease survive till late
childhood, adolescence and even adulthood. Therefore, it
is important to understand the broad principles of medical
management of these children both during the pre- and
postoperative periods. The details of drug dosages and
schedules have been omitted, and the technical intricacies
procedure of choice for an infant, more than 3 months
of age.
2. Gore-Tex interposition shunt—placed between
subclavian artery and ipsilateral PA, is ideal for infants
less than 3 months.
3. Waterston shunt and Potts operation have been
abandoned because of high percentage of compli-
cations.
Conventional repair surgery Timings vary depending upon
the patient, but early surgery is always preferred.
Indications and Timing
1. Symptomatic infants who have favorable anatomy of
RV outflow tract and PAS—An early repair is advised,
any time after four months of age.
2. Mildly cyanotic children who have had shunt
surgery—total repair ito 2 years after shunt operation.
Procedure: Brock’s procedure Total repair of the defect is
carried out under cardiopulmonary bypass and circulatory
arrest. For uncomplicated TOF, mortality is between 2 to 5
percent, during first 2 years.
Complications
1. RBBB on ECG occurs in 90 percent of patient
2. Complete heart block is rare.
Anita Khalil, Bharat Dalvi
of nonsurgical interventions were considered beyond the
scope of this chapter.
Congenital heart disease may broadly be classified
in to 2 main groups. Cyanotic and acyanotic. The medical
management of any congenital cardiac disorder, whether
cyanosed or acyanosed should be on following lines:-
1. Congestive cardiac failure.
2. Cyanosis
3. Prevention of Infestive Endocarditis.
4. Catheter Intervention procedure.

CONGESTIVE HEART FAILURE
Congestive heart failure in children with congenital heart
disease is related to varied mechanical problems like
valvular regurgitation, myocardial failure or excess
pulmonary blood flow and usually requires surgical
correction. The broad principles of non-surgical
treatment are as follows: Important general measures
include reducing physical activity and restriction of
dietary sodium (e.g. potato chips, wafers, papad, pickles,
etc.) intake. Supplemental oxygen should be adminis-
tered in patients with pulmonary edema. Pharmaco-
logical treatment involves use of drugs to improve the
pumping function of the heart (digoxin, sympathomi-
metic amines such as dopamine, dobutamine, epine-
phrine, isoprenaline and amrinone), and control of
excessive salt and water retention (diuretics). If the
combination of these two groups of drugs is not effective,
vasodilators (ACE inhibitors, hydralazine, prazosin or
nitroprusside) should be added. Due to wide variations
in individual’s response to digoxin, its dose should be
tailored to individual patient’s clinical response.
Although digoxin toxicity is uncommon in children as
compared to adults, they should be closely observed for
gastrointestinal symptoms, arrhythmias and electro-
cardiographic evidence suggestive of toxicity. Serum
digoxin levels can also be monitored. Intravenous
sympathomimetic amines are useful in the perioperative
period or during life threatening low-output states
associated with cadiogenic shock.
The most commonly used diuretic in pediatric
practice is frusemide, and to a lesser extent, chlorothia-
zides. Spironolactone when used in conjunction has a
potassium sparing effect. While using frusemide in a dose
greater than 2 mg/kg, it is prudent to add potassium
sparing diuretic to the prescription. Volume depletion,
hypokalemia, hyponatremia, metabolic alkalosis and
hyperuricemia are the known, complications which need
to be monitored in patients on long-term diuretic therapy.
A pure venodilator would be desirable when symptoms
are related to systemic or pulmonary venous congestion,
whereas an afterload reducing agent is preferred in
patients with increased peripheral vascular resistance.
Most agents have both the effects and are best suited for
patient with advanced heart failure. Ventilatory support
and ventricular assist devices (e.g. extracorporeal
membrane oxygenator-ECMO) have an important role
particularly in the perioperative management of patients
with severe cardiac failure.
Diseases of Cardiovascular System 519
CYANOSIS
Most cases of cyanotic congenital heart diseases that
require early intervention for cyanosis have a resting
saturation of less than 80% and do not increase
saturations to above 90% on giving 100% oxygen
inhalation. Some cases of common mixing (e.g. total
anomalous pulmonary venous connection and double
inlet left ventricle) can have higher saturations.
Cyanotic Spell
Cyanotic spell is a life threatening emergency charac-
terized by progressive increase in rate and depth of
respiration, deepening cyanosis culminating into lack of
consciousness and occasionally a hypoxic seizure may
also take place. Peak incidence is between 6 months to
2 years of age and it occurs mostly precipitated by crying,
feeding or straining on defecation.
Management
1. Posture – child should be put in knee-chest position.
2. Sedation – Inj Morphine –relieves anxiety and
sensation of suffocation.
3. Beta blockers- Inj. Propranolol or metaprolol – reduces
heart rate and relieves the infundibular spasm.
4. Oxygen inhalation – mandatory to increase oxygen
saturation.
5. Parenteral administration of sodium bicarbonate to
treat metabolic acidosis more IV methoxemine.
6. In severe cases resistant to these measures general
anesthesia with assisted ventilation is advisable.
7. Correct anemia.
Use of Prostaglandins
Availability of prostaglandins has revolutionized the
management of congenital heart diseases in the neonatal
period, because of its role in keeping for maintaining duct
patent for maintaining pulmonary blood flow. Today,
the obstructed form of total anomalous pulmonary
venous drainage is the only truly cardiac surgical
emergency. In all the other duct dependent circulation
in cyanotic congenital heart disease and left sided
obstructive lesions, the ductal patency can usually be
maintained with prostaglandin infusion to stabilize the
patient so as to permit surgery on a semi urgent basis.
Some indications of prostaglandin infusion include duct
dependent pulmonary circulation as in case of pulmo-
nary atresia with intact ventricular septum or trans-
position of great arteries with intact ventricular and atrial
520 IAP Textbook of Pediatrics
septum condition in neonates with hypoplastic left heart
syndromes. Prostaglanding E1 is available as intravenous
infusion, whereas prostaglandin E2 can be given orally
as well as parenterally. Side effects include apnea and
hypotension.
Use of Indomethacin or ibuprofen
Oral or intravenous indomethacin has been used
successfully for nonsurgical closure of patent ductus
arteriosus (PDA). Results are gratifying when used in
first 10 days after birth and in pre-mature infants. Second
course may be indicated if the clinical signs of ductus
reappear after the initial closure. Indomethacin should
not be administered in infants with renal dysfunction,
overt bleeding, shock, necrotizing enterocolitis or
electrocardiographic evidence of myocardial ischemia
Ibuprofen is being used with similar results.
Management of Eisenmenger Syndrome
Eisenmenger syndrome refers to patients with congenital
heart defects who have a systemic level of pulmonary
artery pressure and high pulmonary vascular resistance
with right to left or bidirectional shunting. Congestive
heart failure may occur which responds to digitalis and
diuretics. Anticoagulants have been recommended to
prevent in situ thrombosis in lungs. Hemoglobin
concentration at 20 g/dl commensurate for the patients
degree of resting desaturation. Repeated phlebotomies
or erythrophoresis may be required in a polycythemic
patient. Oral iron therapy should be used to treat
hypochromia and microcytosis. Vasodilators are
generally not recommended. Pregnancy is absolutely
contraindicated because of high maternal and fetal
morbidity and mortality.
Treatment of Intercurrent Infections
Intercurrent infections in children with congenital heart
disease (e.g. pneumonias in patients with large left to
right shunts, cerebral abscess in cyanotics or infective
endocarditis) needs to be searched diligently and treated
with specific antimicrobial therapy. For suspected
infections, initial empiric antibiotic coverage should be
given sufficiently broad to treat the most likely
pathogens. Delay in accurate diagnosis could lead to
fulminant progression of infection or worsening of
hemodynamics. Infective endocarditis prophylaxis
should be given within 60 minutes prior to the start of an
invasive procedure and should be directed towards the
common organisms involved.
Treatment of Infective Endocarditis
It is imperative that the selection of antibiotic regimen be
guided by blood cultures to demonstrate persistent
bacteremia as well as antibiotic sensitivity testing.
Treatment should begin on clinical suspicion while
awaiting results to treatment. The duration of therapy
varies from 4 to 6 weeks depending on the organism
isolated and on the underlying premorbid condition.
Surgical intervention is necessary if there is progressive
worsening of congestive heart failure, embolic episodes,
nonresponse to treatment or prosthetic valve dysfunction.
Interventional Catheterization in Management of
Congenital Heart Diseases
Therapeutic catheterization has added a new dimension
to the management of congenital heart disease and in some
conditions provide an effective alternative option or
supplement the surgical management. Interventional
procedures can be grouped into four general types:
1. Atrial septostomy,
2. Valve dilations,
3. Vessel dilations, and
4. Occlusion procedures.
These procedures are performed in catheterization
laboratories by trained pediatric interventional cardio-
logists and require a large inventory of catheters and
devices.
Atrial Septostomy Procedures
Atrial septostomy procedure is indicated for palliation in
congenital heart lesions in neonates and young infants in
whom all systemic, pulmonary or mixed venous blood
must travel a restrictive interatrial communication in order
to return to the systemic circulation. This includes
complex defects associated with hypoplastic right or left
ventricles and infants with total anomalous pulmonary
venous drainage. The procedure involves withdrawing
an inflated balloon catheter rapidly across the atrial
septum so as to create a nonrestrictive atrial septal defect.
In infants older than 1 month, a blade septostomy catheter
is recommended to achieve the same result due to the thick
septum. These procedure are emergent in nature and can
be performed in catheterization laboratory under
fluoroscopy control or in intensive care unit under
echocardiography guidance.

Balloon Valve Dilation
Stenotic valves can be opened by the use balloon catheters.
The pressure created by the balloon wall as it expands
across a stenosed valve leads to opening of the valve by
splitting the commissures and dilation of the valve
annulus. The balloon is rapidly inflated to a recommended
pressure, till the waist in the balloon disappears. Pressure
gradients are recorded before and after the dilations to
assess the results. These procedures have been success-
fully used for aortic and pulmonary stenosis. Dilation of
the right ventricular outflow tract in patients with
tetralogy of Fallot with a view to palliation is an emerging
indication. Availability of low profile balloons have
significantly reduced the vascular access complications.
Avoidance of thoracotomy and cardiopulmonary bypass
with their inherent risks and morbidity are definite
advantages of these procedures.
Vessel Dilations and Vascular Stents
This procedure utilizes a catheter with a small, cylindrical,
fixed-maximal-diameter balloon mounted on it. The
balloon catheter is passed over a guide wire, positioned
across the area of stenosis and inflated with relatively
high pressure. This stretches the area of stenosis to the
predetermined diameter of the balloon. Current indi-
cations for vessel dilation include postoperative coarcta-
tion of the aorta and native coarctation. Branch pulmonary
artery dilation can be done successfully using high
11.4 Surgery for Congenital Heart Diseases
Since its inception in the 1950s surgery for congenital heart
disease has evolved to its present stage where most defects
can be corrected with a mortality of less than 1 percent. In
the early years, prohibitive mortality and morbidity
concurrent to the bypass run initiated the concept of two
stage repairs, with an initial palliative procedure (which
avoided cardiopulmonary bypass early in infancy)
followed later by a corrective procedure. The scenario has
dramatically changed since with the thrust being on early
Diseases of Cardiovascular System 521
pressure balloons. Systemic and pulmonary vein dilation
have also been performed. Intravascular stents provide
the necessary scaffolding to prevent recoil and restenosis
following balloon dilatation. These are being particularly
used in branch pulmonary arteries, aorta and pulmonary
veins.
Occlusion Procedures
These procedures have been used to occlude abnormal of
persistent intracardiac (e.g. atrial and ventricular septal
defects) and extracardiac (e.g. PDA and arteriovenous
fistulas) shunts. The occlusion devices are delivered
selectively through specially designed catheters to occlude
the shunts. Rashkind double umbrella device, PDA coils
are amongst the various devices available for closure of
ductus arteriosus. Recent modifications of amplatzer
occluding device and cardiorenal device have shown
encouraging results in cases of ASD closure. Limited
success has been achieved in closure of ventricular septal
detects using clamshell double umbrella device. Newer
devices with different geometries aimed at achieving
procedural ease, complete occlusion of the shunts and
reducing device embolization rates are being continuously
developed.
BIBLIOGRAPHY
1. Emmanouilides GC, Allen HD: Moss and Adams Heart
Disease in Infants, Children, and Adolescents (7th edn).
Baltimore: William and Wilkins, 2008.
KS Dagar, KS Iyer, Srikant Basu
total corrective repair where possible, because clinical and
experimental data have shown that early intervention
protects the heart from the adverse effects of volume
loading or hypertension as the case may be. In cyanotic
children, early operation reverses or at least halts the insult
to the cardiopulmonary and other organ systems because
of the attendant ischemia and polycythemia. With increa-
sing age the cardiac response changes from mostly
hyperplasia of myocytes and coronary angiogenesis to
522 IAP Textbook of Pediatrics
only hypertrophy without angiogenesis. In the light of
this, repair during the early hyperplastic phase of cardiac
growth is expected to yield normal or near normal left and
right ventricular function. Early repair also decreases the
potential for electrical instability.
An important fraction of lung development and
maturation occurs after birth, particularly within the first
1 to 2 years. The presence of congenital heart defects have
an adverse impact on this phase of lung development.
The obvious inference is that early interventions to
address congenital heart defects are likely to result in
the optimal opportunity for normal development of lung
vasculature and gas exchange apparatus.
Conventionally, depending on the pathophysiology,
the congenital lesions are segregated into cyanotic or
acyanotic defects. The former may be cyanosed due to
diminished pulmonary flows like tetralogy of Fallot,
ventricular septal defect (VSD) with pulmonary stenosis,
pulmonary atresia, Ebstein's malformation or due to
obligatory mixing of the systemic and pulmonary return
to produce cyanosis, e.g. TAPVC, truncus arteriosus,
single ventricle without pulmonary stenosis. However,
because of anatomic and hemodynamic variations in
each subset, treatment modalities have to be tailored for
each individual patient.
The principles of management of the common lesions
are detailed below.
Atrial Septal Defects
Atrial septal defects (ASDs) are surgically repaired
optimally at 1 to 2 years of age or at the time of diagnosis
thereafter. Direct closure by suturing the margins is
reserved for oval defects located in the fossa ovalis area.
The rest are closed with a patch which may be autologous
pericardium or synthetic material like dacron or Gore-
Tex.
Repair of sinus venosus defects entails closure of the
ASD in such a manner that the pulmonary venous return
is directed across the ASD into the left atrium. This is
achieved using a patch sutured around the pulmonary
venous opening into the SVC and then extending the
patch around the right atrial wall to the ASD margin. The
SVC return flows into the right atrium anterior to the patch.
Percutaneous catheter techniques are still undergoing
standardization and are reserved for defects less than 15
mm with good margins. In this the ASD is closed using
a prosthetic device which is delivered through a catheter
passed through the femoral vein under fluoroscopic or
echo guidance.
Ventricular Septal Defects
Infants with large ventricular septal defects (VSDs), heart
failure, significant growth failure or respiratory symptoms
during the first 6 months of life need prompt repair of the
VSD. Elective operation may be deferred in the first 3
months of life in infants without serious symptoms or
medically controlled congestive heart failure because the
VSD may narrow or close spontaneously. Other associated
cardiac anomalies are repaired simultaneously where
appropriate. Exceptions are made for the rare infant with
“Swiss cheese” septum and those with straddling
atrioventricular valve. In these settings pulmonary artery
banding is indicated to protect the pulmonary bed from
high pressures and flows. If no band related complications
occur, definitive repair is executed at 3 to 5 years of age.
When patients are first seen after infancy, surgical
decision is based on the extent of their pulmonary vascular
involvement. Except for small VSDs with the left to right
shunt of less than 1.5:1, all VSDs merit closure. With
pulmonary vascular resistance greater than 8 units/m2
operation is advisable only if it falls below 7 units/m2
after special measures like isoproterenol infusion. A
decrease in postexercise QP/QS is also a contraindication
for surgery.
Juxta-arterial VSDs should be repaired promptly
irrespective of size to obviate the development of aortic
incompetence. When aortic incompetence occurs, it is an
absolute indication for VSD closure. The VSDs are closed
surgically using a patch of woven dacron or PTFE. A right
atrial approach may be used almost exclusively as it
obviates a right ventricular scar with its higher incidence
of ventricular dysfunction and arrhythmias. Juxta-arterial
VSD may be closed transpulmonarily or a combination of
transatrial and transpulmonary approaches may be
utilized for optimal exposure.
Atrioventricular Septal Defects
Atrioventricular septal defects (AVSDs) represent a
spectrum from the mild ostium primum defects to the
complete forms with atrial and ventricular septal defects
associated with a single atrioventricular valve with
abnormal leaflets. Indications for surgery depend on the
form of the atrioventricular canal defect.
 Diseases of Cardiovascular System 523

For the symptomatic patient with complete form of

defect, surgical intervention may be indicated as early as
the first few weeks of life. Complete repair, entailing
closure of the primum ASD and the VSD with a patch and
reconstruction of two competent atrioventricular valves,
is the procedure of choice. Pulmonary artery banding is
considered for unusual situations like multiple muscular
VSDs or uncertainty over the degree of ventricular
imbalance. In the asymptomatic patient elective repair is
undertaken by 6 months of age. This is to guard against
the development of increased pulmonary vascular
resistance which if sufficiently high may render the case
inoperable.
Patients with partial defects should undergo elective
corrective surgery preferably at or before one year of age.
Presence of atrioventricular valve regurgitation is an
absolute indication for intervention at the time of
diagnosis irrespective of symptomatology to obviate the
possibility of development of valve leaflet deformity
precluding a repair at a later date.

Left Ventricular Outflow Tract

Left ventricular outflow tract (LVOT) obstruction is a term
for a wide spectrum of defects which have in common an
anatomic impediment for left ventricular ejection. Before
intervention is contemplated the feasibility of a
biventricular repair should be assured and the entity
distinguished from the spectrum of hypoplastic left heart
syndrome for which the Norwood operation is indicated.
The criteria favoring the more extensive operation include
a mitral valve area less than 4.75 cm2 per m2, left ventricular
inflow dimentions < 25 mm, transverse cavitary and aortic
annular dimentions of 6 mm or less. In patients suitable
for a biventricular repair, the indications for surgery
include gradients more than 75 mm Hg, moderate gradients
with symptomatic status, i.e. NYHA class III or above.
Symptoms of angina or syncope always indicate severe
stenosis.
In the localized form of subaortic stenosis, resection of
the stenotic segment (with or without associated
myectomy) through the aortic orifice usually provides
adequate and long-lasting relief of LVOT obstruction. In
the diffuse form, a more aggressive approach is mandatory
and is best managed by the integrated approach as
depicted in Figure 11.4.1.
Figure 11.4.1: Flow chart depicting surgical approach to
left ventricular outflow tract (LVOT) obstruction
Coarctation of Aorta
Surgery is indicated in all situations where there is
evidence of decrease in the luminal diameter approac-
hing 50 percent at the site of coarctation, as it indicates a
significant lesion. A resting gradient of 20 mm Hg or
more is also an indication for surgery. Elective coarctation
repair is best performed at 3 to 6 months of age and repair
in symptomatic patients should be undertaken at the time
of diagnosis. When it is found with more complex
intracardiac disease, the timing and type of surgery is
largely dictated by the intracardiac lesion.
The neonate presenting in extremes requires urgent
intervention with prostaglandin E1 (0.01-0.1 μg/kg/min)
to reopen the ductus and thereby support the lower body
circulation. Other supportive interventions include
muscle paralysis and mechanical ventilation along with
inotropic support and correction of acidosis.
At the present time the authors believe that either a
resection with end-to-end anastomosis for discrete lesions
or the extended resection and anastomosis for associated
524 IAP Textbook of Pediatrics
arch hypoplasia is the procedure of choice. Standard
subclavian flap aortoplasty and patch aortoplasty may
be preferable over resection and anastomosis in situations
of previous surgery and scarring limiting circumferential
dissection. Balloon dilatation is an acceptable modality
in the postneonatal period and also for the management
of restenosis.
Tetralogy of Fallot
The diagnosis of tetralogy of Fallot (TOF) is generally an
indication for repair. When severe symptoms develop
in the first 2 to 3 months of life an initial shunt, modified
right BT shunt preferably, followed within 12 months
by repair is a reasonable alternative. When diagnosed
later than 3 months and the infant is importantly
symptomatic, prompt primary repair is considered with
low risk of repair at less than 5 percent.
This approach has the advantage of performing the
repair before irreversible effects of long-standing right
ventricular hypertension, cyanosis and polycythemia
induce secondary myocardial and pulmonary changes.
However, the two-stage repair is probably prudent in cases
where the coronary artery crosses the right ventricular
outflow tract in association with a hypoplastic annulus,
unusual circumstance of severe stenosis of the distal
pulmonary trunk and important multiplicity of VSDs.
The surgical plan consists of establishing an unrestric-
tive passage from the right ventricular to the pulmonary
artery with closure of the VSD. The former is achieved
by resecting the stenotic infundibular bands and splitting
the pulmonary annulus when hypoplastic and extending
the incision into the pulmonary artery until normal
caliber vessel is reached. In instances where the
pulmonary annulus is divided the defect is filled in with
a pericardial patch extending from the right ventricle
across the annulus into the normal caliber pulmonary
artery. The infundibular resection and VSD closure can
be achieved via the right atrium or a combination of
transarterial and transpulmonary approach. A right
ventriculotomy is best avoided to protect against right
ventricular dysfunction and arrhythmias in the post-
operative period.
TOF with Pulmonary Atresia
Most patients who have tetralogy of Fallot with pul-
monary atresia (TOF PA) and a duct dependent circu-
lation have sufficiently large (pulmonary artery index
>150 cm2/m2) and confluent (right and left arteries
connected to each other) pulmonary arteries, that they
can be successfully repaired at low operative risks with
good late hemodynamic and electrophysiologic results
using the principles outlined for TOF pulmonary stenosis
with transannular patch. The subset of patients with
diminutive pulmonary arteries and large aortopulmonary
collateral artery (APCA) that supply a variable number of
bronchopulmonary segments or nonconfluent pulmonary
arteries pose a therapeutic challenge.
The repair is staged through early relief of right
ventricular outflow tract obstruction and establishment
of RV to pulmonary artery continuity using outflow tract
patch of pericardium or conduit, leaving the VSD open.
Whenever indicated unifocalization procedures, that join
the multifocal sources of pulmonary blood supply (true
pulmonary artery and one or more nonredundant
collaterals) into a single source are added. Definitive
repair entails patch closure of the VSD and establishment
of continuity between the RV and the pulmonary artery
using either a valved homograft or valve patch repair.
All systemic shunts including redundant collaterals are
retrieved at the time of surgery.
Pulmonary Stenosis with Intact
Ventricular Septum
The cyanosed and critically ill neonate with severe
pulmonary stenosis is initially stabilized on the PGE1.
Thereafter the RVOT relief may be accomplished by
percutaneous balloon valvotomy or open surgical
valvotomy on CPB. The percutaneous technique is
preferred except where the pulmonary annulus is
severely hypoplastic or there is severe reduction of right
ventricular cavity size. The latter is managed with the
insertion of a transannular patch and concomitant
construction of a systemic to pulmonary artery shunt.
Presentation at a later age is managed almost exclusively
by balloon pulmonary dilation.
Pulmonary Atresia with Intact
Ventricular Septum
After medical stabilization of the patient on PGE1,
ventilation and pharmacological support, surgical
intervention aims at stabilization of a reliable source of
pulmonary blood flow and decompression of the RV so
that the cavity can grow towards the fulfillment of an
ultimate biventricular repair. Patients should undergo
RV decompression employing a transannular patch with
systemic to PA shunt to augment pulmonary blood flow
till improvement of RV compliance facilitates antegrade

flow across the opened right ventricular outflow tract. This
approach is contraindicated in patients with a right
ventricle dependent coronary circulation or massive
tricuspid regurgitation. In these patients, palliation is
exclusively with a systemic to pulmonary artery shunt.
In select patients with non-RV dependent right
ventricular coronary fistula, tricuspid valve closure in
addition to the systemic pulmonary artery shunt is done
to prevent coronary steal. The atrial septal defect is left
open to prevent systemic venous hypertension. In non-
RV dependent coronary flow anatomy, the patients with
a Z value of tricuspid valve greater than 2 ultimately have
a biventricular repair. The rest are segregated to a Fontan
limb or a one and a half ventricular repair. In this the
superior vena caval return is directed to the pulmonary
bed as a bidirectional glenn bypassing the right ventricle,
and the inferior vena caval blood is ejected by the dimi-
nutive right ventricle into the pulmonary artery.
Fontan Procedure
A variety of complex congenital heart defects consisting
of a functional single ventricle are managed under the
tenants of the Fontan principle. The Fontan procedure
and its modifications separate the systemic and
pulmonary venous return and create a passive direct
connection between the systemic venous return and the
pulmonary arteries devoid of a functioning pulmonary
ventricle. The elevated systemic venous pressure becomes
the principle driving force to maintain both adequate
pulmonary blood flow and systemic ventricular preload.
Most centers favor performing a modified Fontan
procedure between 2 and 3 years of age. The timing for
each patient must be individualized to allow time for
adequate growth and development of the pulmonary
circulation but to avoid excessive delays that may lead to
compromise of ventricular function or development of
raised pulmonary vascular resistance which would
preclude a Fontan procedure. For inadequate blood flow
in the neonatal period, a systemic to pulmonary artery
shunting procedure on the side opposite the patent duct
is preferred. Beyond 4 to 6 months of age a bidirectional
glenn is performed wherein the SVC is divided and the
distal end is anastomosed to the right pulmonary artery
with closure of the right atrial end.
In situations of excessive blood flow, a pulmonary
artery banding is done to reduce volume load on the
systemic ventricle and treat CHF and also protect the
Diseases of Cardiovascular System 525
pulmonary artery against the adverse effects of high
pressures leading to high pulmonary vascular resistance.
Truncus Arteriosus
The presence of truncus is an absolute indication for
surgery. Repair should be undertaken in the neonatal
period or as soon as the diagnosis is made. Eisenmenger's
physiology is the only absolute contraindication to
correction. Early repair appears to greatly reduce the
incidence of pulmonary vascular hypertensions and
pulmonary hypertensive crises in the postoperative
period.
The surgical approach should include closure of the
VSD, use of a valved allograft conduit for the right ventricle
to pulmonary artery reconstruction and retain patency of
the foramen ovale. In limited subsets autologous tissue
flaps may be used to re-establish right ventricular and
pulmonary artery continuity with the aim to avoid later
reoperations.
D-transposition of Great Arteries
Currently infants are initially palliated with a balloon
atrial septostomy to increase mixing of blood and to
increase the saturations and also to decompress the left
atrium in the presence of a patent ductus. This is followed
by the arterial switch during the neonatal period, up to 4
weeks and preferably by 2 weeks, when the left ventricle
is still prepared to support the systemic circulation.
Even in patients with D-TGA VSD, the arterial switch
operation (ASO) is recommended shortly after the
diagnosis is made to prevent the development of raised
PVR and protect against the adverse effects of VSD closure.
In ASO, the aorta arising from the RV is transferred along
with the coronary buttons to the LV and the PA is
reconnected to the systemic ventricle. The early hospital
mortality in case of both simple TGA and TGA, VSD is
about 2 to 5 percent.
Patients with D-TGA IVS presenting later in infancy
where the LV preparedness is questionable, a rapid two-
stage arterial switch is probably recommended over an
atrial switch. The rapid two-stage repair consists of
pulmonary artery banding, to achieve a LV pressure that
is approximately 75 percent of systemic, with a systemic
to PA shunt followed within 7 to 10 days by debanding,
closure of shunt and an arterial switch.
The other situations are managed by an atrial level
switch like Senning or Mustard operation. In these
526 IAP Textbook of Pediatrics
procedures, the atria are partitioned in such a manner
that the pulmonary venous blood is tunnelled across the
tricuspid valve to be ejected by the RV into the aorta.
11.5 Rheumatic Fever and
Rheumatic Heart Disease
RHEUMATIC FEVER
Acute Rheumatic Fever (RF) occurs as a result of complex
interaction between group A streptococcus(GAS), a
susceptible host and the environment. An abnormal
immune response to a GAS infection leads to an acute
inflammatory illness that most commonly affects the
joints, brain, heart or skin. Although the other manifes-
tations may resolve without any sequelae. Carditis may
result in significant morbidities and mortality. The acute
rheumatic cardiac involvement may resolve or persist
and evolve into chronic rheumatic valvular disease with
cardiac symptoms developing later. There is a strong
relationship with streptococcal infection of the throat,
and it is possible to prevent further attacks of rheumatic
fever by preventing throat infection.
Prevalence
RF continues to be a major public health problem in
developing countries, where it is the most common cause
of the aquired heart disease in children and young adults.
The prevalence of rheumatic fever in the most vulnerable
age group (5-15 years) is 5.3/1000 in school children, and
there appears to be no obvious decline. Though it has
been almost eradicated from the western countries, a few
outbreaks have been reported from the United States.
Etiopathogenesis
1. Though etiology of rheumatic fever is unknown, it is
believed to be an immunological lesion that occurs
as a delayed sequel of group A beta hemolytic
streptococcal infection of the pharynx and not of skin.
The common strains responsible are M-1, 3, 5, 6, 18
Concurrently, the systemic return is channelled across
the ASD through the MV to be ejected into the PA by the
LV.
Anita Khalil
and 24. The attack rate of acute rheumatic fever
following acute streptococcal infection varies with the
severity of the infection ranging from 0.3 to 3 percent.
2. The most common age group involved is 5 to 15 years,
peak incidence being at 8 years and both the sexes
are equally affected.
3. Predisposing factors include low socioeconomic
status, which predisposes to overcrowding, poor
nutrition, and poor hygiene leading on to low
immunological status and, thereby, increasing the
susceptibility. A mendelian recessive pattern has also
been suggested as a genetic predisposition.
Considerable evidence now suggests that the
rheumatic fever is an antigen-antibody reaction, and
patients suffering from streptococcal throat infection
produce antibodies against streptococcal cell wall and
cell membrane proteins. The streptococcal antigen and
human myocardium appear to be identical antigenically.
These antibodies react with human connective tissue of
cardiac muscle, striated muscle and vascular smooth
muscle, and the antibodies have been demonstrated to
be attached to the sarcolemma of the cardiac muscle.
Mitral valve is the most commonly affected, more
frequently in females followed by aortic valve which is
more commonly affected in males. Tricuspid valves are
also involved but pulmonary valves are almost never
affected. Presence of Aschoff bodies in the atrial
myocardium is the hallmark of rheumatic fever. These
are inflammatory lesions associated with swelling with
fragmentation of collagen fibers.
Streptococcal products against which antibodies can
be demonstrated are streptolysin, hyaluronic erythro-
genic toxin, streptokinase, deoxyribonucleases and
several others, and these are utilized for the identification
of a previous streptococcal infection.

Figure 11.5.1: Antigenic structure of streptococcus 1—Capsule
(hyaluronic acid), 2—(A): Peptidoglycan (cell wall rigidity), (B):
Carbohydrate (group specific), (C) : Lipoteichoic acid fimbriae,
3—Cytoplasmic membrane, 4—Cytoplasm, and 5—Pili covered
with lipoteichoic acid
Streptococcus is a bacterium which has a hyaluronic
acid capsule which prevents phagocytosis (Fig. 11.5.1).
Underneath the capsule, there are hair like fimbriae
which are made up of lipoteichoic acid as well as MT and
R proteins. Lipoteichoic acid provides mucosal attachment
and MT, and R proteins dipoteichoic are responsible for
typing of Streptococcus. Each strain of Streptococcus has a
type-specific M protein. The carbohydrate in the strepto-
coccal cell wall is N-acetyl glucosamine which is group
specific and is also present in human connective tissue.
N-acetyl glucosamine is immunologically active and cross-
reacts with antiserum against human connective tissue.
Thus, rheumatic fever appears to be the result of the host’s
unusual response to Streptococcus both at the humoral and
cellular level. Human leukocyte antigen (HLA) studies
suggest association with HLA-DR3 and serum 833, a B-
cell alloantigen identified in 85 percent of rheumatic
patients. These findings favor a genetic susceptibility to
rheumatic fever which is probably inherited as a
mendelian recessive pattern.
Clinical Manifestations
Acute rheumatic fever is diagnosed by the use of revised
Jones criteria. These criteria were put forward by Dr. T.
Duckett Jones in 1944, which were revised in 1965 and
later updated once again in 1992.
The criteria are three groups of important clinical and
laboratory findings (Table 11.5.1).
Diseases of Cardiovascular System 527
TABLE 11.5.1: Guidelines for diagnosis of initial attack of
rheumatic fever (Jones criteria updated 1992)
Major Manifestations Minor Manifestations
Carditis Clinical
Polyarthritis Fever
Chorea Arthralgia
Erythema marginatum Laboratory findings
Subcutaneous nodules Elevated acute phase reactants
(erythrocyte sedimentation rate)
C-reactive protein)
Prolonged P-R interval
Plus
Supporting evidence of antecedent group A streptococcal infection
Positive throat culture or Rapid streptococcal antigen test
Elevated or rising streptococcal antibody titer
1. Five major manifestations
2. Minor manifestations
3. Supporting evidence of an antecedent group A
streptococcal infection.
History
1. Streptococcal pharyngitis, 1 to 5 weeks (average 3
weeks) before the onset of symptoms is common. This
latent period may be as long as 6 months in case of
chorea.
2. Pallor, malaise, easy fatiguability and other history
such as epistaxis (5-10%) and abdominal pain may be
present.
3. Family history of rheumatic fever may be present.
Major Manifestations
Carditis occurs in 50 percent of the patients. The signs of
carditis include some or all of the following in increasing
order of severity:
1. Tachycardia (out of proportion to the degree of fever)
is common. Its absence rules out myocarditis.
2. Pericarditis (friction rub, pericardial effusion, chest
pain and ECG changes) may be present.
3. Valvulitis (a murmur indicating MR and/or AR) is
always present, and if not present then carditis should
not be diagnosed. Now echocardiographic exami-
nation helps in confirming and evaluating the severity
of myocarditis, the presence and severity of MR and
AR and the presence of pericardial effusion.
4. Cardiomegaly on chest radiograph indicates pancar-
ditis, pericarditis or congestive heart failure.
5. Clinical signs of CHF (gallop rhythm, distant heart
sounds, cardiomegaly) are indications of severe
carditis.
528 IAP Textbook of Pediatrics
Arthritis
The common manifestations of acute rheumatic fever (70%
of cases) usually involves large joints (knee, ankles, elbows,
wrists). Often, more than one joint, either simultaneously
or in succession is involved with a characteristic migratory
nature of the arthritis. Swelling, heat, redness, severe pain,
tenderness, and limitation of motion are common. The
arthritis responds dramatically to salicylate therapy; if
the arthritis does not respond within 48 hours the
diagnosis of rheumatic fever is probably incorrect.
Sydenham’s Chorea
Sydenham’s chorea (St. Vitus Dance) is found in
15 percent of the patients with acute rheumatic fever. It
occurs more often in prepubertal girls (8-12 years). It
begins with emotional lability and personality changes
and loss of motor coordination invariably appear.
Characteristic spontaneous purposeless movements
develop, followed by motor weakness. The adventitious
movement, weakness and hypotonia continue for an
average of 7 months (up to 18 months) before slowly
waning in severity.
Erythema Marginatum
Erythema marginatum occurs in fewer than 10 percent of
the patients with acute rheumatic fever, and it is very rarely
seen in Indian subcontinent. The characteristic nonpruritic
serpiginous or annular erythematous rashes are most
prominent on the trunk and inner proximal portions of
the extremities, but never seen on face. The rashes
disappear on exposure to cold and reappear when covered
with a warm blanket.
Subcutaneous Nodules
Subcutaneous nodules are found in 2 to 10 percent of the
cases. They are hard, painless, nonpruritic, freely mobile
and less than 2 cm in diameter. They are distributed
symmetrically, singly or in clusters over the extensor
surfaces of large and small joints, scalp and along the
spine. They last for weeks and are significantly associated
with carditis.
Minor Manifestations
1. Arthralgia refers to a joint pain without the objective
changes of arthritis.
2. Fever (with a temperature usually of at least 39°C)
generally is present early in the course of rheumatic
fever.
3. In laboratory findings, acute phase reactants (elevated
C-reactive protein levels and ESR) are objective
evidences of an inflammatory process.
4. A prolonged P-R interval on electrocardiogram— is
neither specific for acute rheumatic fever nor an
indication of active carditis.
Evidence of Antecedent Group A
Streptococcal Infection
1. A history of sore throat—unsubstantiated is not
adequate evidence of recent group A streptococcal
infection.
2. Positive throat swab cultures or rapid streptococcal
antigen tests for group A streptococci are less reliable
than antibody tests, because they do not distinguish
between recent infection and chronic pharyngeal
infection.
3. Streptococcal antibody tests are the most reliable
laboratory evidence of antecedent streptococcal
infection capable of producing rheumatic fever. The
onset of the clinical manifestations of acute rheumatic
fever coincides with the peak of the streptococcal
antibody response.
a. Antistreptolysin 0 (ASO) titer is well standardized
and therefore is the most widely used test. It is
elevated in 80 percent of the patients and low ASO
titer does not exclude acute rheumatic fever. If three
other antistreptococcal antibody tests (anti-
deoxyribonuclease B, antistreptokinase and
antihyaluronidase tests) are obtained, at least one
antibody test titer is elevated in 95 percent of the
patients.
b. The streptozyme test is a relatively simple slide
agglutination test, but it is less standardized than
other antibody tests. It should not be used as a
definitive test for evidence of antecedent group A
streptococcal infection.
Other Clinical Features
1. Abdominal pain, rapid, sleeping pulse rate, tachy-
cardia out of proportion to fever, malaise, anemia,
epistaxis and precordial pain are common but not
specific.
2. A positive family history of rheumatic fever may
heighten the suspicion, but cannot be used as a definite
diagnostic manifestation.
 Diseases of Cardiovascular System 529

Diagnosis 4. Antistreptolysin O titer (In presence of chorea, another

antibody titer has to be estimated).
The revised Jones criteria (1992) are used for diagnosis of
5. Chest radiograph might show cardiomegaly and
rheumatic fever (Table 11.5.2). Only the major and minor
pulmonary congestion if carditis is present.
criteria and evidence of an antecedent group A strepto-
6. Electrocardiogram—first or second degree heart block.
coccal infection are included in the criteria, although other
Pericarditis—T wave inversion and reduction QRS
findings play a supporting role. A diagnosis of acute
voltages.
rheumatic fever is highly probable when either two major
7. Echocardiography—chamber dilatation, valve
manifestations or one major and two minor manifestations
abnormalities, presence of pericardial effusion and LV
with evidence of antecedent streptococcal infection are
dysfunction.
present. The absence of supporting evidence of a group A
streptococcal infection makes the diagnosis doubtful. Treatment
Differential Diagnosis Bedrest depending on the severity of the manifestation. In
isolated arthritis, it is recommended for one to two weeks
• Juvenile rheumatoid arthritis
and in presence of severe carditis, ambulation is not
• Other collagen disorders—systemic lupus erythe-
recommended till all evidences of activity have subsided,
matosus, reactive arthritis, infectious arthritis, serum
i.e. may be up to two to three months, especially in presence
sickness.
of congestive heart failure.
• Acute arthritis due to viruses, e.g. rubella, parvovirus,
hepatitis B virus, herpes viruses—more common in
Diet
adults.
• Hematologic disorders—sickle cell anemia, leukemia. A nutritious high calorie, high protein diet supplemented
with vitamins and minerals is recommended. Salt
TABLE 11.5.2: Guidelines for diagnosis of initial attack of restriction is advised only in presence of congestive heart
rheumatic fever (Jones criteria updated 1992) failure due to carditis.
Major manifestations Minor manifestations
Penicillin
Carditis Clinical
Polyarthritis Fever After throat swab cultures have been obtained, penicillin
Chorea Arthralgia is recommended to eradicate streptococci. Initially
Erythema marginatum Laboratory findings procaine penicillin G is administered intramuscularly at
Subcutaneous nodules Elevated acute phase reactants 40,000 units/kg once a day for 10 days, following which
(erythrocyt sedimentation rate)
long acting Benzathine penicillin is given once in 2l days,
C-reactive protein)
Prolonged P-R interval 6,00,000 units for children up to 6 years and 1.2 mega
Plus units for those who are older. This prophylaxis is
recommended till the age of 25 to 30 years.
Supporting evidence of antecedent group A streptococcal infection
Positive throat culture or Rapid streptococcal antigen test Counseling
Elevated or rising streptococcal antibody titer
Once the diagnosis of rheumatic fever is confirmed, the
patient and the parents have to be educated about need to
Management prevent further streptococcal infection through
continuous, antibiotic prophylaxis. In presence of cardiac
Investigations
involvement, prophylaxis against infective endocarditis
When rheumatic fever is suspected by history and physical is also recommended.
examination, the following investigations as elaborated
above have to be carried out: Anti-inflammatory Therapy
1. Complete blood counts. Anti-inflammatory or suppressive therapy should not be
2. Acute phase reactants—erythrocyte sedimentation rate started until a definite diagnosis is made. The anti-
(ESR) and presence of elevated C-reactive protein. inflammatory drugs include aspirin (salicylates) or
3. Throat swab culture. steroids. The clinical response to steroids is faster in
530 IAP Textbook of Pediatrics
comparison to aspirin and so, a few guidelines are
followed so as to decide which anti-inflammatory drug
should be administered.
1. The untreated rheumatic fever subsides in 12 weeks
so the duration for anti-inflammatory therapy should
also be 12 weeks.
2. In carditis with congestive heart failure, use of steroids
is mandatory.
3. In carditis without congestive heart failure, use of
steroids is preferable but has to be monitored closely.
4. In arthritis only aspirin is to be given.
Salicylates
Soluble aspirin is the most commonly used salicylate,
administered in a dose of 90 to 100 mg/kg in four to six
divided doses. The full dose is given for 2-3 weeks or till
the symptoms have subsided, then to 60-70 mg/kg/day
to complete a total duration of 12 weeks. Else, give aspirin
in a dose of 20-60 mg/kg/day for 12 weeks. Blood
salicylate level should be maintained at 20 to 25 μg/dl.
Steroids
The commonly used steroid is prednisolone.
Dose 2 mg/kg per day.
Indications
1. In carditis with congestive heart failure given in full
doses for the first 6 weeks and tapered off slowly for
the next 6 weeks.
2. In carditis without congestive heart failure, their use
is controversial but in Indian children, because of low
immunologic status, steroids are recommended in full
doses for first 4 weeks and tapered off slowly for the
subsequent 8 weeks. Aspirin may be added as the
steroids are being tapered off.
During the full course of anti-inflammatory therapy,
antacids are added to overcome irritation to gastric mucosa.
Management of Chorea
Sydenham’s chorea is a late manifestation of rheumatic
fever, when acute phase reactants may be normal.
1. Physical and emotional stress should be reduced.
2. Injection of benzathine penicillin for prophylaxis
indicated as in other rheumatic patients.
3. Anti-inflammatory drugs not needed in isolated
chorea.
4. For severe cases, any of the following drugs may be
used.
Phenobarbitone 15 to 30 mg every 6 to 8 hours.
Haloperidol 0.5 to 2 mg every 8 hours.
Chlorpromazine, diazepam carbamazine or sodium
valproate are sometimes used steroids.
Prognosis
Presence or absence of permanent cardiac damage
determines the prognosis. The development of residual
heart disease is influenced by the following factors.
1. Cardiac status at the initial period—the more severe
the cardiac involvement initially, the greater is the
incidence of residual heart disease.
2. Recurrence of rheumatic fever—severity of valvular
involvement increases with each recurrence.
3. Regression of heart disease—evidence of cardiac
involvement in the first attack may disappear in 25
percent of patients if anti-inflammatory therapy is
given in adequate dosage and also for a required
duration and not stopped early. Valvular heart
disease resolves more frequently when prophylaxis
is followed.
Prevention
Secondary Prevention
Patients with documented histories of rheumatic fever,
heart disease and also isolated cases of chorea must
receive prophylaxis.
Duration
Ideally prophylaxis should be given to patients
indefinitely. Chance of recurrence is highest in the
subsequent 5 years after the first attack, so, prophylaxis
is recommended every 3 weeks till the age of 25 to
30 years. After the age of 30 years, rheumatic fever is not
known to occur.
Method
The method of choice is long acting benzathine penicillin
6,00,000 units to be given to patients weighing 27 kg or
less and 1.2 million units for patients weighing more than
27 kg. It is given intramuscularly after every 21 days. If a
patient is sensitive to penicillin, then alternative drugs
are given although not as effective. They are:
1. Erythromycin 40 mg/kg/24 hours to be given once a
day.
2. Oral sulfadiazine—0.5 g once a day for less than
27 kg and I g once a day for those more than 27 kg.

Primary Prevention
To eradicate rheumatic fever, primary prevention is what
is required. For this, we have to isolate the population
“at-risk” which consists of families of low socioeconomic
status living in overcrowded areas. Throat swabs from
children between 2 and 15 years living in these areas are
taken and cultured for beta hemolytic Streptococcus.
Rapid laboratory isolation of streptococcus will isolate
the children “at-risk” and prophylaxis as detailed above
has to be given for primary prevention. It is necessary to
educate the community regarding the consequences of
streptococcal sore throat.
RHEUMATIC HEART DISEASE
The most commonly seen sequel of acute rheumatic fever
in the pediatric age group are mitral, aortic and tricuspid
valve disease. Mitral valve involvement is seen mainly
as mitral regurgitation and less commonly as mitral
stenosis. Aortic and tricuspid valve disease are mostly
seen as regurgitation. Tricuspid stenosis is known to
occur though very rarely, and rheumatic aortic stenosis
manifests only after the age of 20 years.
MITRAL REGURGITATION
Mitral regurgitation (MR) is the most common valvular
involvement in children with rheumatic heart disease.
Mitral valve leaflets are shortened because of fibrosis
vhich leads to dilatation of mitral valve ring, because of
which mitral regurgitation is produced.
Clinical Manifestations
History
Patients are usually asymptomatic during childhood
because of the initial phase of MR, pulmonary congestion
is rare. Barely fatigue (due to reduced cardiac out put)
and palpitation (due to atrial fibrillation) manifest. On
examination in severe MR, hyperdynamic apex heat is
palpable. The heart sounds (S1 and S2) are mostly
diminished, and S3 is present and loud. The hallmark of
MR is a prolonged blowing regurgitant murmur starting
with the first sound (sometimes drowning it), and being
transmitted with equal intensity to the axilla and back,
and is best heard in the left decubitus position.
Occasionally, a short low density diastolic rumble is also
heard at the apex.
Diseases of Cardiovascular System 531
Electrocardiography
In mild cases, ECG is normal, but in most cases, there is
left ventricular hypertrophy (LVH) or left ventricle (LV)
dominance. Atrial fibrillation (AF) is a common finding
in adults but is rare in children.
Radiographic Study
The left atrium (LA) and LV are usually enlarged in
varying degrees. Pulmonary vascularity is usually within
normal limits, but a pulmonary venous congestion
pattern may develop if CHF supervenes.
Echocardiogrpahy
Two dimensional echo shows dilated LA and LV
depending on the severity of MR. Color flow mapping
of regurgitant jet into LA and Doppler studies can assess
the severity of the regurgitation.
Patients with MR are stable for a long time and in
some, mitral stenosis supervenes because of fibrosis,
infective endocarditis is a rare complication and LV
failure and pulmonary hypertension may develop in
adult life.
Management
Medical
1. Preventive measures, e.g. dental hygiene against SBE
and prophylaxis against further recurrence of
rheumatic fever is important and should be carried
out.
2. In mild cases, activity is not restricted, and salt
restricted diet is advised.
3. Decongestive measures, e.g. diuretics and digoxin are
provided if CHF develops.
Surgical
Indications for mitral valve surgery include:
1. Intractable CHF
2. Progressive cardiomegaly with symptoms
3. Pulmonary hypertension.
Mitral valve repair or replacement is performed
under cardiopulmonary bypass. In children, valve repair
is preferred over valve replacement because their valve is
pliable, has a low mortality rate (< 1%) and anticoagu-
lation is not necessary. If the valve is thick, scarred and
grossly deformed, then the valve has to be replaced.
532 IAP Textbook of Pediatrics
Frequently used low profile prostheses are the Bjork-Shiley
tilting disk or the St. Jude pyrolite carbon valve. If prosthetic
valve is used, anti- coagulation is compulsory The
mortality rate of valve replacement varies between 2 and 7
percent.
MITRAL STENOSIS
Although mitral stenosis (MS) is rare in pediatric age group
(it takes 5 to 10 years from the initial attack), it is commonly
seen in patients less than 15 years of age in the third world
countries where rheumatic fever is prevalent.
In MS, the leaflets are thickened with fusion of
commissures and calcification sets in resulting in
immobilization of the valve. The left atrium (LA) and right
ventricle (RV) become hypertrophied and dilated, and
severe pulmonary changes take place in the form of
pulmonary congestion, venous and arterial hypertension,
fibrosis of alveolar walls and loss of lung compliance.
Clinical Manifestations
Exertional dyspnea is the most common symptom. In
severe cases, paroxysmal nocturnal dyspnea, palpitation
and orthopnea are common. On examination, precordium
may be prominent with palpable RV impulse. Peripheral
pulses are weak and neck veins may be distended. The
hallmark of mitral stenosis is loud S1 with closely split S2
and a loud audible P2 (if pulmonary hypertension is
present). An opening snap is followed by a low frequency
mitral diastolic rumble. A crescendo presystolic murmur
may be audible at the apex.
Electrocardiography
There is left atrial hypertrophy (LAH) and right ventricular
hypertrophy (RVH). Atrial fibrillation is rare in children.
Chest Radiography
LA and RV are usually enlarged and main pulmonary
artery (MPA) segment is prominent. Lung fields show
pulmonary venous congestion, interstitial edema as
Kerley’s B lines in the upper lobes.
Echocardiography
This is the most accurate noninvasive tool. M-mode shows
a diminished E-F slope and 2D shows thickened mitral
valve leaflets with doming and dilated LA, MPA, RV and
RA. Doppler studies can estimate the pressure gradient
across mitral valve and level of pulmonary artery (PA)
pressure.
Management
Medical
• Prophylaxis against recurrence of rheumatic fever and
good dental hygiene and antibiotic prevention against
SBE are important.
• Salt restriction and restriction of activity depending
upon severity.
• Balloon valvulotomy is an alternative to closed surgical
commissurotomy and delays valve replacement.
Surgical
Indications Exertional dyspnea with paroxysmal
nocturnal dyspnea or pulmonary edema. The other relative
indications may be recurrent atrial fibrillation, hemoptysis
and thromboembolic phenomenon.
Procedure
1. Closed mitral commissurotomy. Mitral valve repair is
ideal for a pliable mitral valve without calcification or
mild MR.
2. Valve replacement indicated in calcified valves and
with severe MR. Prosthetic valves (Starr-Edwards
Bjork-Shiley, St. Jude) are for longer durability, but
require lifelong anticoagulant therapy.
Complications
Postoperative CHF, arterial embolization and bleeding
diathesis are known.
AORTIC REGURGITATION
Aortic regurgitation (AR) is less common than MR. The
semilunar cusps of aortic valve are deformed and
shortened, thereby, the aortic valve ring gets dilated and
the cusps fail to appose tightly.
Clinical Manifestations
In mild AR, the patients are asymptomatic but in severe
AR, there is exercise intolerance and breathlessness.
On examination, precordium is mostly hyper-
dynamic with a laterally displaced apical impulse. A
wide pulse pressure and a bounding water hammer pulse
is present in severe AR. On auscultation, the heart sounds
are diminished in intensity and a high pitched soft
diastolic decrescendo murmur is best heard at the left 3
to 4th intercostal space and radiating down the left
sternal border. The longer the murmur, the more severe
is the AR

Electrocardiography
In severe cases, LVH is the usual manifestation.
Chest Radiography
Cardiomegaly with dilated LV is common. A prominent
aortic knuckle is frequently seen. Pulmonary venous
congestion is seen in presence of LV failure.
Echocardiography
Aortic valve and LV are dilated. Color flow and Doppler
are used to assess the severity of aortic regurgitation. The
patient with aortic regurgitation remains asymptomatic
for a long time, but once symptoms appear e.g. angina,
palpitation, etc. develop, the patient deteriorates rapidly.
Management
Medical
1. Good oral hygiene and prophylaxis for SBE as well
as prophylaxis for recurrence of rheumatic fever.
2. Salt restricted diet and restricted activity in presence
of CHF.
3. If CHF develops, then digoxin, lasix, potassium
supplementation and ACE-inhibitors as and when
indicated should be administered.
Surgical
Indication for aortic valve replacement
1. When symptoms such as angina or exertional
dyspnea have appeared.
2. In asymptomatic patients when either cardiothoracic
ratio is more than 55 percent or left ventricular
ejection fraction is less than 40 percent.
Procedure
Aortic valve replacement is performed under cardio-
pulmonary bypass. The antibiotic sterilized aortic
homograft has been widely used and appears to be the
device of choice. The other alternative procedures are
porcine heterograft or Bjork-Shiley and St. Jude prosthesis
which require lifelong anticoagulation therapy and are
also not suited for children.
TRICUSPID REGURGITATION
Tricuspid regurgitation (TR) is frequently seen in 20 to 50
precent of all patients with rheumatic heart disease.
Diseases of Cardiovascular System 533
Sometimes it becomes difficult to decide whether it is
organic or functional. Most of the time, TR is associated
either with mitral stenosis or regurgitation. If the TR is
associated with severe MS, then it is mostly functional
because of associated pulmonary hypertension, but if the
TR is associated with pure or dominant MR, then TR
probably is organic in origin because severe pulmonary
hypertension does not develop only due to MR.
Clinical Manifestations
There are no specific symptoms of tricuspid regurgitation.
Physical examination shows some specific signs, e.g.
1. Prominent “V” waves in jugular veins.
2. Systolic pulsation of liver.
3. Pansystolic murmur in lower left sternal border
which increases on inspiration.
In addition to signs of TR, there may be signs of
pulmonary hypertension and mitral stenosis.
Electrocardiography
ECG shows severe RVH.
Echocardiography
Color flow and Doppler can quantitate the severity of
TR.
Management
All patients of TR have to be treated with digoxin, lasix
and potassium supplements. If TR is associated with MS,
then it will disappear following balloon mitral valvo-
tomy. If associated with MR. then mitral valve replace-
ment is indicated.
BIBLIOGRAPHY
1. Guidelines for the diagnosis of rheumatic fever. JAMA
1992;73:268-85.
2. Kumar V, Narula J, Reddy KS, et al. Incidence of rheumatic
fever and prevalence of rheumatic heart disease in India.
Tnt J Cardiol 1994;221-8.
3. Mccarty M. Streptococci. In Davis BD, Dulbecco R, Eisen
HN, Ginsberg HS (Eds): Microbiology (4th edn).
Singapore: Harper and Row Publishers 1990;525-38.
4. Park MK. Pediatric Cardiology for Practitioners (3rd edn).
St. Louis: Mosby Year Book 1996;302-19.
5. Veasy LG, Wiedmeier SE, Garth SO, et al. Resurgence of
rheumatic fever in intermountain areas of United States.
N Engl J Med 1987;316:421-7.
534 IAP Textbook of Pediatrics
11.6 Congestive Heart Failure in Children
Congestive heart failure (CHF) is defined as a state in which
the heart cannot maintain the cardiac output required to
sustain the metabolic needs of the body, without evoking
certain compensatory mechanism, at rest or during stress.
Pathophysiology
Cardiac output is determined by preload, myocardial
contractility, afterload and heart rate. Myocardial
contractility is directly proportional to the filling volume
(Frank Starling principle), which depends on the preload.
However, dilatation beyond a certain limit does not
further increase the cardiac output. Neurohormonal
excitation is the pathophysiological hallmark of
congestive heart failure evident by activation of
vasopressor and sodium retention forces, i.e. sympathetic
and renin angiotensin system and also sodium excretory
forces, i.e. increased plasma natriuretic factor and
prostaglandins. There are physiological responses aimed
at restoring perfusion of the vital organs. Retention of
sodium and water leads to increased circulating volume
which in turn, causes increased venous return and
increased preload. Increased sympathetic activity causes
tachycardia and increased systemic vascular resistance
(afterload), which, in turn, increases the work of
ventricles, causing a vicious cycle of failure begetting
failure. Thus, in CHF there is increased preload, afterload
and heart rate, attempting to maintain tissue perfusion.
There is also a decrease in number of beta-I receptors in
myocardium, probably due to high catecholamine levels
in CHF. The causes of CHF at different ages are listed in
Table 11.6.1.
Clinical Manifestations
In infants, poor feeding, tachypnea, with intercostal and
subcostal recessions, excessive sweating, wheezing or
mild cyanosis may occur. In older children, fatigue,
anorexia, pain in the abdomen and dyspnea on exertion
are the presenting complaints. On examination,
tachycardia, tachypnea, and enlarged and tender liver
are found. Jugular venous pressure is raised, but is
difficult to appreciate in infants and young children.
Anita Khalil
Edema or anasarca may appear in older children but are
rarely seen and are ominous in infants. Severely ill patients
may be in cardiogenic shock. One should look for
precipitating events for CHF, i.e. anemia, fever, respiratory
infection, infective endocarditis, rheumatic activity or
arrhythmia.
The chest radiograph reveals cardiomegaly cardio-
thoracic ratio more than 60 percent in newborn and 55
percent in older children. Changes due to the underlying
cardiac lesion as well as state of the lung parenchyma
help in arriving at diagnosis. Electrocardiogram may be
helpful in the diagnosis of underlying heart disease.
Echocardiography is very useful in assessing
ventricular function (Normal LVEF 55-65%) and detection
of underlying heart disease. Serum electrolytes and arterial
blood gases may be altered in critically ill patients. The
serum sodium may be low, even though, the total body
sodium and water are increased.
MANAGEMENT OF CHF
Management can be broadly categorized as follows (Table
11.6.2) :
1. General supportive measures
2. Increasing cardiac output
3. Treatment of the underlying cardiac abnormality
General Measures
A very sick child should rest in a propped-up position.
Morphine 0.1 to 0.2 mg/kg is beneficial in sedating an
anxious patient with pulmonary edema. Restriction of
activity is monitored according to the patient’s condition.
Oxygen may be given by a hood at the rate of 8-10
L/min.
In an acutely sick child, intravenous fluids or
nasogastric feeding may be mandatory with restriction of
fluids to 75 ml/kg. In chronic CHF, there is no need for
very low sodium formulas as they are poorly tolerated
and also cause malnutrition. Normal, more palatable
formulas with chronic diuretic administration are
preferable. Infants and children should receive “no added
salt diets”.
 Diseases of Cardiovascular System 535

TABLE 11.6.1: Causes of CHF at different ages TABLE 11.6.2 : Guidelines for the management of CHF

1. Fetus 1. Rest, propped up position

Severe anemia (hemolysis, fetomaternal transfusion supra 2. Humidified oxygen
ventricular or ventricular tachycardia, Complete heart block 3. Salt restricted diet
2. Neonates Diet for Infants—Infants in CHF lack sufficient strength for
a. Birth to I week effective suckling due to rapid respiration and fatigue.
Birth asphyxia, hypoglycemia, sepsis, transposition of Nasogastric feeding with calorie dense formula (0.8 cal/ml) is
great vessels (TGA), coarctation of aorta, neonatal recommended to reduce fluid intake and to provide extra
myocarditis energy to meet the enhanced metabolic requirement.
b. 1 week to 1 month 4. Precipitating and aggravating factors for CHF include anemia,
Coarctation of aorta electrolyte imbalance, infective endocarditis, hypertension,
TGA arrhythmia and pulmonary embolism which must be looked
Endocardial fibroelastosis for and treated.
Large shunts (VSD, PDA) 5. Drugs
Viral myocarditis Digoxin – a potent inotropic drug
Cor pulmonale Diuretics added to complement action of digoxin:
Large mixing cardiac defects Vasodilator, angiotensin converting enzyme inhibitors
Fluid overload recommended in selected situations
TAPVC (obstructed)
3. Infant
a. 1 to 3 months Increasing Cardiac Output
TGA
Endocardial fibroelastosis The cardiac output may be increased using a combination
Anomalous pulmonary venous drainage of inotropic drugs, diuretics and vasodilators.
Coarctation of aorta
b. 3 to 6 months Inotropic Agents
Endocardial fibroelastosis
Supraventricular tachycardia Digitalis
Large VSD, FDA
TGA It is argued that stimulating the failing myocardium by
c. 6 to 12 months inotropic agents may further damage it. The heart is
Large VSD, FDA already exposed to potent inotropic agents in CHF. On
Endocardial fibroelastosis the other hand, an increase in available contractility
AV communication
Pulmonary venous anomaly
decreases the preload and reflexly the afterload with a
4. Toddlers consequent diminished oxygen consumption which is
Large VSD, PDA beneficial for the failing myocardium.
Supraventricular tachycardia
AV malformation Digitalis withdrawal in patients may cause deterioration
Metabolic cardiomyopathy of symptoms. It was found to be superior to captopril in
Acute hypertension improving the quality of life. Digoxin depresses
Anomalous origin of left coronary artery conductors in the SAandAV nodes. Digoxin is reported
Myocarditis to be useful in treatment of cases with CHF both in
5. Older children and adolescents
Rheumatic carditis
normal sinus rhythm, in atrial fibrillation and
Infective endocarditis supraventricular tachycardias.
Acute glomerulonephritis Digoxin is an important drug to control CHF. It has a
Viral myocarditis half-life of 36 hours, an initial effect after 30 minutes and
Cardiomyopathy—dilated a peak effect at 2 to 6 hours. Absorption is up to 60 to 80
Thyrotoxicosis
Constrictive pericarditis and pericardial effusion
percent from oral route, is not affected by meals, and 60
Drugs, e.g. adriamycin to 70 percent is excreted unchanged in the urine. Rapid
Hemosiderosis digitalization is achieved at 24 hours by giving
Cystic fibrosis intravenously. One-half to three- fourths of the total
536 IAP Textbook of Pediatrics
digitalizing dose initially, and the remaining half in two
divided doses 8 to 16 hours later. Slow digitalization in a
less sick child maybe achieved in 7 to 10 days by
maintenance dose daily, i.e. one- fourth to one-fifth of
the total digitalizing dose.
First degree heart block in the form of prolongation
of P-R interval and ST and T wave changes may occur
with digoxin and do not necessitate stopping the drug.
Development of new arrhythmias, when on the drug
should be considered to be digoxin related, until proven
otherwise. Digoxin has a low therapeutic margin, and
blood levels should be maintained between 0.08 and
0.16 pg/dl.
Sympathomimetic agents These drugs combine inotro-
pism with peripheral vasodilatation.
Dopamine
It has inotropic and vasodilatory action up to 5 μg/kg/
min. This dose causes increased renal blood flow and
diuresis. Higher doses may cause vasoconstriction and
are not useful for control of CHF. Side effects are
tachycardia, arrhythmia and increased myocardial
oxygen demand. It is a precursor of noradrenaline and
especially useful in chronic CHF with acute deterioration
where the myocardial catecholamine stores are absent.
It is used in cardiogenic shock, asphyxia and postsurgical
situations.
Dobutamine
It has similar actions with lesser side effects. A dose of
5 to 10 μg/kg/min is appropriate.
The drugs including adrenaline and noradrenaline
are not recommended.
Phospho-diesterase Inhibitors
1. Combine inotroprism with peripheral vasodilation-
reduce afterload.
2. Decrease mycocardial oxygen demand.
Amrinone
It is an inotropic drug with peripheral vasodilatory action.
The drug is administered in a dosage of 0.75
mg/kg intravenously initially and then by an infusion
of 5 to 10 μg/kg/minute. Side effects include hypotension
and reversible thrombocytopenia. The drug is useful in
acute CHF, but causes intolerable side effects on long-
term use.
Milrinone
It has been tried orally for prolonged use, and it increases
exercise capacity and cardiac output. However, studies
showing an increased long-term mortality in patients
receiving the drug have precluded its routine use.
Other drugs like devosimeudan has also been used
and tried in CHF in adults with encouraging results,
however, their use in children has not been evaluated.
Diuretics
Diuretics are generally used along with digoxin. They
decrease the circulating blood volume and preload and
relieve pulmonary congestion and dyspnea. However,
the benefit is at the expense of stimulation of the renin-
angiotensin aldosterone system, causing vasoconstriction
and increased afterload. Long-term diuretic use causes
hypokalemia and alkalosis. Vigorous use can decrease
cardiac output by diminishing the filling pressure. This
may result in lower renal blood flow and lead to an
increase in blood urea nitrogen. When used judiciously
(start with low-dose and titrate slowly), diuretics are
useful in the management of CHF Frusemides, spirono-
lactone and chlorthiazide are some of the commonly used
diuretics. Torasemide - loop diuretic with anti-
aldosterone properties less hypokalemic effect.
Vasodilators
Venodilators
They increase venous capacitance (preload) and relieve
pulmonary and systemic venous congestion. Patients
with pulmonary edema due to mitral or aortic valve
regurgitation and postoperative patients with CHF
respond well to venodilators. If the initial filling pressure
(pulmonary wedge pressure or LVEDF) is low, venodila-
tors can cause hypotension and reflex tachycardia and
should be selected carefully.
Nitrates (Nitroglycerine)
Tolerance to nitrates is one of the majors factors limiting
their use. Depletion of the sulfhydryl group has been
postulated as the mechanism for tolerance. Major and
rapid kemodynamic effects of nitroglycerine limit its use
to ICU settings. Only intravenous preparation is
available.

Arteriolar and Mixed Dilators
They decrease systemic vascular resistance (afterload) and
increase cardiac output without altering the heart rate,
blood pressure and myocardial oxygen consumption.
Hydralazine
Being primarily an arteriolar dilator, it also relaxes
venous vessels. It is also used in hypertension. It has
diverse side effects including precipitation of a lupus like
syndrome. The oral dose is 0.5 to 7.5 mg/kg/day in three
divided doses.
Angiotensin Converting Enzyme (ACE) Inhibitors
They are more effective than vasodilators alone, as they
decrease the cardiac adrenergic drive and improve renal
sodium and water handling, correct intracellular
electrolyte abnormalities, prevent arrhythmia and
progress of left ventricular dysfunction. The sulfhydryl
group of captopril has many theoretical benefits. It
increases the levels of endothelium derived relaxing factor
and vasodilatory prostaglandins. It can also serve as free
radical scavenger in high doses. Captopril is absorbed 95
percent orally. It decreases generation of angiotensin II
and consequently the afterload. It is used in the dose of 0.5
to 0.6 mg/kg/day in two to four divided doses. Side effects
are hypotension rash (in 5-8% patients), neutropenia and
proteinuria. Enalapril is another ACE inhibitor,
successfully used in adults, so far trials regarding its safety
in children are not available. These drugs are contra-
indicated in renal vascular disorders. Dry cough is a major
side effect because of Bradykinine release.
Prazosin
It is an blocker and a mixed vasodilator. It is administered
orally in the dose of 25 μg/kg/day initially and increased
slowly over a few days to 25 μg/kg/day 6 hourly with
blood pressure monitoring.
Nitroprusside
Nitroprusside which is a mixed vasodilator can also cause
hypotension. If used for long, or in high-doses
(> 5 μg/kg/min.), it can cause thiocyanate or cyanide
poisoning. Thiocyanate toxicity begins at plasma levels
of 5-10 μg/dl. Nitroprusside is photosensitive and
degenerates in light, within six hours. This drug is reserved
for critically ill-patients and should be used for the shortest
possible time.
Diseases of Cardiovascular System 537
Angoitensin II Receptor Blocking Agents
Losartan Potassium- Haemodynamically same effects as
Ace-inhibitors and can be added to Ace-inhibitors in
chronic CHF for better results.
Beta-adrenergic Blockers
They are controversial agents and generally contra-
indicated in congestive heart failure. However, they are
being tried in some chronic CHF conditions, based on the
concept that prolonged exposure to adrenergic stimulation
in CHF causes desensitization i.e. decreased activity of
adrenal cyclase due to down regulation of beta receptors.
Beta blockade will cause reversal of this, normalization of
receptors density and restoring the maximum response to
adrenergic stimulation. The adrenergic blockade also
protects the myocardium from cardiotoxic effects of
catecholamines and inhibits tachyarrhythmias and renin
angiotensin activity. The results of trials of these drugs in
dilated cardiomyopathies are still preliminary, through
carvedilol is prescribed in children with dilated
cardiomyopathy.
Treatment of Underlying Cardiac Abnormality
Congestive heart failure is basically the manifestation of
an underlying disease. After the CHF has been treated
symptomatically, the underlying abnormality should be
identified and treated, if possible.
BIBLIOGRAPHY
1. Adam DT. A new look at digoxin in CHF and sinus
rhythm. Postgrad Med I 1989;65:715-7.
2. Alarcon SD, Wakin KG, Worthington JW, et al. Clinical
and experimental studies on the hydralazine syndrome
and its relationship in systemic lupus erythematosus.
Medicine 1967;46: 1-33.
3. Armstrong PW, Walker DC, Burton JR, et al. Vasodilator
therapy in acute myocardial infection. Circulation
1975;52:1118-22.
4. Artom M, Grahom T. Guidelines for vasodilator therapy
of congestive heart failure in infants and children. Am
Heart J 1987;113:121.
5. Bain DS. Effect of amrinone on myocardial energetics in
severe congestive heart failure. Am J Caro 1985;56:168.
6. Behrman RE. The cardiovascular system. In Behrman
RE, Kleighmen RM, Nelson WE, Vaughan VC (Eds):
Textbook of Pediatrics (13th edn). Philadelphia: WB
Saunders Company, 1992;1212-5.
7. Bristow MR. Myocardial beta adrenergic receptor down
regulation in heart failure. Tnt J Cardiol 1984;5:648-51.
538 IAP Textbook of Pediatrics
8. Francis GS. Neurohumoral mechanisms involved in
congestive heart failure. Am J Cardiol 1985;55:15A-21A.
9. Freidman WF. The intrinsic physiological properties of
the developing heart. Cardiovasc Dis 1972;15:87-91.
10. Friedman WE, George BL. Treatment of congestive heart
failure by altering, loading conditions of the heart. J
Pediatr 1985;106:697.
11. Grinstead CW, et al. Discontinuation of chronic diuretic
therapy in stable congestive heart failure patients.
Circulation (Suppl) 1992;1:1-808.
11.7 Systemic Arterial Hypertension in Children
Systemic hypertension is an important condition in
childhood, with estimated population prevalence of 1-5%
in the developed countries. Nutritional surveys, in the
USA show a significant secular increase in systolic and
diastolic blood pressures. The causes for increase in blood
pressure are attributed to increasing obesity, change in
dietary habits, decreased physical activity, increasing
stress and growing awareness of this disease. Similar data
is lacking from India; small surveys in school children
suggest a prevalence ranging from 2-5%. There is evidence
that childhood hypertension can lead to adult
hypertension. Hypertension is a known risk factor for
coronary artery disease (CAD) in adults, and the presence
of childhood hypertension may contribute to the early
development of CAD. Patients with severe cases of
childhood hypertension are also at increased risk of
developing hypertensive encephalopathy, seizures,
cerebrovascular accidents, and congestive heart failure.
Both hypertension and prehypertension have become a
significant health issue in the young because of the strong
association between high BP and being overweight and
the marked increase in the prevalence of overweight
children. Based on these observations, early detection of
and intervention in children with hypertension are
potentially beneficial in preventing long term complica-
tions of hypertension.
Definition, Staging and Measurement of Hypertension
Systemic hypertension is defined as the systolic blood
pressure (SBP) or diastolic blood pressure(DBP) more
12. Hayes CJ, Butler VP Jr. Gersony WM. Serum digoxin
studies in infants and children. Pediatrics 1973;52:561- 64.
13. Lejemtel TH, Sonnenblick EH. Should the failing
myocardium be stimulated? N Engl J Med 1984;310:1384.
14. Loggie JMH, Kleinman IT, Van Maanen EF. Renal function
and diuretic therapy in infants and children. I Pediatr
1975;86:657.
15. Packer M, et al. Comparison of vasodilatation and ACE
inhibition (Enalapril) on exercise capacity and quality of
life in chronic CHF. N Engl J Med 1987;317:799.
16. Packer M, et al. Prospective randomized milrinone survival
evaluation (PROMISE). N Engl J Med 1991;325: 1468.
Srikanta Basu, S Srinivasan
than 95th percentile. The percentiles used for pediatric
hypertension are based on sex, age, and height. BP
measurements need to be taken on 3 separate occasions. If
percentiles of systolic and diastolic pressures are different,
the higher percentile is used for defining and staging
hypertension. The classification of pediatric hypertension
as proposed by the Pediatric Nephrology group of the
Indian Academy of Pediatrics is the endorsement of the
fourth report of the National High Blood Pressure
Education Program (NHBPEP) Working Group on High
Blood Pressure in Children and Adolescents. The
committee has classified pediatric hypertension into four
groups:
• Normal: SBP and DBP less than< 90th percentile;
Normatine data from the fourth report and second
report are to be used in defining hypertension in
children more than 1 year and infants less than 1 year,
respectively.
• Prehypertension: SBP or DBP greater than or equal to
90th centile but less than 95th percentile or BP levels
greater than or equal to 120/80 mmHg.
• Stage 1: SBP or DBP from 95th percentile to 99th plus
5 mm of Hg
• Stage 2:SBP or DBP greater than 99th percentile plus
5 mmHg.
Screening for Hypertension
It is recommended that all children more than 3-year-old
should have their blood pressure measured, who are seen
in clinics or hospital settings. Blood pressure should also
be measured in at-risk younger children with: (i) history
of prematurity, very low birth weight or interventions in

NICU; (ii) malignancy, post organ transplant; (iii) recurrent
urinary tract infections, known renal or urological
diseases, hematuria or proteinuria; (iv) family history of
congenital renal disorders; (v) congenital heart disease;
(vi) conditions associated with hypertension, e.g.,
neurofibromatosis, tuberous sclerosis and ambiguous
genitalia. Blood pressure should be measured in patients
who present with features of kidney or heart disease,
seizures, altered sensorium and headache or visual
complaints. The preferred method for blood pressure
measurement is auscultation. Accurate techniques for
measurement of blood pressure are necessary for its
diagnosis, staging and follow up.
Measurement Devices
Mercury sphygmomanometer: Normative values for blood
pressure are based on sphygmo-manometry, which
continues to be the preferred method for blood pressure
estimation. By convention, an appropriate cuff size
(Table 11.7.1) is one with an inflatable bladder width that
is at least 40 percent of the arm circumference at a point
midway between the olecranon and the acromion. The
cuff bladder length should cover 80 to 100 percent of the
circumference of the arm. An oversized cuff can
underestimate the blood pressure, whereas an under-
sized cuff can overestimate the measurement. If an
appropriate cuff size is not available, the next larger size
is used. Blood pressure should be measured in a
controlled environment after five minutes of rest in the
seated position with the right arm supported at heart
level. With the stethoscope on the brachial artery, the
mercury column is lowered slowly (2 mm per second).
Systolic blood pressure is the point when Korotkoff
sounds are first heard (K1) and disappearance of sounds
(K5) is the diastolic pressure. If Korotkoff sounds persist,
the measurement is repeated with less pressure on the
TABLE 11.7.1: Dimensions for blood pressure cuffs
Age Width Length Circumference
(cm) (cm) (cm)*
Newborn 4 8 10
Infant 6 12 15
Child 9 18 22
Adolescent 10 24 26
Thigh 20 42 52
*Calculated so that the largest arm would still allow the bladder
to encircle the arm by at least 80 percent.
Diseases of Cardiovascular System 539
stethoscope head. If the sounds persist at low intensity,
then K4 (muffling of sounds) is recorded as the diastolic
pressure. Blood pressure recordings should be expressed
to the nearest 2 mm Hg. A high reading should be
confirmed after the child has rested for 5 minutes and
the average of 2-3 readings is taken as the value for that
occasion. If the blood pressure is greater than the 90th
percentile, the blood pressure should be repeated twice
at the same office visit to test the validity of the reading.
Oscillometric devices: These devices are increasingly used
in infants (in whom auscultation is difficult) and in
intensive care settings when frequent blood pressure
measurements are needed. However, neither are most
oscillometric devices validated for children, nor are there
normative data based on these readings. Blood pressure
values on oscillometry, which exceed the 90th percentile
must therefore be confirmed by sphygmomanometry.
Aneroid and other devices: These instruments, based on
spring-based technology require frequent calibration and
validation. The use of aneroid devices and wrist or finger
band oscillometry for blood pressure measurements is
discouraged. Direct intra-arterial BP monitoring is used
in intensive care setting and is the most accurate method
of measuring blood pressure.
Ambulatory blood pressure monitoring (ABPM): Continuous
recordings over 12- or 24-hr are believed to reflect true
blood pressures accurately, are more reproducible and
correlate with target organ damage. A lack of availability
of these instruments and normative standards has
limited the utility of ABPM for the diagnosis of hyper-
tension in children.
TABLE 11.7.2: Causes of childhood hypertension
according to age group
Age Causes
One to six years Renal parenchymal disease; renal vascular
disease; endocrine causes; coarctation of the
aorta; essential hypertension
Six to 12 years Renal parenchymal disease; essential hyper-
tension; renal vascular disease; endocrine
causes; coarctation of the aorta; iatrogenic
illness
12 to 18 years Essential hypertension; iatrogenic illness;
renal parenchymal disease; renal vascular
disease; endocrine causes; coarctation of the
aorta
Note: Causes listed in order of prevalence.
540 IAP Textbook of Pediatrics

TABLE 11.7.3: Classification of hypertension in children and adolescents, with measurement of

frequency and therapy recommendations

Frequency of BP Therapeutic Pharmacologic

measurement lifestyle change therapy

Normal Recheck at next Encourage healthy diet,

scheduled physical sleep and physical activity
examination

Prehypertension Recheck in 6 months Weight management None useless compelling

counseling if overweight;
introduce physical activity
and diet management**
indications such as chronic
kidney disease, diabetes
mellitus, heart failure or
left ventricular hyper-
trophy exist

Stage 1 hypertension Recheck in 1 to 2 Weight –management Initiate therapy based on

weeks or sooner if the counseling if overweight; indications*** or if compel-
patient is symptomatic; introduce physical activity ling indications(as shown
if persistently elevated and diet management** above) exist
on two additional occa-
sions, evaluate or refer
to source of care within
1 month

Stage 2 hypertension Evaluate or refer to Weight- management Initiate therapy++

source of care within counseling if overweight;
1 week or immediately introduce physical activity
if patient is symptomatic. and diet management

(Based on The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents.
Pediatrics 2004;114:560).
**—parents and children to modify their eating plan to the dietary approaches to stop hypertension after consultation with a nutritionist.
***—indications for antihypertensive drug therapy in children include symptomatic hypertension, secondary hypertension, hypertensive
target – organ damage , diabetes( types 1 and 2), and persistent hypertension despite nonpharmacologic measures.
++—more than one drug may be required.

Etiopathogenesis anxiety and hyperthyroidism. Therapy for hypertension

Most childhood hypertension in children is often
secondary to an underlying renal disease; approximately
60-70% patients have renal parenchymal disorders and
5-25% has reno-vascular disease(Table 11.7.4). Coarcta-
tion of aorta is an important cause during infancy.
Adolescents usually have primary or essential hyper-
tension making up 85 to 95% of cases. Essential hyper-
tension is rarely found in children younger than 10 years
and is diagnosis of exclusion. Significant risk factors for
essential hypertension include family history and
increasing BMI. Hypertension may be transient in certain
conditions, e.g., acute glomerulonephritis, acute inter-
mittent porphyria, Guillain Barre syndrome, raised
intracranial pressure, corticosteroid administration,
may be required in some of these cases (Table 11.7.2).
Persistence of elevated blood pressures requires detailed
evaluation.
Pathogenesis
Systemic arterial blood pressure is determined by the
cardiac output (COP) and the peripheral arterial resistance
(PVR) (BP= COP × PVR). Any factor, which results in the
increase of anyone of these two parameters without a
reciprocal decrease in the other factor, will result in arterial
hypertension.
The predisposing high-risk factors such as obesity,
stress, heredofamilial disposition, excess dietary intake
of sodium chloride, abnormal lipid profile, alcohol and
tobacco smoking or use, use of oral contraceptives play a
well-known role.
 Diseases of Cardiovascular System 541

TABLE 11.7.4: Conditions associated with persistent Increased peripheral arterial resistance is due to
(chronic) hypertension arteriolar vasoconstriction, which follows alpha adrener-
Renal
gic receptor stimulation. Angiotensin stimulation of
• Chronic pyelonephritis medulla oblongata, baroreceptor reflex overactivity,
• Chronic glomerulonephritis hypothalamic or cortical stimulation of sympathetic
• Reflux nephropathy nerve activity, increased levels of circulating catecho-
• Obstructive uropathy lamines as seen in pheochromocytoma/neuroblastoma,
• Hydronephrosis excess glucocorticoids are known factors which increase
• Polycystic kidney
the peripheral vascular resistance. Increased renin levels
• Congenital dysplastic kidney
• Renal tumors play a significant role in some cases of hypertension,
• Renal trauma including the cases of essential hypertension. Salt
• Postradiation renal dysfunction sensitive vessel wall changes have been identified to be
• Post-transplantation renal rejection a factor in some cases of hypertension.
• Renal involvement—collagen vascular diseases:
• Systemic lupus erythematosus
Clinical Features
Vascular Most patients with pre-hypertension and hypertension
• Renal artery stenosis
are asymptomatic or have non-specific symptoms.
• Renal artery thrombosis
• Renal vein thrombosis Infants may show irritability, failure to thrive, vomiting,
• Renal artery compression (extrinsic) feeding problems, seizures or respiratory distress. The
• Coarctation of aorta occurrence of epistaxis is rare.
• Aortoarteritis (Takayasu)
• Systemic vasculitidis syndromes Hypertensive crises: Patients with stage 2 hypertension are
at risk for hypertensive crises, which are classified as
Endocrine emergencies or urgencies, based on the respective
• Congenital adrenal hyperplasia (deficiency of 11 β
presence or absence of acute end organ damage (e.g.,
Hydroxylase or 17 Hydroxylase)
• Cushing's syndrome: adenoma/carcinoma hypertensive encephalopathy, intracerebral bleeding,
• Hyperthyroidism acute left ventricular failure and renal failure). The
• Hyperaldosteronism—primary hyperparathyroidism occurrence of these complications is related to the rate
• Pheochromocytoma of rise and duration of hypertension, rather than absolute
• Neuroblastoma
blood pressure values.
Neurological Hypertensive encephalopathy is characterized by lethargy,
• Intracranial tumors
dullness, headache, seizures and visual disturbances
• Intracranial hypertension
including blindness. Cerebral infarction, hemorrhage and
Miscellaneous (Drugs, toxins, metabolic, etc.) facial nerve palsy may occur. Neuroimaging shows
• Corticosteroids, oral contraceptives, licorice, lead/mercury features of white matter degeneration in the parieto-
poisonings; porphyria, and Riley Day syndrome (familial occipital area (posterior leukoencephalopathy), which are
dysautonomia)
reversible with treatment. Examination of the retina
Essential Hypertension
might shows hemorrhages, exudates or papilledema.
• Low renin hypertension While hypertensive emergencies require reduction of
• Normal renin hypertension blood pressure within hours, the same can be achieved
• High renin hypertension over 2-3 days in patients with hypertensive urgencies.

Chronic Complications (target organ damage)

Increased sympathetic activity of whatever etiology,
e.g. anxiety, increased ventricular preload secondary to
increased blood volume (excess salt intake, infusion of
large volumes of fluid, excess mineralocorticoid states
and others) will result in increased cardiac output.
Left ventricular hypertrophy (LVH) is the most
prominent clinical evidence of end organ damage in
childhood hypertension. Data show that LVH can be seen
in as many as 41 percent of patients with childhood
542 IAP Textbook of Pediatrics
hypertension. Acute left ventricular failure is another life-
threatening complication of severe hypertension.
Sustained hypertension can also results in changes in
eyes (hypertensive retinopathy),kidneys (albuminuria),
brain and blood vessels (increased initimal and medial
thickness). There is evidence that these changes are
common, even in patients with long standing stage 1
hypertension.
Evaluation
Once hypertension has been confirmed, an extensive
history and careful physical examination should be
conducted to identify underlying causes of the elevated
blood pressure and to detect any end-organ damage.
With the appropriate information, unnecessary and often
expensive laboratory and imaging studies can be
avoided. A child with primary hypertension often has a
positive family history of hypertension or cardiovascular
disease. Other risk factors including metabolic syndrome
and sleep-disordered breathing . It is helpful to remember
that secondary hypertension is more likely in a younger
child with stage 2 hypertension, thus data about systemic
conditions( specially renovascular) associated with
elevated blood pressure should be elicited. History is
taken for dietary habits, abdominal trauma, physical
activity, and symptoms related to renal, cardiac or
thyroid disorders. Infants are assessed for history of
oligohydraminos and invasive procedures in NICU (e.g.,
umbilical artery catheterization). Family history is taken
for hypertension, diabetes, dyslipidemia, obesity,
premature cardiovascular or cerebrovascular disease and
renal disorders. A medication history should include any
use of over-the-counter, prescription, and illicit drugs
because many medications and drugs can elevate blood
pressure. The physician should also ask about the use of
performance-enhancing substances, herbal supplements,
and tobacco use. Physical examination should include
calculation of BMI because of the strong association
between obesity and hypertension. Obtaining blood
pressure readings in the upper and lower extremities to
rule out Coarctation of the aorta also is recommended.
Examination of the retina should be included to assess
the effect of hypertension on an easily accessed end
organ. In the majority of children with hypertension,
however, the physical examination will be normal.
Investigations
Laboratory testing and imaging in a child with hyper-
tension should screen for identifiable causes, detect co
morbid conditions, and evaluate end-organ damage
Screening tests (Table 11.7.5) should be performed on all
children with a confirmed diagnosis of hypertension.
Decisions about additional testing are based on
individual and family histories, the presence of risk
factors, and the results of the screening tests. Young
children, those with stage 2 hypertension, and those in
whom a systemic condition is suspected require a more
extensive evaluation because these children are more
likely to have secondary hypertension. The child who is
older or obese, with a family history of diabetes or other
cardiovascular risk factors, will require further work-up
for the metabolic abnormalities associated with primary
hypertension.
A cause for hypertension is suggested in most instances
based on clinical features and initial evaluation.
Confirmation of the diagnosis requires specific
investigations tailored to specific needs (Table 11.7.6).
Occasionally, the cause for hypertension may not be found
despite detailed evaluation. Hormone levels and 24-hour
urine studies are readily available to most physicians, but
more specialized tests such as renal angiography often
require referral to a center with pediatric radiology,
nephrology, and cardiology services. When renovascular
disease is strongly suspected, conventional or intra-arterial
digitally subtracted angiography are recommended.
Scintography with or without angiotensin-converting
enzyme (ACE) inhibition also can be used. These older
TABLE 11.7.5: Screening work up of children with
hypertension
Evaluation for cause
• Hemogram
• Blood urea, creatinine, electrolytes
• Fasting lipids, glucose, uric acid
• Urinalysis, culture
• 24-hr urinary protein or spot protein to creatinine ratio
Chest X-ray
• Renal ultrasonography
Screen for target organ damage
• Retinal fundus examination
• Urine: microalbumin, spot protein to creatinine ratio Chest
X-ray, ECG, echocardiography

TABLE 11.7.6: Specific diagnostic tests for
sustained hypertension
Condition Diagnostic investigations
Glomerulonephritis Complement (C3), ANA, ANCA, anti-
dsDNA, renal biopsy
Reflux nephropathy Micturating cystourethrogram, DMSA
scintigraphy
Renovascular Doppler flow studies, captopril
hypertension renography
Angiography (MR, spiral CT, digital
subtraction or conventional)
Renal vein renin activity
Coarctation of aorta Echocardiography, angiography
Endocrine causes Thyroxine, thyroid stimulating hormone
Plasma renin activity, aldosterone
Plasma and urinary cortisol
Plasma and urine catecholamines;
MIBG scan, CT/MR imaging
imaging techniques are quite invasive. Data on newer
studies such as magnetic resonance angiography and 3-
dimensional or spiral computed tomography in children
are limited, but documentation of their usefulness is
increasing. Documenting LVH is an important component
of the evaluation of children with hypertension. Because
echocardiography is noninvasive, easily obtained, and
more sensitive than electrocardiography, it should be part
of the initial evaluation of all children with hypertension
and may be repeated periodically.
Management
The first step in the treatment process is to distinguish
between essential and secondary hypertension. Manage-
ment of childhood hypertension is directed at the cause of
the elevated blood pressure and the alleviation of any
symptoms. End-organ damage, comorbid conditions, and
associated risk factors also influence decisions about
therapy. Nonpharmacologic and pharmacologic treat-
ments are recommended based on the age of the child, the
stage of hypertension, and response to treatment
(Table 11.7.3).
Nonpharmacologic Treatment
Non pharmacologic therapy is generally recommended
in any child with hypertension or prehypertension and
usually consists of two important lifestyle changes: weight
reduction and dietary modification. Cessation of smoking
and abstinence from alcohol is also recommended.
Diseases of Cardiovascular System 543
Weight Reduction
Achievement of ideal body weight is important. Weight
reduction is the primary therapy for obesity-related
hypertension. Obesity increases the occurrence of
hypertension threefold while favoring the development
of insulin resistance, hyperlipidemia, and salt sensitivity.
Significant obesity also increases the likelihood of LVH
independent of blood pressure level. Weight loss is
associated with increased HDL cholesterol and decreases
in triglycerides and body fat. When increased physical
activity is combined with weight loss, the antihypertensive
effect may be greater than that with weight loss or exercise
alone. A reduction in BMI by 10% is reported to lead to 8-
12 mm Hg fall in systemic blood pressure. Weight
reduction is achieved by regular physical activity and diet
modification. Regular moderate aerobic activity for 30-60
minutes on most days and limiting sedentary activities to
less than 2 hours per day is recommended. While children
often find defined physical exercises (aerobics, tread mills)
boring, they are likely to continue activities incorporated
into their routines, e.g., walking or cycling to school, playing
with friends outdoors and swimming. Adolescent girls in
our country should be specifically targeted, since they
spend considerably less time than boys in outdoor sport.
Participation in competitive sports is avoided in
patients with stage 2 hypertension or target organ damage,
until blood pressure is controlled satisfactorily. Strength
training (isometric) exercises (e.g., weight lifting,
gymnastics, karate and judo) should be avoided.
Dietary Recommendations
Dietary modification should be strongly encouraged in
children and adolescents who have BP levels in the
prehypertensive range as well as those with hypertension.
Recommendations for daily sodium intake in children
range between 1-1.5 g (45-65 mEq sodium, 2.6-3.8 g salt).
Dietary sodium restriction is associated with small
reductions in blood pressure in children. A ‘no added salt
diet’ is a satisfactory approach to restrict salt intake. Intake
of food products high in sodium (processed and canned
foods, items prepared in fast food shops including pizzas,
pickles and salted potato chips) should be avoided.
Increased potassium intake, through vegetables and fruits,
is associated with modest reduction of systolic and
diastolic blood pressure in adults with essential
hypertension.
544 IAP Textbook of Pediatrics

TABLE 11.7.7: Treatment of hypertensive emergencies

Drug Dose/Route Onset/Duration of Action Comments
(After Discontinuation)

Sodium 0.25-10 mcg/kg/min in 5%
nitroprusside dexotrose) by continuous infusion;
maximal dose for 10 min only
protects Infusate from light
Immediate/2-3 min after Cyanide poisoning in patients with
infusion renal failure, nausea, vomiting;
methemoglobinemia acidosis;
thiocyanate intoxication with
prolonged use; bags, bottles, and
delivery sets must be light-resistant

Labetalol 0.2-1 mg/kg/dose by bolus 5-10 min/15-30 min Contraindicated in CHF, diabetes
over 2 min period mellitus and asthma
or Bronchoconstriction, heart block,
0.4-3 mg/kg/hr orthostatic hypotension
Max: 40 mg/dose or
300 mg/total dose
By cont IV infusion
Hydralazine 0.1-0.5 mg/kg/dose Onset:10-20 min IV; Tachycardia, flushing,salt retention.
Max: 50 mg/dose 20-30 min IM
IV, IM Duration:/>1hr (IV);
4-6 hr (IM)

Diazoxide 1-5 mg/kg/dose q5-15 min IV Pain at injected vein,sodium

Max:150 mg/dose retention,use with diuretics
Onset: 2 min

Glyceryl 1-3 mcg/kg/min 2-5 min/5-10 min Headache, tachycardia, vomiting,

trinitrate flushing, methemoglobinemia;
requires special delivery system due
to drug binding to plastic tubing

Esmolol 50-300 µg/kg/min by infusion 1-5 min/15-30 min First-degree heart block, congestive
heart failure, asthma

An increased intake of fresh vegetables and fruits,
whole grains and non-fat dairy is recommended. These
foods are low in sodium and saturated fat and rich in
minerals (potassium, calcium, magnesium) and fiber. The
IAP Consensus Committee on Obesity and the Nephro-
logy chapter expert group on hypertension recommends
the daily food composition in the form of a ‘thali’, where
half (50%) is vegetables, salads and fruits, a quarter (25%)
is cereals (rice and/or chapattis), and the remainder is
protein based (legumes, milk, egg, animal protein). The
intake of fried foods, snacks and sweet dishes should be
limited.
Pharmacologic Therapy
Drug therapy is indicated in patients with symptomatic
hypertension; (i) acute or chronic complications of
hypertension, including evidence of target organ damage,
(ii) secondary hypertension, (iii) stage 2 hypertension, (iv)
stage 1 hypertension that persists despite 6-months’ of
lifestyle modifications, and (v) pre-hypertension or stage
1 hypertension with comorbid conditions (diabetes,
chronic kidney disease or dyslipidemia). The goal for
treatment is the reduction of blood pressure to levels <95th
percentile, unless comorbid conditions or target-organ
damage is present, when it should be lowered to <90th
percentile. Therapy is initiated with one agent, at an
appropriate dose and the dose is increased until the
desired blood pressure is achieved. If the highest dose is
not effective or if there are side effects, a drug from a
different class is added or substituted. Medications with
a longer duration of action (once, twice daily dosing) are
preferred for better compliance and less side effects. Dose
 Diseases of Cardiovascular System 545

TABLE 11.7.8: Oral pharmacologic treatment of chronic hypertension in children

Drug Dosage and Comments
frequency of dosage

Diuretics Monitor for hypokalemia, hyperglycemia and

hyperuricemia
Hydrochlorothiazide 1-3 mg/kg/day;qd
Longer duration
Furosemide 1-6 mg/kg/day; qd-bid Hypercalciuria, Ototoxicity
Ototoxicity; Loop diuretics
Bumetanide 0.015-0.1 mg/kg/dose (max. 10 mg/day)
Spironolactone 1-3 mg/kg/d; qd-bid Aldosterone antagonist
Distal tubular blockade of Na:K
exchange
Metolazone 0.2-0.4 mg/kg/day qd Inhibition of reabsorption of Na+
Vasodilators
Hydralazine 1-8 mg/kg/day; qid Tachycardia, headache, lupus synd.
Minoxidil 0.1-1 mg/kg/day; qd-bid Hirsutism, salt-water retention
α- Adrenergic Antagonists
Prazosin 0.05-0.5 mg/kg/day; bid-tid First dose hypotension
Calcium Channel Blockers
Nifedipine
(extended release) 0.25-3 mg/kg/day; qd-bid Tachycardia, headache, flushing, dizziness
Amlodipine 0.05-0.5 mg/kg/day; qd-bid
Isradipine 0.1-0.8 mg/kg/day; bd-tid
β - Adrenergic Antagonists
Propranolol 1-4 mg/kg/day; tid Hypoglycemia, bronchospasm
Atenolol 0.5-2 mg/kg/day; qd-bid
Labetalol+ 1-4 mg/kg/day; bid-tid + 1:4 alpha:beta blockade
Metoprolol 1-6 mg/kg/day; bid-tid
Angiotensin-Converting Enzyme Inhibitors
Captopril 0.02-2 mg/kg/day bd-tid (neonates) ↓GFR; ↓ Platelets and neutrophils;
0.5-6 mg/kg/day bd-tid (children) ↑K+; Angioedema; cough
Enalapril 0.1-0.6 mg/kg/day bd-qid (max 40 mg/day) Caution- use in renal artery stenosis
Adolescents 2.5-5 mg/24 hr (max 40 mg/day)
Lisinopril 0.06-0.6 mg/kg/day; qd
Ramipril 6 mg/m2; qd
α- Adrenergic Agonists
Clonidine 0.005-0.025 µg/kg/day bd-qid Drowsiness and rebound hypertension
(max. 0.9 mg/day)
Angioedema,cough, headache, dizziness
Angiotensin receptor blockers
Irbesartan 4-5 mg/kg/day Anemia, neutropenia, dry cough infrequent
Losartan 0.7-1.4 mg/kg/day; qd

adjustment of antihypertensive medications need not be
made more frequently than every 2-3 days. The choice of
initial drug therapy is largely at the discretion of the
physician. Diuretics and beta blockers have documented
safety and effectiveness in children. Commonly used
medications in children include ACEI, calcium channel
blockers (CCB), angiotensin-receptor blockers (ARBs),
vasodilators, beta blockers and thiazide diuretics
(Tables 11.7.7 and 11.7.8). It should be noted that all of these
agents can have adverse effects and interactions that need
to be carefully addressed when prescribing for anyone, but
especially for children, in whom less is known about these
effects than in adults. For example, salt restriction
increases ACE inhibitors’ antihypertensive effect.
546 IAP Textbook of Pediatrics
Nifedipine and amlodipine are effective CCB for
children. The availability of long acting preparations
permits once or twice daily dosing. Sustained release
preparations of nifedipine should be swallowed whole,
and not crushed or chewed. Captopril, chiefly used in
young infants, requires dosing every 6-8 hr. Beyond
infancy, enalapril (1-2 daily doses) is preferred. Newer
ACEI (lisinopril, ramipril) require once daily dosing and
have fewer side effects. Angiotensin receptor blockers used
in children include losartan, valsartan and irbesartan.
Cardioselective β-blockers (atenolol, β metoprolol) are
effective agents, requiring once or twice daily dosing and
have few side effects. The use of propranolol is limited in
view of the need for multiple daily doses and side effects.
Labetalol, a α- and β-blocker, is useful in patients refractory
to other medications.
Specific Recommendations
Following are the recommendation by the expert committee
of IA P nephrology group on the management of
hypertension.
Essential hypertension: While there is no consensus on the
appropriate initial therapy, the choices are between CCB
and ACEI. Therapy with β-blockers is recommended in
patients who cannot tolerate ACEI or CCB.
Acute glomerulonephritis: Hypertension in post-infectious
glomerulonephritis is of short duration and associated
with salt and water retention. Fluid and sodium restriction
and judicious use of loop diuretics are useful in patients
with circulatory congestion, hypertension and edema.
Severe hypertension with or without encephalopathy is
an emergency and usually responds to treatment with
CCB and furosemide. Occasionally treatment with a β-
blocker or ACEI may be necessary.
Chronic kidney disease: The target blood pressure in these
patients is <90th percentile. For patients with chronic
kidney disease stage I-III (GFR >30 mL/min/1.73 m2)
therapy should be initiated with ACEI, since these agents
also reduce proteinuria and retard progression of renal
damage. Monitoring of serum potassium and creatinine
is necessary, initially at 7-14 days and then every 1-3
months. The dose of ACEI (or angiotensin receptor
blockers) is reduced if serum creatinine exceeds 30-35%
from the baseline or there is hyperkalemia. Treatment with
ACEI should be avoided in patients with advanced chronic
kidney disease (stage IV-V; GFR <30 mL/min/1.73 m2).
Therapy in these cases is initiated with either a CCB or β-
blocker.
Renovascular disease: In patients with high probability or
confirmed renovascular disease, therapy should be
initiated with a CCB or/and a β-blocker. Additional
agents include prazosin, labetalol, clonidine, hydralazine
and/or minoxidil. While therapy with ACEI or
angiotensin receptor blockers is avoided in patients with
suspected or confirmed bilateral renovascular disease,
these agents might be used cautiously in those with
unilateral renovascular hypertension.
ACEI are the preferred initial agents in subjects with
ventricular dysfunction. Additional therapy may be given
with loop or thiazide diuretics, β blockers and aldosterone
antagonists. ACEI or angiotensin receptor blockers are
recommended for patients with associated proteinuria.
Blood pressure should be monitored every 3 months.
Screening for end organ damage and renal dysfunction
(proteinuria, serum creatinine) and surveillance for side
effects of drugs is required annually.
Drug Step-down
“Step-down” treatment is usually recommended in
overweight children with uncomplicated essential
hypertension, who successfully lose weight. This
approach attempts a gradual reduction of the medication
after 8-12 months of satisfactory blood pressure control.
Hypertensive Emergencies
Patients with stage 2 hypertension may present with acute,
life threatening target organ damage involving central
nervous system (encephalopathy, seizures), heart
(pulmonary edema) or kidneys (acute renal failure). These
patients need hospitalization for monitoring and
supportive care. Blood pressure levels are usually
5-15 mm above the 99th percentile, and should be reduced
to safe levels. Rapid reduction of blood pressure might,
however, compromise blood flow and result in ischemic
complications in the brain, retina, spinal cord and kidneys.
Blood pressure reduction, therefore, must be regulated in
order to prevent end organ damage to these organs.
The difference between the observed and desired (95th
percentile) blood pressure is estimated; 25-30% of the
desired reduction should occur in the first 3-4 hr, another
25-30% in the next 24 hr, and then to the desired level over
next 2 days. Agents of choice include short acting,
intravenous (IV) preparations that are titrated to response
(sodium nitroprusside, nitroglycerine, labetalol and
nicardipine) (Table 11.7.7). Therapy with enteral
antihypertensive drugs should be instituted within 6-12
hr of parenteral therapy, and the latter gradually
withdrawn over the next 12-24 hr. Sodium nitroprusside

is the agent with the longest track record, readily available
and the least expensive of all parenteral drugs. This agent
can be used in most hospital settings, provided there is
facility for monitoring of blood pressure. Initially infused
at a rate of 0.3-0.8 mg/kg per minute, the dose may be
increased in increments of 0.1-0.2 mg/kg per minute, every
15 minutes, if the desired reduction is not achieved. Blood
pressure is measured at least every 15 minutes; pupillary
reflexes, visual acuity and level of consciousness are also
monitored. Two IV lines should be maintained, one for
drug infusion and the other for saline infusion (if the blood
pressure were to fall precipitously). Loss of pupillary reflex
to light is an early indicator of retinal vascular ischemia,
requiring immediate infusion of normal saline. Patients
receiving nitroprusside at doses exceeding 2-3 mg/kg per
minute for longer than 48 hr are at risk of cyanide toxicity,
and even earlier if there is hepatic or renal dysfunction.
Nifedipine has been used safely and effectively, by
pediatricians, for hypertensive emergencies. The risks of
side effects due to sudden fall of blood pressure are limited,
particularly if the dose of nifedipine is between 0.1-0.25
mg/kg. Physicians should however be aware that the
response to short acting nifedipine might be inconsistent
and unpredictable (requiring more than one dose) or
uncontrolled (sudden fall of blood pressure).
Volume depletion is common in patients with severe
hypertension and IV administration of loop diuretic
together with a potent anti-hypertensive agent might lead
to a precipitous drop in blood pressure. Diuretics should
therefore be avoided unless specifically indicated for
volume over- load as occurs in glomerulonephritis
coexisting pulmonary edema.
Hypertensive Urgencies
Hypertensive urgencies are not associated with acute
target organ damage. Patients have stage 2 hypertension
and less dramatic symptoms (e.g., headache and/or
vomiting), but are at risk for progression to hypertensive
emergencies. Controlled reduction of blood pressure,
using oral medications, over several hours is desirable.
Effective oral agents include nifedipine, clonidine and
labetalol. Despite overall efficacy of the above agents, a
predictable reduction of blood pressure is often not
possible. Patients with hypertensive urgencies should be
observed closely, since use of IV medications might be
required.
Neonatal Hypertension
Blood pressure in neonates is determined by birth weight
and gestational age. Renovascular (renal artery or venous
Diseases of Cardiovascular System 547
thrombosis) and renal parenchymal disorders are
important causes of hypertension. Newborns with severe
hyper-tension are managed with continuous IV infusion
of nitroprusside or labetalol. Effective oral agents include
CCB, hydralazine and minoxidil; ACEI should be
administered at lower doses.
Conclusions
Elevated blood pressure in children may be a sign of an
underlying disease or represent early onset essential
hypertension. Pediatricians should be aware of the
principles of early detection, evaluation and management
of such patients. Children with hypertension need long
term follow up, counseling and treatment, which should
be achieved by their primary pediatricians in collabora-
tion with pediatric nephrologists.
BIBLIOGRAPHY
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3. Egger DW, Deming DD, Hamada N, Perkin RM, Sahney
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4. Houtman PN, Dillon MJ. Medical management of
hypertension in children . Child Nephrology, Urology
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11.8 Pericardial Diseases and Disorders

S Srinivasan, Srikanta Basu

The heart is safely enclosed in a pericardial cavity, the TABLE 11.8.1: Classification of pericarditis and
seromembranous visceral pericardium forming the outer pericardial effusion
layer of the heart and the fibrous parietal pericardium Clinical
separating it from the lungs. It contains about 15-50 ml a. Acute (< 6 weeks)
of ultrafiltrate of plasma. • Fibrinous • Effusive
Congenital absence of pericardial sac, either totally • Serous • Purulent
• Hemorrhagic • Chylous
or partially, is a rare disorder. It is often asymptomatic.
• Serofibrinous
Herniation of main pulmonary artery and left atrium b. Subacute (6 weeks to 6 months)
may occur through the partial defect, occurring more on • Effusive
the left side. Congenital pericardial cysts and diverticula • Constrictive
are reported, but they are not large enough to pose clinical • Effusive-constrictive
c. Chronic (> 6 months)
problems but may cause diagnostic confusion. • Constrictive
• Effusive
ACUTE PERICARDITIS AND • Adhesive
PERICARDIAL EFFUSION
Etiological
Pericardium gets involved in acute infective, inflam- I. Infectious
matory, neoplastic or traumatic processes. Pericardial • Viral: Coxsackie A and B, ECHO, adenovirus, Ebstein-Barr
involvement is most often seen as one of the clinical virus, mumps, influenza, varicella zoster, vaccinia,
cytomegalovirus, rubella, herpes simplex, hepatitis and HIV
manifestations of a systemic disorder or a generalized • Bacteria: Staphylococci, Streptococci, Pneumococci,
illness. Whenever pericardial involvement is detected Haemophilus influenzae, Meningococci, Legionella,
clinically, a thorough clinical examination to detect the Salmonella, Mycobacterium tuberculosis, Mycoplasma,
presence of generalized disease is essential. The clinical Nocardiosis and Actinomycosis
• Fungal: Histoplasmosis, Coccidioidomycosis, Candidiasis,
and etiological classification is presented in the Table
aspergillosis, blastomycosis
11.8.1. • Protozoa: Amebiasis, Toxoplasmosis, Hydatidosis,
The symptom suggestive of acute pericarditis is chest • Rickettsial: Coxiella burnetii
pain. The cardinal signs of effusion are pericardial rub, II. Noninfectious, Inflammatory (Hypersensitivity/autoimmunity)
and pulsus paradoxus. • Rheumatic fever
• Collagen vascular disorders: SLE, rheumatoid, arthritis,
scleroderma, Wegener's granulomatosis
Pathophysiology • Drug induced: Procainamide, hydralazine, minoxidil,
phenytoin, isoniazid, postcardiac injury, postpericardiotomy,
Pericardial involvement, often as a result of infective or post-traumatic, postmyocardial infarct/ischemia
inflammatory process, results in variable accumulation III. Noninfectious, Noninflammatory:
of fluid within the pericardial sac, the degree of which • Uremia • Myxedema
• Cholesterol • Chylopericardium
will determine the clinical picture. From a normal amount
• CHF, nephrotic syndrome, cirrhosis liver
of 15-50 ml of fluid, there can be massive amounts of fluid • Neoplasia: Primary and metastatic: Lymphoma, leukemia
accumulation. Mild effusion occurring in cardiac failure • Trauma: Aortic dissection, familial mediterranean fever,
or nephrotic syndrome as a transudate may go unnoticed. cardiomyopathy, acute idiopathic
Pyogenic infection will cause pyopericardium in which IV. Miscellaneous: Kawasaki, sarcoidosis, ulcerative colitis,
amyloidosis, bleeding disorders, radiotherapy.
even a small amount may be significant clinically. The

symptoms and signs are due to severe cardiac
compression, impairment of ventricular diastolic filling,
increased systemic and pulmonary venous pressures and
eventually due to severly compromised cardiac output
and shock.
Clinical Features
The chest pain of acute pericarditis is dull, sharp and
stabbing precordial pain, radiating to the epigastrium,
neck, shoulder or left arm, increasing on lying down and
on deep inspiration, decreasing on sitting position with
forward leaning. Pericardial sac is devoid of nerve supply
and hence, the pain is due to adjacent diaphragmatic or
pleural irritation. Cough, fever and breathlessness of a
mild degree may be associated symptoms. The symptoms
of primary etiology may overshadow the mild secondary
symptoms.
In acute pericarditis without significant effusion, in
the early stages, the only clinical finding may be a
pericardial friction rub, heard best with the diaphragm
of the stethoscope kept firmly pressed on the left sternal
border and over the base of the heart. It resembles the
sound produced by the friction of sandpaper on wood
or creaking leather, better heard during expiration. It has
a to and fro component and is always in phase with the
heart sounds. The ECG shows generalized elevation of
the S-T segments (current of injury of the underlying
myocardium). After a week, the S-T segments return to
normal but there will be T wave flattening and inversion
in the same leads, which may persist for months after
resolution of the acute phase.
Pericardial Effusion
Within a short period of 48-72 hours, most cases will go
on to develop pericardial effusion. Pyogenic organisms,
still one of the most important causes of pericardial
involvement, cause pyopericardium and there is often
high fever, toxemia and other clinical evidences of
pyogenic infections like pneumonia, empyema or
pyoderma. Tuberculous effusion is the next most com-
mon cause of pericardial effusion in developing
countries. This is followed by viral infections.
Symptoms of chest pain with a feeling of compres-
sion over the chest in a child while lying down, eleva-
tion of jugular venous pulse, presence of pulsus para-
doxus, enlarged area of cardiac dullness with a quite
precordium and diffuse apical impulse, well within the
Diseases of Cardiovascular System 549
outer border of cardiac dullness, shifting dullness, Ewart's
sign, muffled heart sounds with friction pericardial rub
and unexplained hepatomegaly all suggest pericardial
effusion with moderate collection.
Radiograph of the chest shows “waterbottle” type of
cardiomegaly with no increased lung shadows. Flu-
oroscopy shows diminished myocardial contractility.
ECG often shows diminished QRS voltages with
generalized S-T segment elevation. The diagnosis is easily
made with ultrasonography, and the area of collection—
either posterior or anterior can be made out. Pericardio-
centesis is done through the subxiphoid approach and
the fluid content is analyzed microscopically, biochemi-
cally and microbiologically. Gram staining and Ziehl-
Neelsen staining is done to identify the bacteria and the
mycobacteria. In hemorrhagic effusions, cytoanalysis for
malignant cells is also undertaken.
Acute Cardiac Tamponade
This term is applied to the state of acute heart failure
due to compression of the heart by massive, rapidly accu-
mulating pericardial effusion or moderate degree of
effusion in an otherwise rigid, nondistensible pericar-
dial sac. Significant rise in intrathroacic pressures and
ventricular end diastolic, atrial, systemic and pulmonary
venous pressures occur due to impaired ventricular
relaxation and filling, resulting in poor cardiac output.
The characteristic clinical symptoms are precordial
oppression, breathlessness, exercise intolerance, mild
facial puffiness and minimal pedal edema. The charac-
teristic clinical signs of raised jugular venous pulse with
prominent X-descent, pulsus paradoxus, low volume
pulse, cold and clammy peripheral extremities, relatively
silent precordium, muffled heart sounds with hepato-
megaly suggest cardiac tamponade. A positive
Kussmaul's sign of paradoxical rise in jugular venous
pulse is less characteristic of tamponade than of
constrictive pericarditis. Similarly, prominent X-descent
is present in tamponade whereas prominent, deep Y-
descent is characteristic of constrictive pericarditis.
Low ECG-QRS voltages and electrical alternans may
be present in cardiac tamponade. Ultrasonogram shows
significant pericardial effusion, right atrial collapse and
right ventricular diastolic collapse with absent increased
early diastolic filling and mitral flow velocity.
The common causes of cardiac tamponade are
tuberculosis, neoplasms, trauma, uremia and idiopathic
pericardial effusion is an exclusion diagnostic state.
550 IAP Textbook of Pediatrics
Diagnosis
A high index of suspicion of pericarditis and/or effusion
is essential in any child with fever, chest pain and
breathlessness, elevated jugular venous pressure, mild
pedal edema, unexplained hepatomegaly and a pulse of
low volume or of paradoxus which then needs confir-
mation by ultrasonography. Radiology and elec-
trocardiography may be only suggestive of its presence
but is not absolutely diagnostic.
The diagnostic confirmation of pericarditis and/or
effusion invites a proper clinical and appropriate
laboratory evaluation to find out its cause, e.g. pyogenic,
tuberculous, viral, rheumatic, etc.
Myocarditis and cardiomyopathy are important
differential diagnoses which can be excluded by careful
history, physical examination, radiology, electrocardio-
gram amd ultrasonography.
The diagnosis of tamponade is mainly indicated by
the clinical signs of pulsus paradoxus, prominent X-
descent and absent Kussmaul's sign.
Pericardiocentesis
Removal of pericardial fluid by needle and syringe (20
gauge) aspiration for diagnostic and therapeutic purpose
is termed pericardiocentesis. The approach is through
subxiphoid region, with the needle advancement being
directed slowly towards the midthoracic spine at an angle
of about 20 degrees below the perpendicular to the body
surface. This can be done under electrocardiographic
monitoring, with the V lead attached to the advancing
needle and the other limb leads in position. Whenever
the needle touches the epicardium of the heart, marked
ST elevation will indicate the need to stop further
advancement of the needle.
The fluid collected is analyzed microscopically for the
cellular reaction, biochemically—transudative or
exudative and microbiologically for the identification of
the offending organism—pyogenic bacteria, myco-
bacteria, virus or fungus.
Management
In pyogenic pericardial effusion, the pus in the pericardial
sac is surgically drained after the institution of appropriate
antibiotics. This has resulted in improved survival, and
the mortality is now less than 15 percent with early
intervention. Constrictive pericarditis may occur and the
child must be on regular follow-up protocol.
Tuberculous effusion, diagnosed by history of contact,
unimmunized status or immunologically compromised
status, positive clinical, radiological, biochemical,
tuberculin hypersensitivity and microbiological studies
is treated with a minimum of 3 antituberculous drugs and
initial course of steroids. Chronic constrictive pericarditis,
a common complication, is treated surgically. It can be
prevented by early pericardiectomy. Pericardiocentesis is
done for diagnostic purpose, but if the collection is large
resulting in tamponade, therapeutic removal of significant
amount of fluid becomes essential.
Viral effusion needs only symptomatic treatment,
and it resolves spontaneously in 2 to 4 weeks. Other
conditions like collagen vascular diseases are treated
appropriately and the effusion resolves slowly with
steroids.
CHRONIC CONSTRICTIVE PERICARDITIS
Though less common in children, constrictive pericarditis
may follow tuberculous pericardial effusion or pyoperi-
cardium. Rarely, it may occur secondary to viral or
traumatic (hemorrhagic) pericarditis. It usually occurs
months or years after the treatment of primary condition.
The thick, fibrous and sometimes calcified pericardial
sac impairs diastolic ventricular filling, myocardial
contractility and effective cardiac function. These changes
gradually result in the development of the characteristic
clinical signs and symptoms of systemic venous congestion:
elevated jugular venous pulse with prominent ‘y’ trough,
pulsus paradoxus, low volume pulse, low blood pressure,
quiet precardium, muffled or distant heart sounds, early
pericardial knock heard at the time of prominent ‘y’ descent.
These signs must be carefully looked for in those children,
with gradually developing pedal edema, minimal puffiness
of face and swelling of eyelids, raised JVP and unexplained
hepatomegaly.
The differential diagnosis is chronic restrictive car-
diomyopathy. Roentgenographic evidence of moderate
cardiomegaly is seen in only half of these cases. Calcifi-
cation of pericardial surface may also be noted in similar
number of cases. Echocardiography may be helpful.
Radical pericardiectomy with decortication including
the sheathing over the great veins gives great relief in a
significant number of children. Postoperative cardiac failure
is managed by conventional decongestive measures.
BIBLIOGRAPHY
1. Chiappin E, Gall L, de Martino M, et al. Recurrent
pericarditis after Meningococcal infection. Pediatric
Infectious Disease Journal 2004;23:692-3.
2. Dupuis C, Gronnier P, Kachaner J, et al. Bacterial
pericarditis in infancy and childhood. Am J Cardiol
1994;74:807-9.

3. Feldman WE: Bacterial etiology and mortality of purulent
pericarditis in pediatric patients. Review of 162 cases.
Am J Dis Child 1979;133:641-4.
4. Jayashree M, Singhi SC, Singh RS, Singh M: Purulent
pericarditis: clinical profile and outcome following
surgical drainage and intensive care in children in
Chandigarh. Ann Trop Paediatr 1999;19:377-81.
11.9 Cardiac Arrhythmias in Children
The sinoatrial node (SA node) located at the junction of
superior vena cava and right atrium acts as an electrical
impulse generator or pacemaker with its own intrinsic
rate, controlled by the autonomic nervous system. The
impulse from SA node passes through atrioventricular
node (AV node), Bundle of His, to depolarize the atria
and ventricles in sequence determined by the slower
conductivity of AV node.
If the sinus rate slows down considerably, shift in
pacemaker activity occurs and the AV node (nodal
rhythm) or the ventricle (idioventricular rhythm) takes
over the function of impulse generation and propagation.
An arrhythmia is a disturbance in the electrical
activity of the heart, which may be episodic or conti-
nuous. When heart rate slows down to less than 60 per
minute, it is termed as bradycardia and when the same
is more than 120/min, it is called tachycardia.
On the standard surface ECG, P wave corresponds
to SA node depolarization, the P-R segment to the con-
duction time in the AV node and the Purkinje system
and the QRS complex to the ventricular depolarization
and the T wave to the ventricular repolarization.
The two basic mechanisms that initiate tachycardia
are: (i) increased automaticity resulting in ectopic
impulse formation and (ii) re-entry loop or closed circuit
propagation of ectopic impulse generated.
SINUS RHYTHMS
Sinus Bradycardia and Sinus Tachycardia
Sinus bradycardia (heart rate less than 60/min) occurs
in older children who are athletic. It occurs also following
therapy with drugs such as beta-blockers, digitalis,
verapamil; and conditions like hypothyroidism,
hypothermia, and raised intracranial pressure, etc.
Diseases of Cardiovascular System 551
5. Morgan RJ, Stephenson LW, Woolf PK, Singh M: Surgical
treatment of purulent pericarditis in children. J Thorac
Cardiovasc Surg 1983;85:527-31.
6. Zahn EM, Houde C, Benson L, Freedom RM:
Percutaneous pericardial catheter drainage in childhood.
Am J Cardiol 1992;70:678-80.
S Srinivasan, Srikanta Basu
Sinus tachycardia (heart rate > 120/min) occurs with
sympathetic stimulation after exercise, fever, anxiety,
anemia, heart failure, pregnancy, thyrotoxicosis, and
administration of drugs which stimulate sympathetics.
Sinus arrhythmia is a manifestation of normal auto-
matic nervous activity with increase in sinus heart rate
during inspiration and a decrease during expiration. This
is seen in young children.
TACHYARRHYTHMIAS
Supraventricular Tachyarrhythmias
(SVT, Paroxysmal Atrial Tachycardia,
AV Nodal Re-entrant Tachycardia)
Supraventricular tachyarrhythmia is the most common of
the rapid rhythm abnormalities encountered in children,
the greatest frequency being recorded in infancy. It is
known to occur in fetus as early as in middle fetal life.
The mechanism of the supraventricular tachycardia
is commonly a re-entry of the electrical impulse back into
the conducting system either through an accessory
pathway (Wolff-Parkinson-White syndrome) or within the
atrioventricular node. It may originate in a localized focus
of enhanced automaticity in the atria or AV junction. In
the absence of the antegrade conduction by the bypass
accessory pathway, re-entry through the AV node or
through a concealed bypass tract, is responsible for more
than 90 percent of all SVTs.
AV nodal re-entrant tachycardia, being the most
common of all SVTs, has no specific predisposing factors.
It most often occurs in children who are otherwise normal.
In infancy, it is more common in children below 6 months
of age.
The heart rate is regular and often ranges between 200
and 320/minute and all impulses are conducted to the
552 IAP Textbook of Pediatrics
ventricles. These children are often asymptomatic. In
infants, if it persists for more than 24 hours, symptoms
and signs of congestive heart failure (CHF) occur besides
pallor, fatigue and tachypnea. The onset of the paroxysm
is as sudden and abrupt as its termination. An older child
may sense palpitation with the sudden onset. Syncope
and hypotension may be the presenting symptoms. Acute
pulmonary edema can ensue. In the fetus, when the
arrhythmia is prolonged, heart failure and nonimmune
hydrops fetalis are known to occur. Polyuria may occur
due to release of atrial natriuric peptide during such
paroxysms.
ECG shows marked tachycardia (> 200/min) with
regular narrow QRS complexes and the P waves may be
absent, buried in the QRS complex or appear as distortions
at the terminal part of the QRS complexes. QRS complexes
become wider in presence of associated bundle branch
block.
Treatment
Drug treatment is not essential as simple vagal maneu-
vers like carotid sinus massage can effectively terminate
SVT in majority of cases. Adenosine with its short half-life
is the most preferred drug and verapamil is the next drug
of choice. Verapamil is not to be given in children below
one year of age. Beta-blockers, disopyramide and digitalis
are less preferred alternatives and digoxin is not helpful
in acute case.
Prevention of AV nodal re-entry is achieved by the use
of digitalis, beta-blockers or calcium channel blockers
which act primarily on the antegrade slow pathway. In
an emergency, DC cardioversion terminates the attack.
Temporary percutaneous venous, atrial or ventricular
pacing terminates the attack when drugs fail to do so or in
recurrent cases.
Catheter radiofrequency ablation of the re-entrant
circuit is frequently being resorted to in refractory cases.
In AV re-entrant tachycardia retrograde conduction
occurs from the ventricles back to the atrium by a concealed
bypass tract.
Wolff-Parkinson-White Syndrome
(Pre-excitation syndrome)
An abnormal band of specialized electrically conductible
atrial tissue acts as an accessory pathway bypassing the
junctional tissue. This occurs in association with some
congenital heart diseases and most commonly with
Ebstein's anomaly.
Wolff-Parkinson-White syndrome refers to antegrade
conduction by AV bypass tract resulting in a short P-R
interval, a slurred upstroke of the QRS complex termed
delta wave and a wide QRS complex. Differential
conducting speeds of accessory and normal pathways
with differing refractory periods cause re-entry pheno-
menon to occur resulting in paroxysmal SVT. Atrial flutter
and atrial fibrillation also occur commonly in this
condition. This in turn, may lead to very rapid ventricular
rates, even resulting in ventricular tachycardia and
fibrillation because of the lack of decremental conducting
properties in the bypass tract as in AV node.
SVT is treated as mentioned earlier. Class 1A drug
(quinidine, procainamide, disopyramide) or Class 1C
(flecainide) may be used to slow conduction and increase
refractoriness primarily in the bypass tract. Flecainide is
to be limited to be used in otherwise normal heart. Digitalis
and verapamil can precipitate ventricular fibrillation by
shortening the refractory period of the bypass tract.
Radiofrequency ablation of an accessory pathway is
another treatment option commonly used in patients with
re-entrant rhythm or atrial ectopic tachycardia.It is often
used electively in children and teenagers, as well as
patients who require multiple agents or find drug side
effects intolerable or for whom arrhythmia control is poor.
The overall initial success rate ranges from approximately
80-95 %,depending on the location of bypass tract. Surgical
ablation of bypass tract may also be successful in related
patients.
Flecainide is to be limited to be used in otherwise
normal heart.
ATRIAL TACHYARRHYTHMIAS
Atrial Ectopic Beats/Extrasystoles
Premature atrial beats are recognized by abnormally
shaped premature ‘P’ waves followed by near normal P-R
interval with normal QRS complex. Rarely, QRS complex
may be aberrant. They may occur in normal newborns
and disappear with age and do not cause symptoms.
Multiple atrial premature beats may sometimes result in
transient atrial fibrillation.
Atrial flutter and Atrial fibrillation
These two types of atrial arrhythmias are less common in
children than in adults.

Atrial Flutter
In Atrial flutter, the characteristic features is a very rapid
atrial activity (250-400 beats per minute) with the ventri-
cles responding to every second to fourth atrial beat
resulting in a regular or regularly irregular tachycardia.
Causes
Congenital heart diseases resulting in a grossly enlarged
atria, e.g. mitral or tricuspid insufficiency, tricuspid
atresia, Ebstein's anomaly, acquired rheumatic mitral
valvular heart disease, acute viral myocarditis, peri-
carditis and intra-atrial surgery.
Pathophysiology
An electrically active (irritable), abnormal focus in atria
produces abnormal impulse which gets repeatedly
propagated by a circus rhythm resulting in extremely rapid
atrial rate. All of these rapid atrial beats cannot get
transmitted through AV node. Varying degrees of
atrioventricular block results in, anywhere from, 2:1 to
8:1 atrial ventricular rate ratios.
Symptoms
They depend upon the ventricular rate. No symptoms
occur in atrial flutter with reasonable ventricular rate.
Prolonged episodes of atrial flutter with very rapid
ventricular rate precipitates congestive heart failure.
Electrocardiogram is characteristic showing the rapid
and regular atrial sawtoothed flutter “F” waves.
Treatment
Direct current cardioversion is the most effective
method of reverting back to sinus rhythm. If the clinical
status is stable, the ventricular rate is first slowed by
administration of AV node blocking drugs like beta-
blockers, calcium channel antagonist (verapamil) or
digitalis. Once the ventricular rate is slowed, attempt is
made to convert the flutter into normal sinus rhythm by
the use of Class 1A drugs (quinidine, procainamide or
disopyramide), Class 1C drugs (flecainide) or amioda-
rone. The same drugs also prevent recurrences of atrial
flutter and fibrillation.
Atrial Fibrillation
Atrial fibrillation is characterized by totally distorted,
chaotic, rapid and ineffective atrial contractions with
irregular and erratic ventricular response resulting in the
Diseases of Cardiovascular System 553
diagnostic “irregularly irregular” radial arterial pulse
with pulse deficit. It may be paroxysmal or persistent.
The same causes mentioned above in atrial flutter, may
also result in atrial fibrillation. It may represent the
tachycardia phase of the sick sinus syndrome.
Symptoms
They occur with rapid ventricular rate—fatigue, palpi-
tation, giddiness or syncope, symptoms of heart failure
and symptoms of systemic embolization in children with
mitral valvular disease.
The electrocardiogram is characteristic—no organized
discernible ‘P’ waves, except for irregular, fibrillatory “f”
waves in the baseline with irregular but normal QRS
complexes.
Treatment
The therapeutic goal is to immediately slow down the
ventricular rate by using either beta-blockers (propranolol)
or calcium channel antagonists (verapamil). Quinidine
or other Class 1A drugs as mentioned above, or Class 1C
drugs like flecainide may then correct the condition to
sinus rhythm. If no response occurs within 24 hours,
electrical DC conversion is resorted to. The causative
factors have to be immediately attended to.
Anticoagulation 2 weeks prior to and 2 weeks after any
attempt at cardioversion, is indicated to prevent the
dreaded thromboembolic complications in situations
where atrial fibrillation has been persistent for more than
48-72 hours.
In exceptional circumstances of refractory atrial
fibrillation, surgical or transvenous catheter radiofre-
quency ablation may be resorted to deliberately induce
complete heart block with simultaneous permanent
pacemaker implantation.
VENTRICULAR TACHYARRHYTHMIAS
Ventricular Tachycardia (VT)
Ventricular tachycardia is defined as occurrence of at least
three or more ectopic ventricular beats in sequence.
Sustained ventricular tachycardia means a run of
ventricular premature contractions (VPCs) in succession
for a period of 30 seconds or more.
It is less common in children, and it indicates the
presence of a serious underlying structural or functional
cardiac problem. The prognosis is poor and carries a great
risk of mortality unless corrected immediately.
554 IAP Textbook of Pediatrics
Cause
Myocarditis, ischemic damage, anomalous origin of the
coronary artery, cardiomyopathy, mitral valve prolapse,
prolonged Q-T interval (congenital or acquired), proarrhy-
thmogenic drugs, Wolff-Parkinson-White syndrome, drug
abuse with cocaine or amphetamine, hypokalemia,
hypomagnesemia, hypoxia and severe acidosis are all
known predisposing factors. In a significant number of
children with SVT, an underlying cause may not be found.
Syncope, chest pain and dyspnea are the common
presenting symptoms.
It must be differentiated from SVT and all broad QRS
tachycardias should be considered as ventricular
tachycardia, until proved otherwise. The electrocardio-
graphic features which are helpful in the diagnosis of VT
is the AV dissociation, capture fusion beats, extreme left
axis deviation, no response to carotid sinus massage or IV
administration of adenosine, besides the very broad QRS
complexes.
Treatment
Treatment is immediately initiated. DC conversion
(1-2 Watt/sec/kg) is the treatment of choice; if it is not
available or if VT is relatively well-tolerated, bolus dose of
lignocaine (1 mg/kg) is intravenously administered with
continuing IV infusion, at a rate of 10-50 mg/kg/min.
Bretylium is alternative drug in lignocaine refractory
cases. Mexilitine, flecainide, disopyramide and
amiodarone are suitable alternatives.
Phenytoin is effective in VT, especially when it occurs
following digitalis toxicity. The precipitating factors have
to be identified and immediately correc-ted—hypokale-
mia, hypomagnesemia and others. Myocardial tumor,
anomalous origin of the coronary artery and similar
surgical problems are appropriately handled. Failure of
drug therapy necessitates alternative, treatment
strategies—implantation of automatic cardioverter,
defibrillator or surgical resection of the diseased
myocardial area.
Ventricular Fibrillation (VF)
VF is a chaotic ventricular tachyarrhythmia with no
effective ventricular contraction. The ECG record shows a
wavy line without any discernible QRS complexes;
P waves may be discernible.
VF may be a preterminal event in many illnesses.
Hypokalemia, digitalis or quinidine toxicity, myocardial
inflammation or damage, catecholamines aminophylline,
anesthetic drugs and plant toxins may precipitate VF.
Uncontrolled VT or multifocal ventricular ectopic beats or
long Q-T interval syndrome may result in VF. If not
terminated instantaneously, death ensues.
A thump in the chest may restore sinus rhythm.
External cardiac massage with artificial ventilation and
DC defibrillation are immediate measures to be under-
taken. The precipitating factors are corrected without
delay. After defibrillatory conversion, VT is treated with
drugs. Refractory cases are treated by implantable
automatic cardioverter-defibrillator.
Bradyarrhythmias
Sinus Arrest and Sinoatrial Block
Failure of impulse formation within the sinus node is
termed sinus arrest and blockade of the generated sinus
impulse from reaching the atrium is sinoatrial arrest.
Though rare in children, these disturbances may occur
secondary to digitalis toxicity and extensive atrial surgery.
Atrioventricular Block (AV Block)
AV Block occurs when interference occurs in normal
conduction of the electrical impulses from the atria to the
ventricles through the atrioventricular node.
First degree AV block P-R interval prolonged beyond what
is normal for that age and heart rate without blockage of the
conduction of any of the atrial impulses to the ventricles, is
defined as first degree heart block. No evidence of heart
disease is seen in majority of such cases. However, it may
be seen in children with congenital heart disease like atrial
septal defect, corrected transposition of great vessels.
Ebstein's anomaly, primary myocardial disease, rheumatic
carditis, diphtheria and in children receiving drugs like
digitalis and quinidine. Children with 1 degree block are
asymptomatic, and need no treatment except for the
treatment of primary cause.
Second degree AV block Some of the atrial impulses are
blocked and hence, not conducted to the ventricles.
In Mobitz type I (Wenckebach phenomenon) while P-
P interval remains constant, progressive increase in P-R
interval occurs with successive beats until an atrial
impulse seen as P wave is not conducted to the ventricle
(absent QRS complex). The P-R interval is again shorter in
the cycle following the dropped ventricular complex. It
will then progressively increase to result in another
blocked ventricular impulse.
In Mobitz type II, atrial conduction is blocked at
intervals without a change in P-R interval, once every
three, four or five beats.
 Diseases of Cardiovascular System 555

Intravenous antiarrhythmic agents

Drug Dosage Comments Monitoring

Verapamil 0.1-0.2 mg/kg Contraindicated in For hypotension

IV (5-10 mg max) children < 12 months
of age
Propranolol 0.02 mg/kg IV Contraindicated in Pulse, BP
every 5 min to children with asthma,
max 0.1 mg/kg congestive heart
failure. Not to be given with verapamil
Procainamide 10-15 mg/kg IV Continuous monitoring Dizziness,
over 30 min hypotension
Lidocaine 1-2 mg/kg IV over Causes respiratory BP
15 min depression, hypotension
cont, infusion-30-
50 mcg/kg/min
Adenosine 0.05 mg/kg Caution in asthmatics,
through a central contraindicated in pre-existing
line; double the type 2 and 3.
dose until effect is Atrioventricular block
seen to a max of without pacemaker
0.4 mg/kg

It is less often noticed in individuals with normal
hearts. The same predisposing factors mentioned in first
degree AV block also play a role. No treatment is
necessary. If Stokes-Adams syndrome occurs though rare,
pacemaker insertion is undertaken.
Congenital/acquired Complete
AV Heart Block
Autoimmune injury of the fetal conduction tissue by IgG
antibodies transferred from mother with active or inactive
systemic lupus erythematosus (SLE) is one of well-known
causes of this condition. Other autoimmune diseases such
as rheumatoid arthritis are reported to cause congenital
heart block. Myocarditis and postsurgical repair invol-
ving ventricles are other known causes of acquired comp-
lete heart block. In utero, it may result in hydrops fetalis. It
may also result in fetal wastage. In some children it may
occur at 3 to 6 months of age.
Older children are asymptomatic. Syncope, fatigue,
irritability, and night terrors may be some of the symp-
toms. Slow but bounding pulse less than 60 per minute
not increasing by more than 10 to 20 beats per minute
after exercise or atropine administration, cannon a waves,
varying intensity of the first heart sound are diagnostic.
The diagnosis is confirmed by electro-cardiogram. The
prognosis of this condition is usually good. In sympto-
matic children with Stokes-Adams syndrome, insertion
of artificial pacemaker is imperative to prevent sudden
death. All cardiac depressants should be avoided. Cardiac
pacing is recommended in neonates with low ventricular
rate (50/min), evidence of heart failure, wide complex
rhythms, or congenital heart disease. Isoproteronol ,
atropine or epinephrine may be used to try to increase the
heart rate temporarily until pacemaker placement can be
arranged. Transthoracic epicardial implants have
traditionally been used in infants. Transvenous placement
of pacemaker lead is available for young children.
BIBLIOGRAPHY
1. Arrhythmias in infants and children: Current concepts in
diagnosis and management of atrial arrhythmias in
infants and children. 1998. Wolff G, Gelband H, Deal BJ
Futura Publishing Inc.
2. Campbell RM, Dick M, Rosenthal A. Cardiac arrhyth-
mias in children. Annual Review of Medicine 1984;35:
397–410.
3. Losek JD, Endom E, Dietrich A, et al. Adenosine and
pediatric supraventricular tachycardia in the emergency
department: multicenter study and review. Ann Emerg
Med 1999;33:185–91.
4. Sacchetti A, Moyer V, Baricella R, et al. Primary cardiac
arrhythmias in children. Pediatr Emerg Care. 1999;15:95–7.
5. Walsh EP, Saul JP, Triedman JK (Eds). Cardiac arrhyth-
mias in the pediatric patient. Lippincott Williams and
Wilkins 2001.
6. Ziegler, Gillette PC (Eds). Practical Management of Pedia-
tric Cardiac Arrhythmias. Futura Publishing Inc. 2001.
12.1 Examination of the Respiratory System: YK Amdekar ........................................................................................................................ 558
12.2 Diagnostic Procedures and Investigations in Respiratory Diseases: Archana S Kher, Soumya Swaminathan, Milind S Tullu ......... 560
12.3 Flexible Fiberoptic Bronchoscopy: D Vijayasekaran ........................................................................................................................... 564
12.4 Respiratory Distress: MD Shah ............................................................................................................................................................. 567
12.5 Upper Respiratory Tract Infection: SK Kabra ...................................................................................................................................... 573
12.6 Infections of Larynx, Trachea and Bronchi: Keya R Lahiri, Roshani N Taori ..................................................................................... 576
12.7 Pneumonia in Children: A Balachandran, SO Shivbalan ...................................................................................................................... 578
12.8 Acute Bronchiolitis: Uday B Nadkarni ................................................................................................................................................... 583
12.9 Empyema: A Balachandran, Swati Y Bhave, S Thangavelu ................................................................................................................... 586
12.10 Bronchiectasis: A Balachandran, Swati Y Bhave, NC Gowrishankar ................................................................................................... 588
12.11 Lung Abscess: A Balachandran, Swati Y Bhave, T Thangavelu ........................................................................................................... 589
12.12 Hemoptysis: Vibha Mangal, Neeraj Jain, Vibhu Kwatra ......................................................................................................................... 591
12.13 Bronchial Asthma: H Paramesh, L Subramanyam, SO Shivbalan ....................................................................................................... 593
558 IAP Textbook of Pediatrics
12.1 Examination of the Respiratory System
Clinical examination follows history taking and is
intended to arrive at the most probable diagnosis.
Following is the scheme of clinical examination of the
respiratory system, which will help in interpretation of
the signs.
General Examination
Respiratory rate more than 60/50/40 per min in
neonates, infants and children respectively indicates
tachypnea. This has to be correlated with body tempe-
rature and pulse rate for correct interpretation. Presence
of accessory muscles of respiration working such as
alaenasi or sternomastoid muscles often suggests
respiratory distress or dyspnea. Accompanying dyspnea
is often noisy breathing, which helps in localizing the
anatomy of the disease. Stridor indicates supratracheal
inspiratory obstruction and manifests as suprasternal
retraction. Grunting denotes nature's attempt to increase
end-expiratory pressure to improve oxygenation in lung
parenchymal disease as in pneumonia and often is
accompanying with chest retractions. Wheeze suggests
expiratory obstruction as seen in case of asthma. Marked
tachypnea without chest retraction is a feature of bron-
chial disease as in asthma or meconium aspiration in
newborn, while moderate tachypnea with chest retrac-
tion denotes parenchymal disease as in pneumonia or
hyaline membrane disease (HMD) in neonates. Most of
the children with tachypnea or dyspnea are irritable or
crying. However, if they are not—silent dyspnea—may
indicate paralyzed respiratory muscles as in GB
syndrome. These children are not able to phonate and
often demonstrate paradoxical or seesaw respiration.
Such a situation exists also in case of respiratory failure
due to other causes. Marked tachypnea without
symptoms or signs of respiratory disease suggests
metabolic acidosis. Cyanosis is bluish discoloration of
mucous membranes or nails. Peripheral cyanosis is seen
only in fingertips or nails and is often accompanied with
cold extremities or pallor. Central cyanosis shows
discoloration of mucous membranes such as lips and
buccal mucosa and denotes extreme degree of oxygen
desaturation, an ominous sign in a respiratory disease.
YK Amdekar
Clubbing of nails indicates chronic hypoxia as seen in
case of bronchiectasis. Early clubbing manifests as
Schomroth’s sign—diamond-shaped window seen on
opposition of two finger nails, while further changes are
seen as obliteration of angle between nail and nailbed
and subsequent swelling. Hence, clubbing is a sign of
chronic respiratory disease while cyanosis may be seen
in acute conditions also.
ENT Examination
This forms the part of respiratory system examination.
Ear should be examined through otoscope to diagnose
early signs of inflammation of the ear drum. Unilateral
nasal disease demands careful examination of the nasal
cavity through nasal speculum. Mouth breathing
suggests nasal obstruction and may result in typical
adenoid facies. Throat is generally examined last with
the help of a spatula or tongue depressor under a good
source of torchlight to assess tonsillar or pharyngeal
inflammation or any exudative membrane.
Chest Examination
Inspection
Shape of the chest may be asymmetrical with localized
flattening as in case of collapse or fibrosis or bulging as
in pneumothorax or pleural effusion. Chest deformity
may result from chronic lung disease. Anteroposterior
diameter of the chest may be increased in emphysema.
Movements of part of chest may be diminished with
underlying diseased lung. Chest retractions often indicate
underlying pneumonia or parenchymal disease. Marked
shift of trachea makes sternomastoid muscle belly
prominent on the same side and is referred to as trail
sign. Position of cardiac impulse is noted.
Palpation
Movements of chest are noted and inspection findings
confirmed. Inserting finger between sternomastoid belly
and trachea on either side assesses position of trachea.
Normally, trachea is central or slightly to the right.
Position of apex beat is also confirmed. Pathology in

upper part of lungs shifts the trachea while that in lower
part may shift only the apex beat. Collapse and fibrosis
cause shift on the same side, whereas pleural effusion
and pneumothorax result in shift on the opposite side.
Tactile vocal fremitus (TVF) is palpated by either placing
palm or medial border of hand on the chest while patient
is asked to phonate.
Symmetrical areas of the chest are compared. TVF is
increased in pneumonia and decreased in pneumothorax
or pleural effusion. Fluid being good conductor of sound,
large pleural effusion may result in increased TVF,
however, in most of the cases, presence of collapsed lung
underneath the fluid dampens the transmission of sound,
hence, TVF is generally decreased in pleural effusion.
Cavity may produce variable signs depending on
patency of bronchus and the contents of the cavity.
Occasionally tenderness may be elicited in empyema.
Percussion
Direct rib sternum, Cloride, Indirect → finger
Chest is normally resonant with liver dullness in fifth or
sixth intercostal space in midclavicular line and cardiac
dullness coinciding with position of apex beat on the left
side and right border usually delineated to right sternal
border. Hyper-resonant note denotes either emphysema
or pneumothorax, while impaired note suggests collapse
or consolidation, stony dull note is characteristic of
pleural effusion. In case of suspected pathology on lower
side or right lung, in order to differentiate liver dullness
from a possible lung disease, percussion note is elicited
in normal breathing and on deep inspiration. This is
referred to as tidal percussion.
Auscultation
Normal breath sounds are equal on both sides and are
vesicular, like rustling of leaves. Bronchial breath sounds
are hollow with pause between inspiration and
expiration. High-pitched bronchial breath sounds are
Diseases of Respiratory System 559
referred to as tubular and are heard typically in
consolidation, while low-pitched cavernous breath
sounds are a feature of a cavity. Vocal resonance on
auscultation is commensurate with TVF on palpation.
Egophony, bronchophony and whispering pectoriloquy
represent merely the variability in the degree of increased
vocal resonance and are often heard in cavity. Post-
tussive suction refers to sudden rush of air during
inspiration following deep cough and is most patho-
gnomonic of a cavity. Succussion splash is elicited in
hydropneumothorax. Crepitations are moist foreign
sounds—fine crepitations suggest alveolar lesion while
coarse crepitations or rales denote bronchial pathology
such as bronchiectasis. Rhonchi are musical sounds as
heard in case of bronchospasm. Pleural rub is a localized
dry creaching sound heard at the end of inspiration and
beginning of expiration in pleuritis.
Interpretation of chest examination is often compli-
cated by many variables in the pathology that accom-
pany most of the respiratory disease. It is most impor-
tant to differentiate the anatomical site of the disease. In
general, bronchial diseases are generalized and bilateral,
while parenchymal lesions are commonly localized.
Often pleural and parenchymal lesions are difficult to
distinguish as both the lesions may produce identical
signs. Most important difference between pleural and
parenchymal lesion is the distribution of signs—lobar
distribution related to the surface anatomy of lobes in
parenchymal lesion as against nonlobar distribution in
pleural lesion. It means that in upper lobe pneumonia,
clinical signs are noted anteriorly in upper half, middle
lobe represents anterior lower half, while lower lobe signs
are predominantly posterior. Clinical signs of pleural
lesions are not bound by lobar boundary and are noted
below a particular level on the chest both anteriorly and
posteriorly. When clinical signs do not follow any pattern,
it is likely to be due to a mediastinal pathology as in case
of a mediastinal tumor.
560 IAP Textbook of Pediatrics

12.2 Diagnostic Procedures and

Investigations in Respiratory Diseases
Archana S Kher, Soumya Swaminathan, Milind S Tullu

A variety of respiratory disorders are encountered in Important Investigations

children. A scientific approach and accurate diagnosis
will enable proper treatment and outcome. This review Hematological
will discuss the investigations (simple and sophisticated) Complete hemogram is informative in infections where
and diagnostic procedures, which aid the diagnosis. there is leukocytosis; eosinophilia in allergic disorders,
Table 12.2.1 gives a broad classification of the investi- and an elevated ESR is encountered in infections and
gations and procedures that can be undertaken. collagen vascular disorders.
TABLE 12.2.1: Broad classification of Arterial blood gas (ABG) analysis is one of the most useful
the investigations and procedures tests of pulmonary function, as arterial levels of oxygen
Investigations Procedures and carbon dioxide reflect the result of ventilation,
perfusion and gas exchange. The samples can be drawn
Hematological
• Hemogram Transillumination from umbilical (in neonates), radial, brachial and
• Blood gas analysis Thoracocentesis temporal arteries. Arterial capillary blood may be used
after local vasodilatation with nitroglycerin. Transcuta-
Serological
• Antibody testing Nasal biopsy (for
neous oxygen monitoring or ear oximetry can be used
immotile cilia syndrome) continuously in critically ill patients. End tidal CO2
• IgE levels Lung puncture (capnography) monitoring correlates well with the
• Immunoglobulins, ECP, Lung biopsy arterial PCO2. The normal arterial blood pH is 7.35 to
RAST, PRIST 7.45, PCO2 is 35 to 45 mm Hg (venous PCO2 is 6 to 8 mm
• ELISA for HIV Laryngoscopy
Hg higher than arterial PCO2), and PO2 is above 90
• alpha-1 levels (for alpha-1 Bronchoscopy
antitrypsin deficiency) Polygraphic monitoring mmHg.

Microbiological Pulse Oximetry: The machine has light emitting diodes

• Sputum and photodetector. Two wavelengths of light-red
• Nasal, throat secretions (660 nm) and infrared (940 nm) are used which are
• Ear fluid differentially absorbed by the oxy- and deoxy-hemo-
• Bronchoalveolar lavage
globin and the difference between the two is used to
Radiographic calculate SpO2 (oxygen saturation). It is accurate from
• Plain X-rays 75-100 percent SaO 2 . It is commonly used in the
• Sonography
emergency room, casualty, ICUs and in operation
• CT, MRI
• Radionuclide scan
theaters to quickly check the oxygen saturation.
• Contrast studies
• Invasive- Angiography Serological
Molecular testing Immunoglobulins (G, A, M, D, E) can be measured in
• MDRTB, CMV, other viruses suspected cases of immunodeficiency. Elevated IgE levels
• Cystic fibrosis help in the diagnosis of asthma and allergy. HyperIgE
• alpha-1 antitrypsin deficiency
syndrome or Job’s syndrome can present with recurrent
Others respiratory and skin infections. Recently, eosinophilic
• Skin tests cationic protein levels [ECP] have been found to be elevated
• Sweat chloride test
in asthma. This is a relatively costly test, but is a sensitive
• Pulmonary function tests (PFT)
test and elevated levels indicate active asthma and the

levels decrease during remission. Antibodies to
mycoplasma, cytomegalovirus, respiratory syncytial
virus and chlamydia can be detected with the use of
special kits. IgE levels can be estimated by using
Radioallergosorbent test (RAST) and paper radioimmuno-
sorbent test (PRIST).
Microbiological Methods
Sputum examination: Large quantities of foul smelling
sputum are seen in lung abscess and bronchiectasis. The
consistency may be serous, purulent, hemorrhagic or
viscid (cystic fibrosis). The sputum sample is concen-
trated by the Petroff’s method and a smear is made from
the deposit obtained after centrifugation. Gram stain and
Ziehl-Neelsen’s stain is done. Abnormal contents include
large number of epithelial cells, pus cells, malignant cells,
Curschmann’s spirals, Charcot-Leyden crystals, fibrinous
casts and parasites. Special stains must be done for fungi
and Pneumocystis carinii.
Nasal cytology: It can be studied for eosinophil counts, in
cases of allergic rhinitis.
Tracheal secretions, throat cultures, bronchial aspiration after
lavage, sputum and ear discharge can be cultured to
detect bacterial growth and antibiotic sensitivity pattern.
Iron stains may reveal hemosiderin granules within
macrophages suggesting pulmonary hemosiderosis.
Viral pneumonia may be accompanied by intranuclear
or cytoplasmic inclusion bodies, as seen on Wright’s
stained smears. Fungal forms can be identified by KOH
mount.
In younger children, sputum cannot be obtained. In
place of sputum, an early morning gastric aspirate is
suitable for smear culture for acid-fast bacilli (AFB) since
gastric motility and acidity are low in sleep. This is the
only specimen available for demonstrating AFB in young
children suffering from pulmonary tuberculosis.
Radiographic Techniques
An appropriate, properly performed and interpreted
posteroanterior and lateral views (upright and at full
inspiration), still remains a valuable diagnostic tool for
the pediatrician. Decubitus films are indicated, if there is
suspicion of pleural fluid. Oblique films help to evaluate
the hilum and area posterior to the heart, while the apices
are best seen in a lordotic view. A lateral neck film yields
Diseases of Respiratory System 561
information in patients with upper airway obstruction,
about the retropharyngeal, subglottic and supraglottic
space. Knowledge of the phase of respiration in which
the film is taken is necessary for interpretation.
The Waters’ projection is done to see the frontal and
maxillary sinus and the Caldwell’s view for frontal,
ethmoidal sinuses and nasal cavity and septal devi-
ations. The frontal sinus develops after 5 years and
maxillary after 2 years of age. Lateral views are taken for
the sphenoid sinus. Schuller’s view is taken to detect
mastoiditis.
Fluoroscopic technique is useful in the evaluation of stridor
and abnormal movement of diaphragm and media-
stinum. Ultrasonography is a simple noninvasive
technique and helps to detect fluid and intrathoracic
masses. Pleural aspirations and lung tap can also be
performed under ultrasonographic guidance.
Computed tomography is an accurate tool and aids
radiodiagnosis of mediastinal and pleural lesions, solid
and cystic parenchymal lesions, and to decide the extent
of parenchymal diseases (collapse/consolidation); while
a high-resolution CT is used for diagnosis of bronchiec-
tasis. Intravenous contrast enhances vascular structures.
CT guided biopsy of mediastinal lymph nodes/suspi-
cious masses can be done to obtain samples for
histopathology. Spiral CT provides a very fast study. CT
angiography aids the diagnosis of abnormalities like
vascular rings.
Magnetic resonance imaging (MRI) is very useful to
evaluate hilar structures, vascular abnormalities like
rings and chest masses. MRI is also being increasingly
used preoperatively in addition to color Doppler and 2D-
echocardiography for complex congenital heart diseases.
Both CT and MRI need to be performed under short
general anesthesia in children.
Contrast Studies
A barium swallow is performed to rule out ‘H’ shaped
tracheoesophageal fistula (thin barium study), where
barium is injected through a catheter, placed at several
locations in the esophagus. It is also used to evaluate
gastroesophageal reflux (which is mostly done with the
help of a radionuclide milk scan), to look for esophageal
indentation with vascular rings and to diagnose
esophageal strictures.
562 IAP Textbook of Pediatrics
Mantoux Test
An injection of 5TU of PPD (2TU, R23 Tween 80) is given
intradermally on the forearm, using a tuberculin syringe.
Induration and erythema is checked after 48 to 72 hours.
The test is considered positive when the induration is
more than 10 mm in diameter.
The other skin tests used for diagnostic purpose are,
the Kveim test for sarcoidosis and Casoni’s test for
Echinococcus or hydatid disease.
Skin tests are also carried out to detect the presence
of atopic reagins (lgE) in skin. The skin bound reaginic
antibody reacts with the antigen, resulting in release of
mediators, which causes a wheal and a flare response at
the site of test within a period of 15 to 25 minutes. There
are three types of skin tests for allergies, i.e. scratch test,
prick test and intradermal test. A number of allergens
can be used for testing.
Sweat Chloride Test
The method used is pilocarpine iontophoresis, where a
3 mA current is used and a minimum of 50 mg of sweat
is collected on a filter paper. The chloride values are
elevated in cystic fibrosis and a value above 60 mEq/L
strongly suggests the diagnosis. Newer methods like
linkage analysis or DNA studies, using polymerase chain
reaction (PCR) are now used for molecular diagnosis of
cystic fibrosis. PCR can be set up to detect common
mutations.
Pulmonary Function Tests
Pulmonary function tests (PFTs) are an essential part of
the investigation of many respiratory diseases. Children
above the age of 6 years usually cooperate enough for
testing. PFTs are used for diagnostic (asthma, restrictive
disorders, etc.), monitoring (efficacy of treatment and
course of disease) and evaluation of disability (disease
severity). The lung volumes and lung capacities are
depicted in Figure 12.2.1. Spirometry is the most
important test of lung mechanics and measures the
volume of air exhaled from the lungs during a maximal
expiratory maneuver. The following parameters are
measured in spirometry:
i. Forced vital capacity (FVC)
ii. Forced expiratory volume in 1 second (FEV1)
iii. Ratio of FEV1 to FVC (normal > 80%, sensitive
indicator of obstructive airway disease)
Figure 12.2.1: Lung volumes as they appear on the spiro
graphic tracing. The four primary lung volumes and lung
capacities are shown. TV: tidal volume, IRV: inspiratory reserve
volume, ERC: expiratory reserve volume, RV: residual volume,
IC: inspiratory capacity, FRC: functional residual capacity, VC:
vital capacity, TLC: total lung capacity
iv. Maximal mid expiratory flow rate (MMEF or FEF
25 to 75%: indicator of small airways obstruction)
In obstructive airway diseases, the flow rates are
decreased while in restrictive diseases the lung volume
is reduced while the flow rates remain normal. The
configuration of the flow volume curve also provides
information regarding the disease class, in obstructive
diseases; the curve is convex towards the volume axis
while in restrictive diseases, it is normal in shape but
smaller (Fig. 12.2.2). Obstructive disorders are characteri-
zed by low FEV1/FVC ratio, low FEV1 and low or normal
FVC while restrictive disorders are characterized by low
FVC and normal FEV1/FVC ratio. Repeating the PFTs
after administration of aerosolized bronchodilator to the
patient and observing an increase in FEV1 of greater than
15 percent above the baseline can make the diagnosis of
reversible airway obstruction. Other pulmonary function
tests like exercise challenge, bronchial provocation,
polysomnography, ventilation-perfusion scans, etc. are
also rarely used.
The mini Wright peak flow meter is a simple, portable
and inexpensive device that measures peak expiratory
flow rate (PEFR) in L/min or L/sec. The test is effort
dependent and can be compared with standard norms
for age and sex and with the patient’s own values. Home
monitoring of PEFR is useful for early detection of an
impending asthma attack and for monitoring efficacy of
treatment. For recording the PEFR, the pointer (marker)
adjusted to zero. The subject should stand upright and
hold the device horizontally. Air is inhaled as much as

Figure 12.2.2: Flow volume curves for a normal child (A) and a child with moderate obstructive airway disease (B)
possible and the lips should be closed over mouthpiece.
Then the air should be blown as hard and as fast as
possible. The attempts are repeated three times at interval
of about 1 min. The best of the three blows is recorded as
the PEFR. The advantages of PEFR monitoring are:
objective measure of severity, correlates with FEV1,
small, simple, portable and convenient device, relatively
inexpensive, easy to maintain, used in children > 5 years
(especially “poor perceivers” of asthma symptoms) and
it can be used in clinics, hospitals and home. PEFR should
not be used for diagnosis of asthma but used only for
monitoring.
Measurement of lung volumes (FRC) is usually made
by either body plethysmography or gas dilution techniques.
Methacholine and histamine inhalation can be used for
bronchial provocation tests. Bronchial hyper-reactivity is
detected by a 20 percent fall in FEV1. Lung volumes and
flow rates vary with age, sex, height and ethnic group
and therefore it is important to have age and sex matched
reference values from the same population and
preferably the same laboratory.
Transillumination
Transillumination of the chest wall may yield positive
results in infants up to 6 months of age. A pneumothorax
can be diagnosed, because free air in the pleural space
often results in an unusually large halo of light in the
skin surrounding the fiberoptic light probe.
Diseases of Respiratory System 563
Laryngoscopy
Inspection of the glottis is mandatory while evaluating
stridor and upper airway obstruction. Indirect (mirror)
laryngoscopy is not feasible in smaller children. Direct
laryngoscopy can be performed under sedation or
anesthesia, with a rigid or fiberoptic scope.
Bronchoscopy
Flexible bronchoscopy is performed under topical
anesthesia in children. Indications include recurrent/
persistent pneumonia, atelectasis, unexplained wheeze,
foreign body, hemoptysis, mass lesions, unexplained
interstitial disease/ pneumonia in immunocompromised
child, etc. Therapeutic procedures can also be carried out
including removal of mucus plug, granulation tissue,
foreign body and instillation of drugs. A rigid scope is
preferred for removal of mucous plugs and foreign body.
Fluid obtained with a bronchoalveolar lavage is
extremely useful for cytological and microbiological
diagnosis of certain lung diseases.
Thoracoscopy
The pleural cavity can be examined through a thoraco-
scope, which is similar to a rigid bronchoscope. This
procedure is less invasive than an open thoracotomy.
Video-assisted thoracoscopic surgery (VATS) can now
be used for various diagnostic and therapeutic proce-
dures (minimally invasive surgery).
564 IAP Textbook of Pediatrics
Thoracocentesis
It is performed when X-ray or ultrasonography is sugges-
tive of fluid in the pleural cavity. Please refer to the
chapter on Pediatric Procedures.
Lung Tap
A percutaneous tap with a needle and after instillation
of saline is the most direct method of obtaining speci-
mens from the lung parenchyma.
Lung Biopsy
This may be the only way to establish a diagnosis in
protracted noninfectious disease, e.g. interstitial disease.
An open biopsy or a transbronchial biopsy through an
endotracheal tube or a bronchoscope can be obtained.
This technique is most appropriate for diffuse lung
disease such as infection due to Pneumocystis carinii.
Polygraphic Monitoring
This is done during natural sleep, the number and
duration of obstructive apneas and upper airway obs-
tructions are monitored. Heart rate, ECG, thoracic and
12.3 Flexible Fiberoptic Bronchoscopy (FFBS)
Flexible Fiberoptic Bronchoscopy (FFBS) has revolutio-
nized the management of respiratory diseases because
of its extensive diagnostic and therapeutic applications.
It is an important tool added in the diagnostic work up
of respiratory medicine and without FFBS contribution
such work up may be incomplete in many instances.
Today a skilled bronchoscopist can sample from any
bronchopulmonary segment. Though pediatric scopy has
many advantages it is widely underutilized because of
lack of awareness, cost, and expertise training programs.
EVOLUTION OF SCOPY
The idea of bronchoscopy was started as early as
1928 by Jackson and Jackson, et al. The initial scopy
consisted of wide bore metal tube fitted with lamp and
lenses. The innovative idea of Japanese scientist, Shigeto
Ikedo, led to the invention of FFBS in early seventies.
abdominal movements, arterial PCO 2 and SaO 2 are
monitored.
BIBLIOGRAPHY
1. Balachandran A, Vijayasekaran D, Shivbalan S.
Bronchopist talks to you. Indian Journal of Pediatrics
2004;71(8):739-42.
2. Brand PLP, Roorda RJ. Usefulness of monitoring lung
function in asthma. Arch Dis Child 2003; 88: 1021-25.
3. Crapo RO. Pulmonary-function testing. New England
Journal of Medicine 1994;331(1):25-30.
4. Fletcher BD. Diagnostic imaging of the respiratory tract.
Chapter 8, Section 1. In: Chernick V, Boat TF, Kendig EL
(Eds): Disorders of the Respiratory Tract in Children (6th
ed). WB Saunders 1998;143-74.
5. Haddad GG, Palazzo RM. Diagnostic approach to respi-
ratory disease, Chapter 359, Part XVIII. In: Behrman RE,
Kliegman RM, Jenson HB (Eds): Nelson’s Textbook of
Pediatrics (17th ed), WB Saunders, 2004;1375-9.
6. Karkhanis V, Joshi JM. Pulmonary function testing in
pediatric practice. Pediatric Clinics of India 2003;41(2):
101-17.
7. Subramanyam L, Balachandran A, Somu N. Interpre-
tation of Pulmonology function tests (PFT). Essentials of
Pediatric Pulmonology 1990;38:229-37.
8. Vijayasekaran D, Subramanyam L, Balachandran A,
Shivbalan S. Spirometry in clinical practice. Indian
Pediatrics 2003;40:626-32.
D Vijayasekaran
FFBS versus Rigid Scope
Both FFBS and rigid scope neither replace nor duplicate
the work of each other. The applications of rigid scope
in pediatric practice are mainly therapeutic, like removal
of foreign bodies and surgical intervention at tracheo-
bronchial level, whereas flexible scope is largely used
for diagnostic work-up. Therapeutic applications of FFBS
is increasing day by day following the introduction of
newer slender scopes with larger working channel
(Table 12.12.1).
Precautions
FFBS is made up of fiberoptic bundles and the diameter
of each glass fiber is around 10 microns. In FFBS, light
undergoes repeated internal reflection through fibreoptic
bundles and the image formed is due to conglomeration

TABLE 12.3.1: FFBS versus rigid scope in pediatric practice
FFBS
a. Done under local anesthesia
b. Meant for diagnostic applications
c. Bronchoscopic vision is possible up to the orifice
of fifth order bronchi
d. Direct intraluminal evaluation of respiratory system
and broncho alveolar lavage are the
important procedures
e. Distal end can be deflected above (180) and below
(100) and upper lobe bronchi can easily be inspected
f. Since the bronchial lumen gets obstructed, the
procedure should be done quickly (within minutes)
and oxygen supplementation is necessary to
prevent hypoxemia
of thousands of points of light. The resolution of image
formed by FFBS is slightly inferior to that of rigid scope.
However, the added magnification gives better image.
Extreme delicacy and gentleness are important precau-
tions to be observed throughout the procedure. At no
time acute bending should be done lest breakage of glass
fiber is imminent.
Since nosocomial infection is the potential hazard, the
scope should thoroughly be cleaned by immersing under
2 percent glutaraldehyde (Cidex) for twenty minutes
after each procedure if infection is suspected. The recent
scopes are so designed that they can safely be submerged
under cleaning tank filled with glutaraldehyde.
Indications
Children with atelectasis, persistent pneumonia, recur-
rent pneumonia, opportunistic pneumonia, bronchiec-
tasis, unexplained hemoptysis, prolonged stridor or
cough, suspected congenital anomalies of the respiratory
tract (tracheomalacia, tracheal stenosis, tracheal web,
bronchial stenosis, bronchial web, hypoplasia or agenesis
of lung, vascular anomalies) endobronchial tuberculosis
and diffuse lung diseases can be benefitted with FFBS
evaluation.
If a child is deemed to be benefitted with FFBS
evaluation it should be done. However, if such infor-
mation could be possible with any other noninvasive
procedures, FFBS can preferably be avoided. Removal
of mucus plug may result in normal expansion of
atelectatic lung especially in young children forms the
Diseases of Respiratory System 565
Rigid scopy
Done under general anesthesia
Meant for therapeutic applications
Can reach safely up to second order bronchi
Removal of foreign bodies and surgical intervention are the
important procedures
Being a rigid tube bending and deflection is not possible
Jet ventilation through wide bore metal tube is advantageous
allowing the procedure fairly long time without any fear of
hypoxemia.
useful therapeutic indication. Fragmented or dissolved
foreign body placed beyond the bronchoscopic vision of
rigid scope can be sucked out at times with FFBS. This
forms another therapeutic indication of FFBS.
Newer indications of FFBS are expanding, which
include laser therapy, selective bronchogram, regional
lung function studies, intrapulmonary stent and bron-
choscopic ultrasonogram. However, these are not prac-
tised with pediatric FFBS because of narrow working
channel.
Preparation
Motivation and explaining the harmlessness about the
procedure both to parents and older children gains their
confidence, alleviates their unnecessary fear and increa-
ses their cooperation. Six hours fasting is advisable with
prior xylocaine sensitivity. In children with cardiac
problems atropine premedication (0.01 ml/kg) may
prevent complications of vagal stimulation (arrhyth-
mias). Some centers do administer midazolam and
ketamine to sedate. Though such things may be required
initially, once mastery of technique is achieved they are
rarely required.
Pep talk and a friendly atmosphere is all that is
required for constant success.
Topical anesthesia of upper respiratory tract can be
achieved with xylocaine instillation supplemented with
a small amount of xylocaine jelly applied over the
selected nostril. Though “spray while you go” technique
is the traditional way of topical anesthetisation few
566 IAP Textbook of Pediatrics
centers claim xylocaine nebulization is useful especially
if noncooperation is anticipated.
Procedure
After lubricating the patient’s nostril with 2 percent
xylocaine jelly, the distal end of FFBS should carefully
be inserted through the floor of the nostril closer to
inferior turbinate bone for better negotiation and
minimum discomfort. On reaching the nasopharynx, the
epiglottis is visualized. The scope has to be pushed
downwards to look for vocal cords at a distance. At this
location we should wait for at least a minute to study
the anatomy of vocal cords. If the child is not fully
cooperative instillation of a small dose of xylocaine over
the vocal cords results in thorough anesthetization and
ensures full cooperation. Negotiating the glottic opening
is an art that needs repeated training under the expert
supervision. The total dose of xylocaine should not
exceed 6 mg/kg of body weight. Once FFBS enters
trachea, the remaining procedure is relatively easy. The
normal side has to be inspected first to prevent conta-
mination from side of lesion. In trained hands inspection
of intraluminal tree hardly takes more than a minute and
prolonging the maneuver is not necessary as it may lead
to hypoxemia. If intraluminal evaluation needs longer
time, the scope can be reinserted after adequate
oxygenation rather than continuing the procedure for a
long time at a single stretch. Two trained assistants are
required to monitor vital signs and to assist in sampling
techniques during flexible scopy. Child’s head and hands
should be held otherwise the agitated child may pull out
the scope resulting scope damage. Young children may
be allowed to cry and older children are allowed to talk
as both these acts may encourage the scopist to do the
procedure easily. Monitoring with pulse oximeter is the
objective evidence of oxygenation status and SaO2 should
be maintained between 92 to 95 percent throughout the
procedure to prevent hypoxemia related complications.
Moreover pulse oximeter monitoring will increase the
confidence of the scopist while he engages in evaluating
the intraluminal tree.
Intraluminal Evaluation
Basic knowledge about the anatomy of the nasopharynx,
epiglottis, vocal cords, trachea and bronchial tree is
mandatory to identify abnormal anatomical features. The
art of visualizing intraluminal aspect of bronchial tree
should be learned before venturing interventions with
scope. During intraluminal evaluation one should look
for mucosal lesions, endobronchial granulations, mucus
plugs, missed foreign bodies, adenomas, bronchial
distortion due to external compression and abnormal
airway anatomy.
Sampling Techniques
Apart from intrabronchial evaluation, the following
sampling techniques can be done with presently
available pediatric scope: (a) bronchial aspiration with
polythene tube, (b) catheter brush biopsy with double
catheter system, (c) bronchoalveolar lavage (BAL).
While doing catheter brush biopsy, double catheter
system is preferred to prevent contamination from upper
respiratory flora. The telescopic (inner) catheter carrying
the brush is protruded out only when it reaches the target
site and after sampling, the inner catheter should be
drawn back into the outer catheter to prevent contami-
nation. Disposable catheters are available whose distal
end can be cut and sent for various bacteriological
investigations after the procedure.
Bronchoalveolar Lavage (BAL)
BAL can rightly be called as “Liquid Biopsy of the Lung”
comparable to urine analysis which is designated as
“Liquid Biopsy of the Kidney”. BAL collects the lining
fluid of bronchial epithelium containing cells and solu-
ble solutes rich in immunoglobulins and biochemical
contents. During BAL the distal end of the scope is
wedged into the desired bronchoscopic segment (affected
segment in localized disease and right middle lobe or
lingular segment in diffuse lung disease). Calculated
amount of normal saline (2 ml/kg) is instilled in three
aliquots to retrieve the maximum lavage fluid. Though
the retrieval after the first aliquot will be hardly anything
as the major quantity of fluid will trickle down to deeper
parts of lung, fair collection will be obtained from other
two aliquots. Usually, the BAL collected will be around
50 to 70 percent of instilled fluid which can be subjected
for cytological, biochemical, immunological and bacterio-
logical investigations.
BAL plays a major role in identification of causative
etiological agents in opportunistic pneumonia (immuno-
suppressive states including HIV) persistent/recurrent
pneumonia, pulmonary hemosiderosis, sarcoidosis,
alveolar proteinosis and other interstitial lung diseases.

Complication
The inherent complications of FFBS are hypoxemia,
subglottic edema, vagal stimulation which can safely be
avoided if the said precautions are meticulously
followed. Minor complications like nasal bleed, blood
tinged sputum, fever can settle without any treatment.
SUMMARY
FFBS is one of the useful gadgets in the diagnostic
armamentarium of respiratory medicine but not widely
applied in pediatric practice. It is the right time that
young doctors interested in the respiratory medicine
should come forward to take up this interesting field.
Methodical training under competent trainer with
expertise in this technique is all that is required. Though
it appears to be a costlier affair initially, considering
enormous benefits obtained in a short time it is definitely
a cost-effective procedure. In trained hands the
procedure is cent percent free of complications and its
risk benefit ratio is highly favorable. Many poor children
with chronic lung disease can immensely be benefitted
with FFBS and the technique is totally radiation free.
BIBLIOGRAPHY
1. Abadco DL, Steiner P. Gastric lavage is better than
bronchoalveolar lavage for isolation of mycobacterium
tuberculosis in childhood pulmonary tuberculosis.
Pediatr Infect Dis J 1992;11:735–8.
2. De blick J, Azevedo I, Burren CP, Le Bourgeois M,
Lallelund D: Scheinmann. The value of flexible broncho-
scopy in childhood tuberculosis. Chest 1991;100(3)
688–92.
3. Gibson NA, Coutts JA, Pator J. Flexible bronchoscopy
under 10 kg. Respiratory Medicine 1994;88(2):131-4.
12.4 Respiratory Distress
Acute respiratory distress is one of the most common
pediatric emergencies. Respiratory distress signifies
potential respiratory failure. Any infant or child who is
having difficulty in breathing, characterized by excessive
work of the muscles of respiration, is said to be in
respiratory distress. It is equivalent to the symptom of
dyspnea in an older child who is able to communicate
Diseases of Respiratory System 567
4. Godfreys, Avital A, Maayan C, Rotschild M, Springer C.
Yield from flexible bronchoscopy in children. Pediatr
Pulmon 1997;23(4)261-9.
5. Monnden Y, Morimoto, Taniki T, Uyama T, Kiard S.
Flexible bronchoscopy for foreign body in airway.
Tokushima J Exper Med 1989;36(1-2):35-9.
6. Phillips E2, Libsekal K. Flexible bronchoscopy in the
management of congenital lobar emphysema in the
neonate. Canad Respir 1998;5(3):219–21.
7. Raine J, Warner JO. Fiberoptic bronchoscopy without
general anaesthetic: Arch Dis Child 1991;66:481-4.
8. Rebort A, Goldstein, Prastiant K, et al. Clinical role of
bronchoalveolar lavage in adults with pulmonary
disease. Am Rev Resp Dis 1990;142:481-6.
9. Rennard SI. Future directions for bronchoalveolar lavage.
Lung 1990;1050–6.
10. Reynolds HY. State of the art: bronchoalveolar lavage.
Am Rev Respir Dis 1987;135:250-63.
11. Schellahase DE, Fawcett DD, Schutze GE, Lensing SY,
Tryka AF. Clinical utility of flexible bronchoscopy and
bronchoalveolar lavage in young children with recurrent
wheezing. Pediatric 1998;132(2):312-8.
12. Schellhase DE, Graham LM, Fix EJ, Sparks LM, Fan LL.
Diagnosis of tracheal injury in mechanically ventilated
premature infants by flexible bronchoscopy a Pilot study.
Chest 1990;98(5):1219-25.
13. Somu N, Swaminathan S, Paramasivam CN, et al. Value
of bronchoalveolar lavage and gastric lavage in the
diagnosis of pulmonary tuberculosis in children.
Tubercle and Lung Disease 1995;295-9.
14. Su YY, Niu CK, Liang CD, Herang CB, Ko SF. Usefulness
of pediatric flexible bronchoscopy in the early diagnosis
and postoperation evaluation of vascular rings: report
of three cases: Chang-Keny 1 Hshn Tsa chih, 1999;(22)4:
627-32.
15. YU HR, Nu CK Su. YT. Huang CB. Flexiable broncho-
scopic diagnosis of airway injuries after intubation in
children. J Formosan Med Assoc 2000;99(8):618-22.
MD Shah
this subjective symptom which is defined as ‘abnormally
uncomfortable awareness of breathing’. However,
dyspnea and respiratory distress are not exactly
synonymous as in some metabolic causes of respiratory
distress such as metabolic acidosis and in cyanotic
congenital heart disease, there may not be dyspnea even
though child is in respiratory distress. Respiratory
568 IAP Textbook of Pediatrics
distress may be acute or chronic. Acute respiratory
distress is more easily recognized by the clinician
whereas chronic respiratory distress is often overlooked.
However, it is important to recognize the later as it is an
important cause of disability in a child.
ETIOLOGY
Most of the conditions producing respiratory distress
involve airway obstructions which may be extrathoracic
and intrathoracic (extrapulmonary or intrapulmonary).
Parenchymal lung diseases and nonpulmonary condi-
tions can also cause respiratory distress. Based on these
considerations, the causes of respiratory distress can be
classified into following major groups.
Extrathoracic Airway Obstructions
Causes in the Newborn
• Bilateral or unilateral choanal atresia
• Stuffy nose syndrome (turbinate hypertrophy)
• Nasopharyngeal encephalocele, dermoid, chordoma
• Pierre Robin syndrome
• Macroglossia (primary or secondary)
• Internal thyroglossal duct cyst
• Laryngomalacia
• Bilateral vocal cord paralysis
• Congenital subglottic stenosis or hemangioma .
• Laryngeal web
• Trauma caused by endotracheal intubation.
Causes in Infants and Children
• Foreign body in nose
• Acute or chronic adenoiditis and tonsillitis
• Hypopharyngeal foreign body
• Croup syndrome caused by
— Acute L TB/Acute epiglottitis
— Spasmodic laryngitis/Laryngeal angioedema
— Laryngeal diphtheria/Laryngeal abscess
— Bacterial tracheitis/Retropharyngeal abscess
• External trauma to neck
• Burns of upper airways
• Postendotracheal intubation and instrumentation.
Intrathoracic Airways Obstructions
• Extrapulmonary
• Vascular anomalies: Double aortic arch, right sided
aortic arch with aberrant left subclavian artery,
pulmonary arterial sling
• Tumors in anterior mediastinum pressing on
intrathoracic trachea, e.g. lymphoma, lymphangioma,
hemangioma, thymoma, congenital goiter
• Tracheal stenosis, tracheomalacia, bronchial stenosis,
T-0 fistula
• Chondrodystrophies e.g., Ellis-van Creveld
syndrome
• Diphragmatic hernia.
Intrapulmonary
• Bronchial asthma
• Foreign bodies
• Congenital bronchial stenosis
• Bronchiolitis
• Endobronchial tuberculosis
• Congenital lobar emphysema.
Parenchymal Lung Diseases
• Pneumonias, bronchopneumonias, aspiration
syndromes
• Respiratory distress syndrome in newborns
• Pediatric acute respiratory distress syndrome (ARDS)
• Air leak syndromes: Pneumothorax, interstitial
emphysema, pneumomediastinum, pneumoperi-
cardium
• Pulmonary hemorrhage
• Bronchopulmonary dysplasia
• Wilson-Mikity syndrome
• Chronic pulmonary insufficiency of prematurity
• Pulmonary hypoplasia or agenesis
• Pleural effusions, empyema, chylothorax.
Nonpulmonary Causes of Respiratory Distress
• Congestive cardiac failure
• Metabolic causes: Acidosis, ketoacidosis, hypogly-
cemia
• Persistent pulmonary hypertension of newborn
• Birth asphyxia and other CNS disorders.
Pathophysiology
Pathophysiology varies with the etiological cause and is
described elsewhere. Hence, here only pathophysiology
of pediatric ARDS is described.
Pediatric acute respiratory distress syndrome (ARDS),
formally known as adult respiratory distress syndrome,
has now been recognized as an important cause of
respiratory distress in children and forms 1 to 4% of PICU

admissions in western countries. It may arise as a result
of a direct pulmonary disease or secondary to systemic
disease elsewhere in the body. Common pulmonary
diseases that may cause ARDS are aspiration, smoke
inhalation, bacterial and fungal infections. Systemic
disorders which may cause ARDS include sepsis, trauma,
near drowning, burns, massive transfusions and drug
overdosage. The hallmark of ARDS is the destruction of
the capillary-alveolar unit which sets in motion all the
pathophysiological changes of ARDS which are charac-
terized by three stages namely the exudative, fibro-
proliferative and fibrotic.
Exudative stage: Injury to lung endothelial cells and
alveolar epithelial cells (type I and II) resulting in protein
rich exudate filling the alveoli and interspaces and
development of microvascular thrombi in capillaries.
Fibroproliferative stage: This stage occurs between
the first and third week after the initial insult and is
characterized by cellular infiltration and proliferation of
type II pneumocytes, firoblasts and myofibroblasts.
Fibrotic stage: This stage occurs 3 weeks after the
initial injury and is characterized by fibrosis, healing and
remodelling of the lungs.
There is release and accumulation of cytokines in
alveolar spaces in early ARDS. It is the migration of these
cytokines into the systemic circulation which contributes
to the development of multiorgan failure (MOF), which
is a serious and often fatal complication of ARDS.
Clinical Features
A child with respiratory distress needs a thorough clinical
evaluation for diagnosis, assessment of severity and
determining the etiology and for this following clinical
features should be carefully evaluated.
Respiratory Rate and Depth
The respiratory rate, when properly measured, is
invaluable to determine both initially and longitudinally
the severity of respiratory dysfunction. It should be
measured for a full 2 minutes, and the total number of
breaths then divided by two. In patients with airway
obstructions, the respiratory rate is either slow or fast
but the excursions are deep. In patient with metabolic
acidosis, the respirations are deep, rapid and sighing
(Kussmaul breathing). In patients with decreased lung
compliance as in pneumonia or pulmonary edema, the
respirations are rapid and shallow. In patients with
encephalitis, the respirations are usually rapid and deep,
Diseases of Respiratory System 569
but can be rapid and shallow. Orthopnea should also be
noted as its presence is indicative of severe respiratory
distress.
Respiratory Rhythm
Cheyne-stokes breathing is characterized by cycles of
increasing and decreasing tidal volumes separated by
apnea. It may occur normally in prematures and in full-
term newborns during sleep but in older children, it is
seen with CCF and increased intracranial pressure. Biot’s
breathing may be seen in children with meningitis or
severe brain damage. Biot’s breathing consists of
irregular cycles of respiration at variable tidal volumes
interrupted by apnea and is an ominous finding in
patients with severe brain damage.
Inspiratory Retractions
The increased negative intrathoracic pressure generated
to move a desired tidal volume past obstructed airways
or into poorly compliant lung, leads to intercostals,
supraclavicular, suprasternal, substernal and subcostal
retractions. Retractions result from an abnormal pressure
relationship between the pleural space pressure and the
atmospheric pressure. Increased effort of breathing results
in increased negative pressure in the pleural space creating
an increased pressure gradient between atmospheric
pressure and pleural space resulting in sinking in of soft
tissues. This is observed clinically as retractions. These are
especially striking in extrathoracic airway obstructions,
as the large negative pressure below the site of obstruction
during inspiration produces collapse of extrathoracic
airways. In premature infants and in patients with frail
chest, marked retractions may occur, even with slightly
increased negative inspiratory pressures. Suprasternal
retractions are particularly marked in cases of upper
airway obstructions. Inspiratory indrawing of the lateral
chest is known as Hoover’s sign and is observed in patients
with obstructive airway disease.
Intercostal Bulging
This is seen in severe asthma, during expiration as the
pleural pressure becomes greatly positive to force the
expiration against increased airway resistance.
Head Bobbing
In head bobbing the head bobs forward in synchrony
with each inspiration. This is observed in infants in whom
570 IAP Textbook of Pediatrics
accessory muscles of respiration are active. Contraction
of the sternocleidomastoid muscles during inspiration
leads to forward bending of neck. The relatively weak
cervical spinal muscles of infants are unable to resist the
strong pull exerted by sternocleidomastoid muscles.
Stridor
Stridor refers to a musical sound of single pitch that is
produced by oscillations of critically narrowed extra-
thoracic airways. Initially, it is inspiratory but when the
obstruction becomes more severe, it is both inspiratory
and expiratory. When stridor is higher pitched, the child
is in more distress. As the patient improves with the
resolution of the primary disease, the stridor becomes
lower in pitch. The pitch of the stridor can be used to
assess improvement or worsening of the condition in
relation to the therapy.
Wheezing
Expiratory wheezing is heard in any condition where
there is intrathoracic airway obstruction, e.g. brochial
asthma, vascular ring, bronchial stenosis, bronchogenic
cyst, etc. Widespread narrowing of airways in asthma
leads to various pitches and so wheezing is polyphonic,
whereas a fixed obstruction in larger airways produces
monophonic wheezing. Wheezing may not be heard in
very severe airway obstruction.
Grunting
It is a low-pitched sound, which is produced by expira-
tion against a partially closed glottis. It is an attempt to
maintain a positive end expiratory pressure (PEEP) as
long as possible, so as to prevent alveolar collapse at end
of expiration. This is most beneficial in small airway
obstruction and in alveolar diseases that produce
widespread loss of functional residual capacity such as
pulmonary edema, diffuse pneumonia, and hyaline
membrane disease (HMD). It is a prominent feature of
RDS in newborn.
Flaring of the Alae Nasi
It is a sensitive sign of respiratory distress. By enlarging
the anterior nasal passages, it reduces upper and total
airway resistance and helps in stabilizing the upper
airway by preventing large negative pharyngeal pressure
during inspiration.
Paradoxical Breathing
Inward motion of the chest during inspiration is called
paradoxical breathing. It is seen when there is paralysis
of intercostals muscles or a very compliant rib cage (e.g.
in premature infants). The development of paradoxical
breathing in an awake, nonparalyzed patient beyond the
newborn period indicates respiratory muscle fatigue and
impending respiratory failure.
Plusus Paradoxus
The widening of systolic blood pressure difference
between inspiratory and expiratory phase of respiration
is known as pulsus paradoxus. A drop of greater than
10 mmHg during inspiration is taken as clinically
significant and indicates increased airway resistance.
Pulsus paradoxus is useful in assessing the severity of
bronchial asthma. It may be as high as 40 mmHg in very
severe asthma. Pulsus paraldoxus can be qualitatively
assessed by palpation of a peripheral pulse during the
respiratory cycle and it can be quantitatively measured
by the difference in systolic pressure with inspiration and
expiration.
Cyanosis
Central cyanosis is frequently associated with significant
respiratory distress. Clinically pediatric ARDS is
characterized by four phases: First phase is of acute lung
injury caused by initial insult and is followed by second
phase of silent latent period of 24-72 hours. Third phase
is of progressive tachypnea, leading to dyspnea and
respiratory failure. This may be followed by fourth phase
of severe respiratory failure and MOF.
Assessment of Respiratory Distress in Newborns
Newborns develop respiratory distress due to several
causes of which the most important is the hyaline
membrane disease (HMD). It is important to diagnose it
early and assess the severity from the point of view of
management. Silverman has designed a scoring system
that takes multiple factors into account to quantify the
severity of respiratory distress into three grades (0, 1,
and 2). The clinical signs observed are movement of
upper chest in relation to abdomen, retractions in lower
chest, xiphoid retractions, dilatation of anterior nares and
expiratory grunt.

Grade 0: Synchronized movements of upper chest and
abdomen, no retraction of lower chest and xiphoid, no
dilatation of nares and no expiratory grunt.
Grade 1: Lag of upper chest on inspiration in relation to
abdomen, mild retractions of lower chest and xiphoid,
minimal dilatation of nares and expiratory grunt heard
with stethoscope only.
Grade 2: See-saw movement of upper chest and abdomen,
marked retractions of lower chest and xiphoid, marked
dilatation of nares and expiratory grunt heard with naked
ear.
INVESTIGATIONS
The following four basic investigations are required in
almost all cases of respiratory distress.
1. CBC
2. Mantoux test
3. X-ray of chest, frontal and lateral views
4. Arterial blood gases.
The correct interpretation of arterial blood gas values
is very valuable in localizing the site of diseases, in
estimating the severity of disease and in diagnosing
presence or absence of respiratory failure (Table 12.4.1).
The following special investigations may be required
only in selected cases: X-ray of soft tissues of neck:
Anteroposterior and lateral views:
• CT Scan/MRI of chest
• Bronchoscopy, laryngoscopy, rhinoscopy
• ECG
• Sonography of chest
• Pulmonary function tests
TABLE 12.4.1: Interpreting blood gas values in
respiratory distress
A. Extrathoracic and central intrathoracic (above the carina)
airway obstruction
PaCO2↑, PaO2↓
Response to supplementary oxygen is good
B. Intrathoracic intrapulmonary airway obstruction.
Mild: PaCO2↓, PaO2↓
Moderate: Normal PaCO2, PaO2↓↓
Severe: PaCO2↑, PaO2↓↓↓
Response to supplementary oxygen is good to fair
C. Alveolar or parenchymal pathology
PaO2 decreased depending on severity
PaCO2 variable, may be increased when exhaustion or
respiratory muscles fatigue supervenes.
Response to supplementary oxygen is fair
Diseases of Respiratory System 571
• Pleural tapping
• Lung biopsy
• Sputum examination: smear and culture
• Ventilation and perfusion scan of lung sleep study
• Aortogram, pulmonary angiorgram
• Esophagoscopy and esophagogram
• Bronchoalveolar lavage fluid examination
In pediatric ARDS examination of BAL fluid for the
levels of inflammatory mediators like TNF-L, IL-1, IL-6
and IL- 8 as they correlate with severity of respiratory
failure and association of MOF. Increased serum levels
of IL-6 correlate with presence of MOF.
DIAGNOSIS
Diagnosis of respiratory distress is easy when the above
described clinical features are present. However, it is
important to determine the site of the problem and in
this regard, Table 12.4.2 which correlates the clinical
features with site of the problem is very helpful.
Next step is to determine the cause of respiratory
distress. Respiratory distress can be caused by airway
obstructive diseases, parenchymal lung diseases or non-
pulmonary causes are ruled out, Tables 12.4.1 and 12.4.2.
are of much help in narrowing down the likely causes.
In pediatric ARDS X-ray chest and CT scan are useful
in diagnosis. X-ray chest shows diffuse bilateral infiltrates
and chest CT scan demonstrates areas of relatively
normal lung interspersed with atelactatic and consoli-
dated regions in the dependent zones.
The diagnosis of ARDS has now become more
uniform and rational since the proper diagnostic criteria
formulated by the 1994 American-European consensus
conference on ARDS. The consensus committee gave the
following diagnostic criteria for ARDS and acute lung
injury (ALl):
1. Acute onset
2. Diffuse bilateral infiltrates on chest radiograph.
3. A pulmonary artery wedge pressure less than or
equal to 18 mm Hg or no clinical evidence of left atrial
hypertension.
4. A ratio of partial pressure of oxygen in arterial blood
to fraction of inspired oxygen (PaO2/FiO2) of less than
or equal to 300 in ALT and 200 in ARDS regardless of
levels of PEEP.
Postnatal diagnosis of RDS in a newborn should be
suspected in a premature baby who develops shortly
after birth tachypnea, retractions, flaring of alae nasi,
572 IAP Textbook of Pediatrics
TABLE 12.4.2: Correlation of clinical features with the site of problem
Clinical features Airway obstruction
Extrathoracic
Extrapulmonary
Tachypnea + +
Retraction ++++ ++
Stridor ++++ ++
Grunting + +
Wheezing — +++
grunting and cyanosis with X-ray of chest showing
diffuse reticulogranular pattern and air bronchogram.
MANAGEMENT
This will depend upon the etiological conditions causing
the respiratory distress and is described elsewhere under
the individual conditions. Hence, here only the manage-
ment of pediatric ARDS is briefly described. Mechanical
ventilation is the key supportive therapy for ARDS and
the most revolutionary change in the ventilation strategy
is the adoption of lung protective strategy in which lower
tidal volume (Vt < 6 ml/kg), lower peak inspiratory
pressure (PIP< 30 cm H2O) and higher PEEP are used as
compared to conventional ventilation. This strategy
prevents or reduces the ventilator induced lung injury
(Volutrauma and barotrauma). Adoption of this strategy
has led to improved oxygenation and survival of the
child. Another lung protective strategy like high
frequency oscillatory ventilation (HFOV) is also used in
selected cases of ARDS. Other adjunctive therapies which
are being evaluated are nitric oxide inhalation, prone
positioning, surfactant administration, use of steroids,
extracorporeal membrane oxygenation (ECMO) and
anticoagulation therapy. Of these prone positioning,
surfactant therapy and steroid therapy appear promising
whereas others are still of questionable benefit. Prone
positioning is safe and simple to apply and it improves
oxygenation and should be considered for all patients
with ARDS. Steroid therapy helps by reducing the
overaggressive inflammatory response and end stage
fibrosis. They should be given for 4 to 6 weeks. It should
be tried in cases which are not improving. Surfactant
therapy improves oxygenation but does not benefit over
all mortality and hence should be tried only in selected
cases which are resistant to treatment. ECMO is
Parenchymal lung disease
Intrathoracic
Intrapulmonary
++ ++++
++ ++
— —
++ ++++
++++ +
recommended only when there is severe respiratory
failure that would otherwise be fatal. It’s use is restricted
because of its serious complications like intracranial
bleeding, sepsis from canula and cerebral injury related
to carotid cannulation. The anticoagulation therapy with
activated protein C, found useful in adults, is still not
evaluated in children. It may be useful in cases of sepsis.
All these recent advances in management of ARDS have
considerably reduced the mortality and morbidity of
ARDS.
FOLLOW-UP
Any newborn, infant or child who has suffered from
respiratory distress should be followed up over a long
period of time by clinical examination, X-ray and PFT in
order to detect long-term sequel and pulmonary
morbidity.
ACKNOWLEDGEMENT
I sincerely thank Dr. Snehal Shah Sharma, ex-lecturer,
BJ Wadia Children Hospital Mumbai, for her valuable
assistance in preparing this manuscript.
BIBLIOGRAPHY
1. Ackerman NB, Hendon BL. Assessment of the Neonate.
In: Barnhart SL, Czervinske MP (Eds): Perinatal and
Pediatric Respiratory Care. (1st edn) WB Saunders
Company 1995;23-44.
2. Anderson MR. Update in pediatric acute respiratory
distress syndrome. Respiratory care, 2003;48(3):261-78.
3. Andrew HN, Christopher JL. Acute respiratory distress
syndrome in the pediatric patient. In: Chernick Victor
EL (Eds): Kendig’s Disorders of the Respiratory Tract in
Children. (7th edn) Saunders Elsevier 2006;639-52
4. Bhakta KY. Respiratory Distress Syndrome. In: Cloherty
JP, Eichenwald EC, Stark AR (Eds): Manual of Neonatal
Care. (6th edn) Wolters Kluwer (India) pvt Ltd, New
Delhi 2008;323-30.

5. Pasterkamp H. The history and physical examination:
In: Chernick Victor EL (Ed): Kendig’s disorders of the
respiratory tract in children. (7th edn). Saunders Elsevier
2006;75-93.
6. Ronald HI, Eugene B. Dyspnea and pulmonary edema:
In Harrison’s principles of internal medidine (13th edn),
McGraw-Hill, New Delhi 1994;74-8.
12.5 Upper Respiratory Tract Infection
INTRODUCTION
Acute respiratory infections are a major cause of
morbidity and mortality in children and of particular
significance in developing countries like India. Out-
patient attendance attributed to acute respiratory
infections is as high as 20-40 percent of all outpatients
and 12-35 percent of in-patients. The overall incidence
of acute respiratory infection in the under-fives may be
between 3-8 episodes/child/year. Of this majority are
upper respiratory tract infection (URTI).
Upper respiaratory tract infection (URTI) is a loose
term which includes, infection of nasal cavity, throat,
nasopharynx, ears and sinuses. URTIs are common
causes of morbidity in children.
ACUTE NASOPHARYNGITIS
Infection of nasopharynx is also called common cold. It
is probably the most common infection in children. In
young children 5 to 8 episodes of common cold may occur
in one year.
Etiology
Acute nasopharyngitis is caused by viruses. The common
viruses include rhinovirus, and corona viruses. The other
viruses include adenoviruses, influenza, parainfluenza
or respiratory syncytial viruses. These are spread by
droplet infection. Predisposing factors include chilling,
sudden exposure to cold air, and overcrowding. Rhinitis
could also be due to allergy.
Clinical Features
Clinical features of common cold are due to congestion,
swelling and increased secretion of nasopharyngeal
Diseases of Respiratory System 573
7. Sarnaik AP, Vernon DO, Mary Leih-Lai. Respiratory
emergencies in children. In: Vidyasagar O, Sarnaik AP (Eds):
Neonatal and Pediatric Intensive Care, Jaypee Brothers
Medical Publishers (P) Ltd, New Delhi, 1991;40-58.
8. Somu N, Devaki V, Thangavelu S. Dyspnea: In Somu N and
Subramanyam L (Eds): Essentials of Pediatric Pulmonology.
(2nd eds) M/s Siva and Co. Chennai 1996; 22-7.
SK Kabra
mucosa. Clinical manifestations are more distressing in
infants and young children. The common manifestation
include nasal discharge, initially watery than thick white
to yellowish, nasal block, cough and conjunctival
congestion. Nasal block causes difficulty in feeding,
irritability, excessive crying and breathing from mouth.
Occasionally may be complicated by secondary bacterial
sinusitis and otitis media. Otitis media should be
suspected in a child with no relief in crying, even after
treatment for nasal block. If a course of common cold is
prolonged beyond 7-10 days, then sinusitis should be
considered in a school going child.
Treatment
Acute nasopharyngitis is caused by virus and self-
limiting requires no specific treatment. For fever
paracetamol can be given 4 to 6 hourly. For nasal block
normal saline can be instilled in nostrils every 4 to 6
hourly and specially, before giving feeds. Child may be
given warm drinks with plenty of liquids. There is no
role of antibiotics, antihistaminics, local decongestive
drops or steroids. Home remedies for cough and cold
such as tulsi, ginger or honey may be beneficial in
common cold. However, mother should be told to bring
the child to hospital immediately, if there is rapid
respiration, lower chest indrawing or poor feeding.
ACUTE PHARYNGITIS
Acute pharyngitis includes infection of pharynx and
tonsils. This is also called acute tonsillopharyngitis. Most
of the times, it is associated with rhinitis, sinusitis and
occasionally laryngitis.
574 IAP Textbook of Pediatrics
Etiology
Commonly caused by viruses such as rhino, corona,
influenza, parainfluenza and adenoviruses. 10 to 20
percent of sore throats are caused by bacteria. The
important bacterial pathogen is Group A beta hemolytic
streptococcus.
Clinical Features
Children with acute pharyngitis may have fever, sore
throat, pain during deglutition, nasal discharge,
conjunctival congestion and discomfort in throat. There
may be enlargement of tonsils and palate, enlarged
tonsils are soreness in throat may cause blockade of
oropharynx, leading to poor intake by children and
occasionally, may present with drooling of saliva.
Cervical lymph nodes may be enlarged and tender.
Viral pharyngitis is self-limiting and recovers in 5 to
7 days. Pharyngitis caused by group A beta hemolytic
streptococcus, may lead to suppurative complication
such as retropharyngeal and peritonsillar abscess.
Presence of these complications may be indicated by
high-grade fever severe dysphagia and bulge in the
posterior wall of pharynx or around tonsils. The non-
suppurative complications due to streptococcal pharyn-
gitis include acute rheumatic fever and acute glomerulo-
nephritis. These complications can be prevented by
administration of antibiotics. It is very difficult to
differentiate viral from bacterial pharyngitis. Presence
of exudates on pharynx with enlarged tender cervical
nodes and absence of nasal discharge, suggests bacterial
pharyngitis and may be used to start antibiotics.
Diagnosis
Acute pharyngitis is a clinical diagnosis. At times, it is
very difficult to differentiate nasopharyngitis from
pharyngitis. Diagnosis of streptococcal pharyngitis can
be made with presence of exudates, enlarged tonsils and
absence of nasal discharge. The diagnosis can be
confirmed by throat swab culture. Now, a rapid
diagnostic test based on latex agglutination is also
available for diagnosis of streptococcal pharyngitis and
can be carried out in office practice.
Treatment
The major consideration in treatment of acute pharyngitis
is to prevent acute rheumatic fever. If a clinical diagnosis
of streptococcal pharyngitis is made, a throat swab
should be taken or rapid diagnostic test performed to
demonstrate streptococci and penicillin should be
administered.
Penicillin can be given orally or by intramuscular
route. The duration of oral penicillin is for 10-14 days. If
compliance is a problem, single injection of Benzathine
penicillin can be given. The other alternative antibiotics
are ampicillin, amoxicillin or oral cephalosporins. If an
individual is sensitive to penicillin, he or she may be
treated with erythromycin. The newer macrolide
antibiotics such as roxithromycin, clarithromycin and
azythromycin are alternative to erythromycin.
ACUTE SUPPURATIVE OTITIS MEDIA (ASOM)
Acute suppurative otitis media (ASOM) is a common
cause of morbidity in children. It is defined as inflam-
mation of mucoperiosteal lining of the middle ear. If the
duration of illness is more than 2 weeks, it is termed as
chronic suppurative otitis media. Children are more
prone for ASOM because, the eustachian tubes commu-
nicating throat with ears are straight and short. ASOM
may be one of the complications of other respiratory
infections.
Etiology
ASOM in children is commonly caused by Streptococcus
pneumoniae, Haemophilus influenzae, and Moraxella
catarrhails. Very rarely, it may be caused due to
Staphylococcus and gram-negative organisms. The later
is more common in immunocompromized hosts.
Clinical Features
ASOM presents with fever, ear pain, ear discharge and
restlessness. In young children, this is common cause of
excessive crying. Once the tympanic membrane perfo-
rates, the child may get relief in pain but could develop
pus discharge from ear. ASOM may cause infection of
mastoids in older children. The intracranial extension
may be in form of pyogenic brain abscess. Sometimes,
ASOM may cause lower motor neurone facial palsy.
Children may develop middle ear effusion even after
treatment with antibiotics, it is self limiting and resolve
in majority in 12 weeks time. If it persist, these children
should be sent to otolaryngologists for consideration of
grommet insertion. Chronic middle ear effusion may lead
to hearing impairment.

Diagnosis
In a setting of URTI if a child crying excessively, his ears
should be examined by otoscope. The eardrum may be
inflamed, and bulging with loss of normal anatomy with
fluid in middle ear. Otoscopic examination should be part
of routine examination in young children, presenting
with fever with localization.
Treatment
ASOM is a bacterial infection and should be treated with
antibiotics. The antibacterial useful in ASOM include
ampicillin, amoxicillin, oral cephalosporins or macro-
lides. Children below 2 years of age may be treated with
antibiotics from the time of diagnosis. However, in
children above 2 years of age with mild disease one can
wait for 2-3 days for improvement in clinical symptoms
without antibiotics. In severe disease as indicated by
presence of high fever (explosive onset, sever otalgia and
toxic appearance and high grade fever >102° F) and
children with mild disease in beginning but deterioration
in 48-72 hours one should consider starting antibiotics.
The antibiotic of choice is amoxycillin. The antibiotic is
continued for 10 days to prevent recurrence and develop-
ment of chronicity. If the child is not improving by 3-4
days, an alternative medicine should be started and the
child should be referred to an otolaryngologist.
Alternative medicines may be amoxycillin clavulinic acid
or cephalosporins. In severe cases injectable third
generation cephalosporin (Cefotaxime or ceftrioxone)
may be started.
For relief of pain, paracetamol or one of the
nonsteroidal anti-inflammatory, i.e. ibuprofen may be
given, round the clock. Occasionally, tympanocentesis
may be required to relieve pain. There is no role of local
antibiotic drugs in ASOM.
For treatment of chronic otitis media (COM), it is
recommended to keep the ears dry by cotton wick. One
course of oral antibiotics sometimes may be useful.
ACUTE SINUSITIS
In children, ethmoid and maxillary sinuses are present
in infancy. Sphenoid sinuses are well-developed by 3 to
5 years and frontal sinus develop between 6 and 11 years
of age. Infection of sinuses is common and associated
with nasopharyngitis and pharyngitis.
Etiology
Commonly, the viruses causing pharyngitis and naso-
pharyngitis, are responsible for sinusitis. Sometimes, they
Diseases of Respiratory System 575
may be invaded by bacterial pathogens. The common
bacterial pathogens include Streptococcus pneumoniae, H.
infuenzae and Moraxella catarrhalis. Gram-negative
bacteria and fungi may invade paranasal sinuses in
immunocompromised patients.
Clinical Features
Common presentation of sinusitis include non-resolving
rhinitis or common cold even after 7 days, thick purulent
nasal discharge, fever and tenderness over sinuses. In
young infants there may be swelling around eyes. There
may be headache-unilateral, bilateral, temporal or
occipital depending on sinus involvement.
Diagnosis
Usually prolonged course of nasopharyngitis in form of
persistence of fever and nasal discharge could be due to
sinusitis. If tenderness over sinuses can be demonstrated
or periorbital puffiness is present in young children, a
clinical diagnosis of sinusitis can be made. It can be
confirmed by demonstrating opacity or mucosal
thickening or fluid level in paranasal sinuses on X-ray
films. Other imaging such as CT or MRI scan of sinuses
may be done in immunocompromised host or compli-
cated cases.
Treatment
The clinical significance of sinusitis is due to bacterial
invasion. A course of amoxicillin, ampicillin or oral
cephalosporin should be given to the child. The suppor-
tive care includes normal saline in nostrils and paraceta-
mol for fever and pain relief. There is no role of routine
administration of antihistamines.
BIBLIOGRAPHY
1. Aroll B. Antibiotics for upper respiratory tract infections:
an overview of Cochrane reviews. Respir Med 2005;99:
255-61.
2. Casey JR, Pichichero ME. Meta-analysis of short course
antibiotic treatment for group a streptococcal tonsillo-
pharyngitis. Pediatr Infect Dis J 2005;24:909-17.
3. Kabra SK, Lodha R. Acute respiratory mortality. In Child
Survival and Development: Recommendations of
National Consultation Meeting on Child Survival and
Development 20-21 Nov 2004, Held at All India Institute
of Medical Sciences, New Delhi. Indian Academy of
Pediatrics 2004;19-29.
4. Mirza A, Wludyka P, Chiu TT, Rathore MH. Throat
culture is necessary after negative rapid antigen detection
tests. Clin Pediatr (Phila) 2007;46:241-6.
5. Simasek M, Blandino DA. Treatment of the common cold.
Am Fam Physician 2007;75:515-20.
576 IAP Textbook of Pediatrics
12.6 Infections of Larynx,
Trachea and Bronchi
Acute infections of larynx, trachea and bronchi are of great
importance in infants and small children. The airway
resistance is inversely proportional to the 4th power of
radius and hence any mucosal edema or inflammation of
the respiratory tract in children, especially involving the
small airways, leads to significant increase in the work of
breathing. These infections produce a dry, hacking cough,
hoarseness of voice and inspiratory stridor, giving them
the common name, ‘croup’. Stridor, produced by turbulent
airflow, is a harsh high-pitched respiratory sound, which
is usually inspiratory in nature but can be biphasic. There
are four clinically distinct syndromes which produce
common clinical features. These include laryngitis,
laryngotracheobronchitis (LTB), spasmodic croup and
acute epiglottitis.
Differential Diagnosis
Infections of the larynx, trachea and bronchi must be
differentiated from one another and from the following
diseases.
• Diphtheritic/ measles croup
• Foreign body aspiration
• Retropharyngeal or peritonsillar abscess
• Extrinsic airway compression or laryngeal web
• Intraluminal obstruction
• Laryngotracheomalacia
CROUP (LARYNGOTRACHEOBRONCHITIS)
Epidemiology
Children are affected between 3 months to 5 years of age
with a peak during second year of life. The incidence is
higher in males and can occur throughout the year with
peaks in winter and late fall. There may be an associated
family history.
Keya R Lahiri, Roshani N Taori
Etiology
Viral agents are more commonly implicated. The
parainfluenza virus type 1, 2 and 3 are the most common
etiologies. Other viruses associated with croup are
influenza A and B, adenovirus, respiratory syncytial
virus (RSV) and measles. Diphtheria and Mycoplasma
pneumoniae are the bacterias implicated in the etiology.
Clinical Features
For the initial 2-3 days, there may be signs of upper
respiratory tract infection characterized by rhinorrhea,
pharyngitis, mild cough, and low grade fever. The child
then develops the characteristic barking cough, hoarse-
ness and stridor. Symptoms are characteristically worse
at night and resolve completely within a week. They are
aggravated by crying and agitation and reduced in
upright position. On examination, there is a hoarse voice,
normal to moderately inflamed pharynx and variable
degree of respiratory distress. As it is a disease of upper
airways and the gas exchange in the alveoli is normal,
hypoxia is seen only when complete airway obstruction
is impending. X-ray of the neck soft tissues show typical
subglottic narrowing called as the steeple sign (Fig.
12.6.1). Croup is essentially a clinical diagnosis and
routine radiographs are not indicated. They should be
considered only after airway stabilization.
Complications
Occur in 15 percent of patients.
• Extension of the infectious process to other regions
of the respiratory tract, e.g. middle ear or pulmonary
parenchyma.
• Bacterial tracheitis (bacterial superinfection of viral
croup).

Figure 12.6.1: Steeple sign (white arrow)
Treatment
Laryngotracheobronchitis needs a supportive care
including intravenous fluids to maintain hydration and
oxygen inhalation to relieve hypoxia. The mainstay of
treatment is airway management. Options available are
cool, mist, nebulized epinephrine (racemic prepararion
preferable) or single dose dexamethasone 0.6 mg/kg/
dose. Inhalation of epinephrine may decrease the
symptoms of stridor and respiratory distress imme-
diately. A single dose of dexamethasone may decrease
the severity and duration of illness. A beneficial effect of
inhalation of budesonide has been shown in some
studies. However, it needs more research before it is
recommended for routine use. Antibiotics are usually not
indicated. Hospitalization is needed if there are any
danger signs like progressive stridor, severe stridor at
rest, respiratoy distress, hypoxia, apnea or altered
sensorium.
If the child with croup is comfortable and stridor is
audible only on stethoscope, the child may be managed
on ambulatory basis. If the stridor is audible without a
stethoscope, he should be kept in the hospital under
observation at least for a period of 24-48 hours.
ACUTE EPIGLOTTITIS
Epidemiology
The typical age group for acute epiglottitis is children
between 2-4 years of age. It is not very common in India.
Diseases of Respiratory System 577
Etiology
The etiology for acute epiglottitis is bacterial and is
mainly caused by Hemophilus influenzae. However, in
countries with high coverage of Hib vaccine, the
organisms are Streptococcus pyogenes, Pneumococcus and
Staphylococcus aureus.
Clinical Features
It is characterized by an acute potentially fulminating
course of high fever, sore throat, dyspnea, drooling of
saliva and rapidly progressing respiratory obstruction.
The degree of respiratory distress at presentation is
variable. Child looks toxic and may assume the tripod
position sitting upright and leaning forward with the
chin up and mouth open while bracing arms. Stridor is a
late finding and suggests a near complete airway
obstruction. It may be difficult to examine the epiglottis
in an irritable, hypoxic child and it should be done
carefully in an emergency room equipped with measures
for resuscitation. On direct larnygoscopy, the inflamed
epiglottis is large, swollen and cherry red. A lateral
X-ray film of the neck shows an enlarged epiglottis, also
known as “thumb sign”.
Complications
Include pneumonia, cervical lymphadenitis, otitis media
or rarely, meningitis or septic arthritis due to local and
systemic spread of infection.
Treatment
Acute epiglottitis is a medical emergency in children. On
suspicion of acute epiglottitis, the child should be
immediately admitted. Antibiotics recommended for use
include chloramphenicol or third generation cephalo-
sporins like ceftriaxone, cefotaxime administered by
intravenous/intramuscular route. Supportive care
including oxygen and hydration should be provided. The
patient may be nursed in the mother’s lap to decrease
the agitation and irritability. Avoid use of sedatives,
however, if unavoidable trichlorofos or chloral hydrate
may be used. Fever can be controlled with antipyretics.
Rifampicin prophylaxis for unimmunized siblings less
than 2 years should be considered.
ACUTE INFECTIOUS LARYNGITIS
It is most commonly caused by viruses, except diphtheria.
It is generally a mild illness, onset of which is charac-
578 IAP Textbook of Pediatrics
terized by upper respiratory tract infection consisting of
sore throat, cough and hoarseness. Respiratory distress
is unusual. Physical examination is usually unremark-
able. However, mild pharyngeal inflammation may be
evident. Treatment is symptomatic.
SPASMODIC CROUP
It is commonly seen in 1-3 years of age. The etiology of
spasmodic croup is controversial and both viral and
allergic mechanisms have been postulated. It occurs most
frequently in the evening or night-time, and maybe
preceded by mild to moderate coryza and hoarseness.
Patient is usually afebrile. The child awakens with
characteristic barking, metallic cough and respiratory
12.7 Pneumonia in Children
Pneumonia in children is a major cause of concern in the
developing countries, because one-third of hospital
outpatients comprise acute respiratory infections and
nearly 30 percent of them are being admitted to the
hospitals for pneumonia. Pneumonia is the leading cause
of death in under-five, in developing countries. In any
hospital about 90 percent of death in respiratory illnesses
are due to pneumonia and its complications. Most often,
the exact etiological diagnosis is difficult to establish.
Definition
Pneumonia: It is an inflammatory process, involving the
lung parenchyma.
Bronchopneumonia: It is primarily a spreading inflam-
mation of the terminal bronchioles and their related
alveoli.
Lobar pneumonia (consolidation): It is a pathological state
of the lung, where the alveolar air has been replaced by
cellular exudate and transudate.
Pneumonitis: It is a localized inflammation of the lung
parenchyma due to noninfectious causes.
Postmeasles bronchopneumonia: It is a mixed pneumonia
involving the alveoli, supportive tissue and bronchioles,
distress. Symptoms diminish within several hours and
such episodes often recur several times.
BIBLIOGRAPHY
1. Bjornson CL, Klassen TP, Williamson J, et al. A rando-
mized trial of a single dose of oral dexamethasone for
mild croup. N Engl J Med 2004;351:1306-13.
2. Knutson D, Aring A. Viral Croup. Am Fam Physician
2004; 69:535-40, 541-2.
3. Kristjansson S, Berg-Kelly K, Winso E. Inhalation of
racemic adrenaline in the treatment of mild and
moderately severe croup: clinical symptom score
and oxygen saturation measurements for evaluation
of treatment effects. Acta Paediatr 1994;88:1156.
4. Roni Grad: Acute infections producing upper airway
obstruction. In Kendig’s disorders of the respiratory tract
in children. WB Saunders Company, 1998.
A Balachandran, SO Shivbalan
usually manifest with or after the onset of measles.
Radiologically, it is seen as peribronchial thickening,
usually bilateral and often extensive.
Interstitial pneumonia: It is characterized pathologically
by massive proliferation and desquamation of alveolar
cells and thickening of alveolar walls. Chest skiagram
may reveal a diffuse, hazy, ground glass appearance,
usually at the lung bases, with poorly defined hilar
densities.
Persistent pneumonia: It is defined as persistence of
symptoms and roentgenographic abnormalities of more
than one month.
Recurrent pneumonia: It is defined as two episodes of
pneumonia in one year, or more than three episodes at
any time with radiographic clearance between two
episodes of illness.
Etiology
The cause of pneumonia depends on age, immune status,
presence of underlying chronic lung disease, exposure
history and the clinical setting. Certain infectious agents
are more common at a particular age. The causative
agents of pneumonia in children according to age are
given in Table 12.7.1.
 Diseases of Respiratory System 579

TABLE 12.7.1: Pneumonia—pathogens in various of the lungs. There will be gross alteration in the properties
age groups of the normal lung secretions. They also inhibit the
Age Bacteria Viruses Others
phagocytosis by the alveolar macrophages. The normal
bacterial flora in the respiratory tract is modified, which
Neonate Group B CMV, Herpes Chlamydia disrupts the normal epithelial layer of the respiratory tract.
streptococci,
E. coli, Klebsiella sp.
Thus, the bacteria and other organisms invade the
Listeria M, S. aureus respiratory tract and produce pneumonic process.
Microorganisms gain access to the lung by hematogenous
1–3 months S. pneumoniae, CMV, RSV, Chlamydia dissemination or local spread descending through the
S. aureus, Influenza, respiratory bronchial tree. Lobar pneumonia occurs when
H. influenzae Parainfluenza
there is a reduction in the defense mechanisms or due to
4 months– S. pneumoniae, RSV, Mycoplasma the pathogenicity of the microorganism like S. pneumoniae,
5 years S. aureus, Adenovirus, Klebsiella and Staphylococcus.
H. influenzae, Influenza
Group A Clinical Features
Streptococcus, Presence of rapid respiration has acceptable sensitivity
Klebsiella,
for clinical diagnosis of pneumonia. The rapid respira-
Pseudomonas sp/
M. tuberculosis tion for diagnosis of pneumonia is defined as respiratory
rate of more than 60 breaths/minute in children below
Over 5 years S. pneumoniae, Influenza, Mycoplasma, 2 months of age, more than 50 breaths/minute in children
S. aureus, Varicella Legionella sp. between 2 months and 12 months of age, and more than
H. influenzae, M. catarrhalis 40 breaths/minute in children between 1 to 5 years of
M. tuberculosis
age. For diagnosis of pneumonia in the community,
presence of rapid respiration is sufficient. Radiograph
S. pneumoniae, H. influenzae and Staphylococcus are the of chest is not required, unless specifically indicated, such
pyogenic bacteria that most commonly cause pneumonia as sick child rapid deterioration, poor response to initial
in children. Mycoplasma pneumoniae and Chlamydia therapy, suspicion of effusion or pneumothorax or
pneumoniae are the most common causes of “atypical” presence of high-risk factors for pneumonia (Table
pneumonia in children. Atypical pneumonia is also called 12.7.3). Chest indrawing, cyanosis, difficulty in feeding,
as walking pneumonia. In contrast to children with indicates the increasing severity of pneumonia.
pyogenic bacterial pneumonia, children with pneumonia
caused by these organisms are often older than 5 years TABLE 12.7.3: High-risk factors for pneumonia
of age and the disease onset is gradual. The salient • Congenital anatomical defects:
differentiating features between typical and atypical – Airway—cleft palate, tracheoesophageal fistula,
pneumonia are depicted in Table 12.7.2. bronchial stenosis.
– Upper Gl tract—Cricopharyngeal incoordination,
Pathogenesis gastroesophageal reflux.
• Newborn, preterm and small-for-date babies and infants
In children, the pneumonia is invariably preceded by viral
< 2 months.
infection. Viral infections disturb the defense mechanism
• Children with immunodeficiency
• Cystic fibrosis
TABLE 12.7.2: Differentiating features of typical and
atypical pneumonia • Congenital bronchiectasis/ciliary dyskinesia
• Iatrogenic factors
Features Typical Atypical
– Trauma, anesthesia and aspiration
Onset Sudden Gradual • Gross nutritional disorders, e.g. Grade III and IV undernutrition
Fever +++ +/– • Congestive cardiac failure and nephrosis
Cough Productive Dry • Poor muscle tone—e.g. poliomyelitis
Symptoms Pulmonary Systemic • Chronically ill children in prolonged bed-ridden state,
Chest X-ray Localized Diffuse nosocomial infections.
580 IAP Textbook of Pediatrics

Neonatal pneumonia is often difficult to diagnose, TABLE 12.7.6: A guide to radiological

since there are some peculiarities which are highlighted
in Table 12.7.4.
Bacterial and viral pneumonia cannot be differen-
tiated without microbiological study. The typical clini-
cal patterns of viral and bacterial pneumonias usually
differ, although the distinction is not always clear for a
given patient. Table 12.7.5 is helpful to identify bacterial
and viral pneumonia.
Diagnosis
In a previously normal child, presence of cough with
rapid respiration is sufficient to make diagnosis of
pneumonia. The following investigations if available,
may provide more information or clue towards to the
severity of illness.
• CBC (complete blood count) to look for evidence of
sepsis.
diagnosis of pneumonia*
• Acute lobar pneumonia—consider pneumococcal pneumonia
(Fig. 12.7.1)
• Right upper lobe pneumonia—suspect aspiration, especially
in neonates and infants
• Upper lobe pneumonia with cavitation—tuberculosis
(Fig. 12.7.2)
• Recurrent right middle lobe pneumonitis—consider partial
bronchial obstruction due to glands and others
• Lower lobe pneumonitis—chemical pneumonitis
• Multiple small abscesses—staphylococcal/Klebsiella pneu-
moniae (Fig. 12.7.3)
• Severe bilateral interstitial pneumonia—virus (Fig. 12.7.4)
• Bilateral interstitial pneumonia with malignancy—Pneumocystis
carinii
*The X-ray changes often lag behind clinical findings, both at the
onset of pneumonia and at the time of resolution

TABLE 12.7.4: Peculiarities of pneumonia in newborn

• WBC count of more than 15,000 cells/mm3 with
• Absence of cough or fever
polymorpholeukocytosis or count less than 5000/
• Apneic spells and increased incidence of periodic breathing
• Grunting is a common feature in neonates mm3 or febrile neutopenia (absolute neutrophil count
• Rapid clinical deterioration, often galloping in nature < 500/mm3) are bad prognostic indicators.
• Cyanosis • Nasopharyngeal aspirate for viral antigen—e.g. CMV,
• •
Progressive air hunger Adenovirus, etc.
• Associated septicemia with progressive abdominal distention,
• M. pneumoniae may be suspected if cold agglutinins
altered sensorium, and bleeding tendency
• Bronchopneumonia is more common than lobar pneumonia
are present in peripheral blood and confirmed by
• High mortality rate in spite of therapy detecting presence of Mycoplasma—specific IgG or
IgM in serum.
• The diagnosis of M. tuberculosis may be considered
TABLE 12.7.5: Clinical differentiation of pneumonia with tuberculin skin test, smear and culture of sputum
Feature Bacterial Viral or gastric juice for tuberculosis.
• Roentgenographic picture (Table 12.7.6).
Onset Abrupt Gradual
Invasive procedures, such as bronchoscopy and
Epidemic pattern – +
Course Progressive Self-limiting bronchoalveolar lavage, lung aspiration, or lung biopsy,
Temperature +++ + /- may be necessary to obtain culture specimens. These
Toxemia +++ – invasive procedures are not used in typical pneumonias,
Respiratory distress ++ + (Infants) but they may be employed in special instances, such as
Associated URTI – + pneumonia in the immunocompromised host or when
Auscultation
Crackles ++ +/–
the clinical picture is unusual.
Wheeze +/– ++
Radiological Confluent infiltrates Diffuse infil- Differential Diagnosis
(Consolidation) trates in
perihilar areas
Infants
Hyperinflation +/– + (RSV • Bronchiolitis
Infection) • Wheeze associated lower respiratory tract infection
Pleural involvement + – (WALRTI)
Pneumatocele + – • Congestive heart failure
 Diseases of Respiratory System 581

Figure 12.7.1: Lobar consolidation right upper lobe

Figure 12.7.4: Interstitial pneumonia

In older children
• Acute exacerbation of bronchiectasis
• Endobronchial TB and secondary bacterial pneumo-
nia
• Lower lobe pneumonia may present as acute
abdomen
• Accompanying ileus with absent bowel sounds, may
mimic acute appendicitis
• Upper lobe pneumonia can present as meningismus
(can be differentiated from meningitis by lumbar
puncture).
Figure 12.7.2: Cavitatory tuberculosis
Treatment of Pneumonia
It is important to decide if the child can be managed as
outpatient or to be hospitalized. Indication for hospitali-
zation are listed in Table 12.7.7.

Antimicrobials in Pneumonia
Choice of antimicrobials depends on causative organi-
sms. In clinical practice often causative organisms are
presumed based on the following:
i. Age of the child and epidemiology
ii. Clinical and radiological features
iii. Extrapulmonary manifestations
iv. Prevailing drug sensitivity pattern in the com-
Figure 12.7.3: Multiple lung cysts munity/hospital.

Outpatient Management
• Aspiration of foreign body
• Sequestered lobe If the child is not sick and is suggestive of viral etiology
• Atelectasis withhold antibiotics, give only supportive care and
• Pulmonary abscess follow-up the child. If clinical features are suggestive of
582 IAP Textbook of Pediatrics
TABLE 12.7.7: Indication for hospitalization
• Features of Hypoxia (Restlessness, anxiety, cyanosis,
Inability to sleep, talk, walk, unconsciousness, seizures)
Reduced urine output/dehydrated
Vomiting/poor intake
• No improvement/Progressive deterioration when on
treatment as outpatient
• Presence of high-risk factors
atypical pneumonia start the child on macrolides. In
other children with suspected pneumonia they can be
either started with oral cotrimoxazole or amoxycillin or
cephalexin. Normal oral diet is to be advised.
Warning signs need to be explained to the parents.
The child should be reassessed after 48 hours or any time
in between if there is deterioration in the condition of
the child.
On follow-up after 48 hours, if there is sense of well-
being and improvement in clinical status of the child
continue with the same management. If the condition
remains same or had deteriorated, reassess the child,
revise your diagnosis and look for associated compli-
cations. Then consider introducing/changing antibiotics,
if need be, hospitalize the child for further management.
Inpatient Management
Consists of specific and supportive care (Table 12.7.8).
In infants below 2 months of age consider and treat
them as sepsis. The antibiotics of choice would be
ampicillin or 3rd generation cephalosporins with
aminoglycoside. If there is a suspicion of meningitis start
on meningitic dose of antibiotics.
In children more than 2 months of age treat with
parental amoxicillin/cefuroxime/third generation ceph-
alosporins with or without aminoglycoside. These
children should be assessed at least twice a day and if
there is rapid deterioration a chest X-ray should be done
TABLE 12.7.8: Inpatient management pneumonia
Specific Supportive
Antimicrobial therapy Hydration
Nutrition
Oxygen
Antipyretics
Physiotherapy
Adjuvants
to look for evidence of staphylococcal infection
(pneumatoceles), if present, the antibiotics should be
changed to cloxacillin.
If there are indication of specific etiological agents
like chlamydia or mycoplasma infection, then macrolides
such as erythromycin or clarithromycin may be given.
Supportive care include treatment of fever with
paracetamol (10–15 mg/kg/dose) every 4 to 6 hourly.
In presence of tachypnea, cyanosis or chest
indrawing, oxygen should be administered by nasal
catheter, nasopharyngeal catheter, oxygen hood or
oxygen mask.
Intravenous fluids should be administered if child is
not drinking milk/water or is dehydrated. Oral feeds
should be started as soon as tachypnea and chest
retractions are under control. Duration of antibiotic
therapy depends on the causative organism and clinical
condition of the patient as depicted in Table 12.7.9.
TABLE 12.7.9: Duration of treatment
Pneumonia (OP) — 5–7 days
Pneumonia (IP) — 10–14 days
Atypical organisms — 10 days
Staphalococcal pneumonia — 3–4 weeks
Complications of pneumonia are empyema, lung
abscess, pyopneumothorax, osteomyelitis, pericardial
effusion, and sepsis. Early recognition, prompt therapy
and a good follow-up would decrease the incidence of
complications.
The prognosis of pneumonia in children is based on
the following factors. Younger the age higher the
mortality. Poor nutritional status like—PEM Grade III
and IV, extensive bilateral bronchopneumonia, asso-
ciated diseases and conditions like cystic fibrosis and
immunodeficiency state, malignancy and associated
complications such as respiratory failure and congestive
cardiac failure act as poor prognostic factor.
BIBLIOGRAPHY
1. Charles G Prober. Pneumonia. In Richard EB, Cictor
(Eds): Nelson Textbook of Pediatrics (15th edn). WB
Saunders Co., 1996.
2. Edwin LK , Chernick V. Disorders of the respiratory tract
in children (5th edn). WB Saunder Co., 1994.
3. Ellen R Wald. Recurrent and nonresolving pneumonia
in children. Seminars in Respiratory infections 1993;8:46–
58.
4. Govan A, Macfarlane PS, Callander R (Eds): Pathology
Illustrated (2nd edn) Churchill Livingstone, 1986.

5. Howard E, James JL, Homrighausen J. Recurrent
pneumonias in children and its relationship to bronchial
hyperreactivity. Pediatrics 1982;70:698–707.
6. Hugh L Moffet. Pneumonia syndromes: Pediatr infec dis
102 JB Lippincott Co, 1975.
7. Kercsmar CM. The respiratory system. In Richard EB,
Kliegman RM (Eds): Nelson Essentials of Pediatrics (3rd
edn). WB Saunders Co., 1998.
12.8 Acute Bronchiolitis
INTRODUCTION
Bronchiolitis is an acute infection of small airways.
Although many pathogens can cause bronchiolitis, more
than 50 percent cases are due to respiratory syncytial
virus (RSV). Two subtypes ( A and B) of this virus exist
subtype A is the more common cause of bronchiolitis
and is associated with more severe disease. It has been
estimated that about 600000 infants and young children
die from RSV annually, and if bacterial coinfections are
included this number may approach 1,000,000 deaths
annually. Thus in developing countries where RSV is the
main cause of lower respiratory tract infections in the
community, its prevention may result in significant
reductions in RSV related morbidity and mortality.
Definition
Bronchiolitis can be defined as first episode of expiratory
wheeze of acute onset in a child less than 2 years of age
who has signs of viral respiratory illness like coryza, otitis
media or fever with or without indications of respiratory
distresses, pneumonia and atopy. It occurs in both
epidemic as well as sporadic forms.
Factors that increase the visit of severe or fatal RSV
infection are:
1. Complicated congenital heart disease (including
pulmonary hypertension)
2. Age < 6 weeks
3. Concomitant pulmonary disease (e.g. BPD)
4. Prematurity
5. Immunodeficiency states.
Diseases of Respiratory System 583
8. Ralph JW, Starkey DD, George C Ray, Cincent CK,
Vincent CK. Infection in Children, Harper and Row
Publishers, 1982.
9. Robbin SL, Cotran RS, Kumar V. Pathologic Basis of
Disease (3rd edn). WB Saunders, 1983;706-8.
10. Schreiner A, SoI’Verg C. Lower Respiratory Infections.
Schering Corporation USA, 1982.
11. Shohet FL, Lieberman JM. Bacterial pneumonia in child-
ren, Seminars in Ped. Infectious diseases 1998;9:191-8.
Uday B Nadkarni
Epidemiology
In our country, epidemics occur in winter and monsoon
and may last for 1 to 5 months. They have also been
reported in newborn nurseries. Parental smoking
increases the risk of bronchiolitis. Peak incidence of the
disease occurs before 6 months of age in 70 to 80 percent
of the cases, peaking between 3 to 4 months. Both sexes
are equally affected and severe cases may require
hospitalization.
Etiology
Respiratory syncytial virus (RSV) is the causative agent
in 50 to 60 percent of the cases, other viruses responsible
are Parainfluenza I, II and III, Adenoviruses, Influenza
virus and Rhinovirus. At times, Mycoplasma and
Chlamydia have also been implicated.
Pathology
Acute bronchiolitis is characterized by bronchiolar
obstruction due to edema and accumulation of mucus
and cellular debris and by invasion of the smaller
bronchiolar radicles by virus. There is necrosis of the
respiratory epithelium in the bronchioles and is
associated with peribronchiolar lymphocytic infiltrations.
Submucosa may be edematous but collagen and elastic
tissues in bronchioles are usually preserved. In most of
the cases, the alveoli escape damage however, occa-
sionally, an increased cellularity of subepithelial tissues
of the bronchus extend to the alveoli also.
Resistance in the small air passages is increased
during the inspiratory and expiratory phases. However,
584 IAP Textbook of Pediatrics
Figure 12.8.1: Pathophysiology
since the radius of an airway is smaller during expiration,
the resultant ball valve respiratory obstruction leads to
air trapping and over inflation. Atelectasis may occur if
obstruction becomes complete and trapped air is
absorbed. Impaired ventilation/perfusion leads to
hypoxia (Fig. 12.8.1).
Clinical Features
Most affected infants present with a history of exposure
to older children or adults with minor respiratory
diseases within a week, preceding the onset of illness. It
starts with mild upper respiratory tract infection with
serous nasal discharge, cough and sneezing, accom-
panied by diminished feeding and fever of 38.5 to 39°C.
There is a gradual increase in respiratory distress,
accompanied by paroxysmal wheezy cough, dyspnea
and irritability. Feeding is also affected due to rapid
respiratory rate. Apnea early in illness with cyanosis is
seen in 10 to 20 percent of cases.
Examination reveals a tachypneic infant often in
extreme distress. Respiratory rate ranges between 60 to
80 per minute, severe air hunger and cyanosis may occur.
The alae nasi flare and use of accessory muscles of
respiration result in intercostals and subcostal retractions,
which are shallow because of persistent distention of the
lungs by the trapped air. Liver and spleen, are palpable
below the costal margin due to overinflated lungs. Fine
crackles may be heard in early expiration. Wheezes are
usually audible in most severe cases, and breath sounds
are barely audible when bronchiolar obstruction is almost
complete.
Investigations
WBC count is usually normal. Neutrophilic leukocytosis
may indicate secondary bacterial invasion. Blood gases
reveal hypoxia and hypercarbia. Serum electrolyte
estimation may show hyponatremia. X-ray of the chest,
AP and lateral view may show marked generalized
emphysema, patchy consolidation, atelectasis and
abnormal linear shadows, due to thickening of the
bronchioles. Virus may be demonstrated in nasopharyn-
geal secretions by antigen detection (by ELISA or PCR)
or by culture.
Differential Diagnosis
Asthma: This condition presents with repeated episodes
of sudden onset wheezing with or without preceding
infection and family history of atopy or asthma.
Postbronchodilator reversibility of an attack confirms the
diagnosis.
Other entities are foreign body, congestive cardiac failure,
pertussis, cystic fibrosis and bacterial pneumonias.
Management
An initial assessment of the disease severity is critical.
Hospitalize babies with moderate to severe bronchiolitis
having retractions, apnea, poor feeding, cyanosis, toxic
appearance, SaO2 < 91 percent and PR > 70/minute.
Monitoring of pulse oximetry is the best predictor of
severity.
General Measures
Treatment of bronchiolitis is mainly supportive with
close observation and minimal handling. Infants with
bronchiolitis are mildly dehydrated due to decreased
fluid intake and increased losses because of fever and
tachypnea. Intravenous fluids are given as two-thirds of
maintenance requirement.
Oxygen
It should be warm and humidified having concentration
of 30 to 40 percent. It is delivered by head box, tent, nasal
prongs, nasopharyngeal catheter or facemask taking care
that SaO2 is maintained at 95 percent. As RSV is shed in
respiratory secretions and cross-infection occurs in 15 to
30 percent cases, cohorting and handwashing by health
professionals and parents is of paramount importance.

Bronchodilators
Wheezing and rhonchi are usually present and it is
difficult to differentiate first episode of asthma from
bronchiolitis. Hence, a trial of bronchodilator salbuta-
mol with or without ipratropium should be given. If there
is improvement, bronchodilators may be continued
round the clock, otherwise they should be stopped. Some
studies have shown modest clinical improvement as an
improvement in pulmonary function with beta agonist
therapy especially with high dose salbutamol 0.5 mg/
kg. Some researchers evaluated efficacy of nebulised
epinephrine versus salbutamol. They found that
nebulised epinephrine superior to salbutamol as regards
improvement in clinical symptoms and length of hospital
stay. Possible explanation is mucosal edema in bronchio-
litis may be diminished by alpha-receptor stimulation
causing construction of precapillary arterioles reducing
microvascular leakage.
Steroids
Use of steroids is not beneficial. In critically ill, hypoxic
and apneic babies, role of steroids is controversial and
should not be used. Even combination therapy of
salbutamol and systemic steroids did not show signi-
ficant improvement in clinical course.
Antibiotics
Though acute bronchiolitis is viral in origin, dual
infections can coexist. In the presence of fever, clinical
deterioration, high WBC count, raised CRP and
infiltrations on chest X-ray, antibiotics are indicated.
Ribavirin
Studies have shown effective in reducing severity of the
disease and shortening the hospital stay, provided they
are given early in the course of the disease. It should be
given to patients with assisted ventilation. It is very useful
in infants < 2 months and babies with congenital heart
disease, pulmonary hypertension, hyaline membrane
disease and bronchopulmonary dysplasia. It is adminis-
tered as a mist for 12 to 20 hours for 3 to 5 days with a
small particle aerosol generator (SPAG).
The American Academy of Pediatrics (AAP) recom-
mends the use of Ribavirin suggesting that it will be
reserved for:
a. Infants at high-risk for severe or complicated RSV
infection.
Diseases of Respiratory System 585
b. Infants hospitalized with RSV and lower respiratory
tract disease who are severely ill.
c. Infants hospitalized with lower respiratory tract
disease that is not initially severe but may be at
increased risk of progressing to complicated course.
d. Mechanically ventilated infants may be benefited.
Palivizumab
A humanized anti-RSV monoclonal antibody (palivi-
zumab) has been developed, which is 95 percent human
and 5 percent mouse in composition. It is directed at an
epitope on the F protein, which is expressed on the
surface of the virus envelope. This monoclonal antibody
is estimated to be 50 to 100 times more potent against
RSV than the polyclonal RSV-IGIV allowing the dose to
be reduced 50-fold.
A large multi-center trial was conducted in 139
centers in North America and UK to test the efficacy of
palivizumab when 15 mg/kg dose was administered IM
monthly for 5 months. There was 55 percent reduction
in hospitalization rate for RSV-related illness. The
decrease was most pronounced in infants with a history
of prematurity without CLD. There was also a substantial
decrease in number of hospital days, the number of days
that supplemental oxygen was required and in the
number of admissions to the intensive care unit.
Follow-up
It is essential to follow-up patients of bronchiolitis for
hyper-reactive airway disease/asthma. Approximately,
33 to 50 percent of all patients with bronchiolitis, develop
bronchial asthma and the incidence is higher, if there is
family history of asthma or other atopic disorders. The
common disease of infancy still merits our close attention
and prompt treatment, as this would go a long way in
preventing hyper-reactive airway disease in later life.
BIBLIOGRAPHY
1. Behram RE, Kliegman RM, Arvin AM, Orenstein DM.
Acute bronchiolitis. In: Nelson’s Textbook of Pediatrics
(15th edn). WB Saunders:Philadelphia 1996;1211–3.
2. Bertrand P, Arinabar et al. Efficacy of nebulized
epinephrine versus salbutamol in hospitalized infants
with bronchiolitis. Pediatr Pulmonol 2001;31(4):284–8.
3. Canny GJ. Acute Bronchiolitis: Recent advances in
treatment. Indian J Pediatr 1996;6345–51.
4. First Annula Saul Krugman symposium on pediatric viral
infection: Viral respiratory diseases in children.
Hemming V (Ed). J Pediatr 1994;124:29–34.
586 IAP Textbook of Pediatrics
5. Groothius JR, Simoes EAF et al. Prophylactic adminis-
tration of respiratory syncytial virus immune globulin
to high-risk infants and younger children. N Engl J Med
1993;329:1524–30.
6. Impact-RSV study group. Palivizumab, a humanized
respiratory syncytial virus monoclonal antibody, reduces
hospitalization from respiratory syncytial virus infection
in high-risk infants. Pediatrics 1998;102:531–7.
7. Johnson S, Oliver C et al. Development of a humanized
monoclonal antibody (MEDI-493) with potent in vitro and
in vivo activity against respiratory syncytial virus. J Infect
Dis 1997;176:1215–24.
12.9 Empyema
A Balachandran, Swati Y Bhave, S Thangavelu
Empyema is the serious complication of bacterial
pneumonia commonly observed in infancy and preschool
age group. Empyema is the term used for the collection of
purulent fluid in the pleural cavity. This has to be
differentiated from hydrothorax, which is a non-
inflammatory fluid collection occurring in conditions such
as nephrotic syndrome and other hypoalbuminemic states.
Tuberculous pleural effusion is the other condition which
needs differentiation, but generally in a preschool child
with fever and respiratory distress pleural fluid indicates
empyema unless proved otherwise.
Etiology
Empyema is a complication of pnemonia caused by
staphylococci and less commonly with pneumococci and
H. influenzae. Empyema secondary to trauma or
mediastinitis is very rare.
Pathology
There are three stages in the evolution of empyema. In
the exudative stage, fluid with relatively low cell amount
and viscosity collects in the pleural space. This fluid is
simple parapneumonic effusion and has a normal pH
and glucose. In the fibrinopurulent stage, neutrophils and
fibrin accumulates, effusion becomes purulent and
viscous, pleural fluid pH and glucose falls and LDH rises.
The term empyema is used at this stage. During the
organizing stage fibroblast activity on both pleural
surfaces produces thickened pleura.
Clinical Features
Clinical diagnosis of empyema is entertained in any child
who presents with high grade fever, tachypnea and
severe respiratory distress. On examination child will
8. Kending EL, Chernick V, Wohl ME. Acute bronchiolitis:
In Disorders of Respiratory Tract in Children, (5th edn).
WB Saunders: Philadelphia 1990;360–70.
9. La via WV, Marks M, Stutman H. Respiratory Syncytial
Virus Puzzle: Clinical features, Pathophysiology,
Treatment and Prevention. J Pediatr 1992;121:503–10.
10. MsConnochie KM: Bronchiolitis—What is the name. Am
J Dis Child 1983;137:11–3.
11. Wang EEL, Milner R, Allen V. Treatment of Mild Bron-
chiolitis: Afactorial randomized trial. Arch Dis Child
1992;67:289-93.
have toxemia, grunting, reduced respiratory movements
with stony dullness and absence of breath sounds on one
side of chest. Urgent chest radiograph will confirm the
diagnosis.
Stages of Empyema Thoracis: Exudative phase, i.e. stage of
parapneumonic effusion is usually present for 1 to 3 days,
followed by fibrinopurulent phase, i.e. stage of empyema
thoracis, which may last for 4 to 14 days. The organizing
phase may occur beyond 14 days, which is commonly
termed as “trapped lung”, a complication of empyema
thoracis.
Investigations
Uniformly dense opacity with obliteration of costo-
pherenic angle on one side of chest is the usual radio-
logical sign (Fig. 12.9.1). Mediastinal shift may or may
not be present. Some times pneumatocele may be present.
Often pneumothorax may be associated and the density
will be an intermediate one between air and fluid. In
pneumonia varying degrees of density with ill-defined
borders are seen with preservation of costophrenic
angles. Radiology cannot differentiate the nature of fluid
and hence needle aspiration is mandatory to ascertain
the nature of fluid. Needle thoracentesis done at the level
of seventh intercostal space in the midaxillary line.
Aspiration of pus confirms the diagnosis of empyema,
which necessitates intercostal tube drainage. In case of
tubeculous effusion needle aspiration of fluid as much
as possible is enough. Sometimes macroscopic appear-
ance does not contribute to probable diagnosis where
other laboratory tests to analyse the pleural fluid will be
useful (Table 12.9.1). Gram staining and AFB staining
are simple and useful bedside investigations to prove
the etiology and to decide about the choice of antibiotics.
 Diseases of Respiratory System 587

is a common complication observed during treatment.

If the pus is not drained immediately, it may cause
adhesion to form a thick envelope restricting lung
expansion.

Figure 12.9.1: Empyema right lung—large collection of pleural
fluid on the right hemithorax with shift of mediastinum towards
left
Blood counts and cultures of blood and pleural fluid are
very useful.
Complications
Empyema may be associated with other septic compli-
cations such as septicemia, meningitis or osteomyelitis.
Untreated empyema may dissect through chest wall
resulting in empyema necessitans. Bronchopleural fistula
Treatment
1. Empyema is a medical emergency. Initial treatment
includes oxygen, IV fluid and antipyretics.
2. Intercostal tube drainage (closed tube throw) should
be done as soon as the child is hospitalized without
any undue delay, as this is the single most important
step that will bring relief. Tube with largest possible
size should be used and connected to under water
seal drainage.
3. Choice of antibiotics is based on suspected micro-
organisms. If staphylococcal infection is suspected,
Cloxacillin, Vancomycin are effective drugs. Pneumo-
coccal infection responds well to penicillin or
ceftriaxone and H. influenzae responds to cefuroxime,
ceftriaxone or cefotaxime. When organism is not
identifiable Ampicillin with Cloxacillin or Cloxacillin
with third generation cephalosporin is the right
combination. When anaerobic organisms are sus-
pected metronidazole should be added. Systemic
antibiotic therapy is required for at least two to three
weeks.

TABLE 12.9.1: Pleural fluid analysis

Test Transudate Exudate Exudate

(Hydrothorax) (TB effusion) (Empyema)
Physical appearance Clear Straw colored Turbicf yellow
Microscopy No cells Lymphocytes Pus cells
Pleural F Protein < 3 gm/dl > 3 gm/dl > 3 gm/dl
Pleural F Protein/Serum Protein < 0.5 > 0.5 > 0.5
Pleural FLDH/Serum LDH < 0.6 > 0.6 > 0.6
Pleural F pH > 7.2 < 7.3 < 7.2
Pleural F Glucose > 40 mg/dl < 40 mg/dl < 40 mg/dl
Pleural F-Pleural Fluid

TABLE 12.9.2: Modified light classification

Class I Parapneumonic Effusion
a. CXR—Lateral decubitus view < 10 mm fluid Antibiotics only
b. CXR—Lateral decubitus view > 10 mm fluid
pH > 7.2, glucose > 40, Gram stain-negative Antibiotics + Thoracentesis
pH < 7.2, glucose < 40, Gram stain-positive Antibiotics + Tube thoracostomy
Class II Empyema (frank pus) Antibiotics
a. ± Loculation + Tube thoracostomy
b. Multiple Loculation/Pleural peel + Thrombolytics (intrapleural) or
Debridement (VATS) or decortication
588 IAP Textbook of Pediatrics
4. Nutrition and physiotherapy are useful adjuncts.
Surgical management (decortications) is needed
when fibrinous envelope restricts expansion of
lung.
5. Video assisted thoracoscpic (VATS) adhesiolysis and
pleural debridement is nowadays recommended for
12.10 Bronchiectasis
A Balachandran, Swati Y Bhave, NC Gowrishankar
Bronchiectasis is the third common chronic respiratory
disease next only to asthma and tuberculosis. It is an
important cause for chronic cough in children, but often
present with complications such as pneumonia. It is a
disease characterized by permanent dilation of the
bronchi caused by previous illness with accumulation of
exudative material resulting in chronic cough with foul
smelling sputum production.
Etiology
Causes of bronchiectasis are traditionally classified as
congenital or acquired. More often it is due to wide range
of acquired condition causing obstruction, infection or
both.
Despite multiple causes bacterial and viral pneumonia
are the common causes. Other causes are preventable
infections like measles, pertussis, undetected or untreated
foreign body aspiration, chronic atelectasis due to various
causes, aspirative pathology such as gastroesophageal
reflux and immunodeficiency syndromes including HIV
infection. Due to various reasons, sinusitis is a common
association. Though cystic fibrosis is the leading cause of
bronchiectasis in the west, it is not that common in our
country.
Congenital causes are rare, which includes Kartage-
ner’s syndrome (triad of bronchiectasis, sinusitis and situs
inversus) and William Campbell syndrome (absence of
bronchial cartilage and ring).
Pathology
Except in cystic fibrosis, bronchiectasis due to other causes
generally follows segmental distribution, commonly
involved segments in the order of frequency are left lower
lobe segment, right middle lobe and lingular segment of
the left upper lobe. Right lower lobe is commonly
involved in foreign body aspiration.
empyema that does not resolve with closed tube
thoracostomy.
6. Modified light classification is a method by which
various stages of empyema are identified. This will help
to make appropriate therapeutic choices such as needle
thoracentesis or tube thoracostomy (Table 12.9.2).
Morphologically two types are described, cylindrical
and secular. It is labeled as cylindrical when dilatation is
reversible.
Clinical Features
Common presentation is chronic cough is with large
quantity of foul smelling sputum production more in the
morning hours. Recurrent pneumonia, hemoptysis,
wheezing episodes, clubbing and failure to thrive are
other features. Systemic examination may show coarse
crepitations over the affected areas. When sputum is
collected in a conical flask it forms three layer: thin and
frothy syperficial layer, thick and mucopurulent inter-
mediate layer, opaque and purulent layer with Dietrich’s
plugs at the bottom. Presence of foul smelling sputum,
hallitosis, clubbing and failure to thrive differentiate this
from asthma. However, this diagnosis must be confirmed
through imaging studies. X-ray chest, high resolution CT
scan and bronchography are more useful. Fiberoptic
bronchoscopy is also useful for visualizing the airway
directly and to collect the secretions from individual lobes.
Investigations
X-ray chest: It is not diagnostic, but following features are
suggestive.
1. Increased bronchovascular markings
2. Loss of lung volume indicated by crowding of vascular
marking (Fig. 12.10.1)
3. Honeycomb pattern
4. Linear streaks (rail road tracks)
5. Cystic lesions with air fluid level.
CT scan: High resolution CT scan has almost replaced
bronchography. Following are the findings diagnostic of
bronchiectasis
1. Air fluid level in the distorted bronchi

Figure 12.10.1: X-ray chest showing bilateral bronchiectasis
2. Linear airway or cluster of cysts
3. Distended bronchi in the periphery of lung
4. Bronchial wall thickening due to peribronchial
fibrosis.
Bronchography: Though a gold standard test, it is less often
performed now because of the risk involved. But it is still
used in selected patients where surgical option is
contemplated and there is a plan to spare few segments
inside an affected lobe. To identify the underlying cause,
other investigations such as mantoux test, sweat chloride
estimation, immunoglobulin assay, screening for HIV and
skin test for aspergillosis are useful.
Management
Following are the aims of management:
1. To provide the patient symptom-free days and good
quality of life. Chronic cough, foul smelling sputum
and hallitosis adversely affect the social life.
2. To reduce further damage to lung and to prevent
complications.
3. To identify whether surgical option will be useful.
12.11 Lung Abscess
A Balachandran, Swati Y Bhave, S Thangavelu
Lung abscess is a subacute suppurative disease of lung
resulting in the formation of cavity containing purulent
material.
Diseases of Respiratory System 589
Primary treatment of bronchiectasis is medical.
Removal of excessive secretions by chest physiotherapy,
treatment of intercurrent infection and good nutrition are
important components of medical management.
Antibiotic therapy is definitely indicated only for acute
infection which is evident by worsening of cough, yellow
sputum production, fever and malaise. Antibiotics should
be directed against organisms such as H. influenzae, S.
pneumoniae, S. aureus, Pseudomonas aeruginosa and Proteus
vulgaris.
Chest percussions and postural drainage are effective
in facilitating clearance of secretions. Postural drainage is
a method by which the mucociliary escalator is enhanced
by gravity, by placing the patient in various positions
where the diseased segment is kept in a higher level. Chest
physiotherapy is done 3 to 4 times a day, each session
lasting for 10 minutes and the duration not exceeding 30
minutes in total.
Surgical Management: Full extent of the disease is carefully
assessed before proceeding with a surgical option. Nature
of surgery is segmental or lobar resection and less
commonly pneumonectomy. Indication for surgical
treatment are:
1. Impairment of normal social life in patient with
localized bronchiectasis despite medical treatment.
2. Localized disease associated with growth delay.
3. Presence of life-threatening hemorrhage from a
demonstrable source.
4. Obstruction with suppurative lesion where the foreign
body eludes bronchoscopic removal.
5. Demonstrable site of recurrent pneumonia.
Contraindication for surgery are extensive bilateral
lesion associated diffuse bronchitis, emphysema or
pulmonary or cardiac insufficiency.
To conclude bronchiectasis is the end result of many
disease processes affecting the lung parenchyma. Majority
of them can lead normal lives, if they are put on a
treatment plan to avoid progressive pulmonary deterio-
ration. If the plan fails, surgical treatment should be
considered.
Etiology
Usually occurs in the setting of chronic and persistent
aspiration. Most common predisposing conditions are
590 IAP Textbook of Pediatrics
seizure disorder, unconscious state, poor oral hygiene,
dental procedures and intubation. It can be a compli-
cation of poorly managed pneumonia. Staph. aureus, H.
influenzae, S. viridans and S. pneumoniae commonly affect
the previously normal host and anaerobic organisms and
Klebsiella are considered in immune compromised.
Posterior segment of the upper lobes and superior
segments of the lower lobes are affected during
aspiration, in recumbent position.
When aspiration occurs in erect position, basilar
segments of the lower lobes are affected.
Clinical Features
Onset is often insidious with high-grade fever with
cough, chest pain, dyspnea, sputum production fetid
breath and hemoptysis. Copius amount of foul smelling,
blood stained purulent sputum is characteristic.
However, lack of putrid sputum does not exclude the
diagnosis. A careful history will often reveal an episode
of aspiration. Sometimes, aspiration of a foreign body
goes unnoticed until after removal of foreign body.
Physical examination may show dullness of percussion,
decreased breath sounds and egophony.
Laboratory Findings
Total WBC count may be elevated with neutrophilic
predominance. Chest radiograph may show one or more
thick walled cavities (Fig. 12.11.1). Air fluid level may
be present. Hydatid cyst, congenital cyst and loculated
empyema may show similar picture in the radiography.
CT scan is useful for localization and for differentiation
from other pulmonary masses. Bronchoscopy is helpful
in assessing bronchial obstruction caused up by a foreign
body and also for aspiration of pus. Gram staining and
microscopy of the sputum may reveal the presence of
numerous polymorphs with microorganism and culture
will identify the organism.
Treatment
Broad spectrum parenteral antibiotics covering Staph.
aureus, H. influenzae and anaerobes are used for a period
of 3 to 4 weeks. Along with antibiotics, nutritional
supplements and postural drainage with physiotherapy
are very useful. Penicillin G, Chloramphenicol,
Amoxicillin-Clavulanate, Metronidazole, Ticarcillin-
Clavulanate, 3rd or 4th generation Cephalosporin and
Carbapenam are antibiotics that are used in combination.
Drainage procedure includes percussion and positioning
Figure 12.11.1: Lung abscess right upper lobe
to increase drainage through airway. Lung abscess often
will rupture spontaneously into the airway. Some
advocate catheter drainage of abscess. Rarely open
drainage is performed with resection.
Prevention
This involves prevention or minimizing aspiration in the
presence of predisposing factors.
BIBLIOGRAPHY
1. Balachandran A, Shivbalan S, Thangavelu S,
Vijayasekaran D, Subramanyam L. Empyema thora-
cis. Indian J Pediatr 2003;70:803-6.
2. David M Orenstein. Diseases of the pleura. In Richard E
Behrmann, Robert M Leigman, Hal B Jenson (Eds):
Nelson’s Textbook of Pediatrics (16th edn). Philadelphia,
WB Saunders 1999.
3. DeLuca A, Kurland G. Empyema in children: Epide-
miology, diagnosis and management. Seminars in
Pediatric Infectious Diseases 1995;9:205-11.
4. Fisher MC. Lung abscess and other anaerobic pulmonary
infections. In: Feign RD (Ed): Seminar on Ped. Infectious
diseases 1998;9(3):199-204.
5. Robert C Stern. Bronchiectasis and lung abscess. In
Richard E Behrmann, Robert M Kleigman, Hal B Jenson
(Eds): Nelson’s Textbook of Pediatrics (16th edn).
Philadelphia. WB Saunders, 1999;1308-10.
6. Thangavelu S, Vijayasekaran D, Somu N. Bronchiectasis
A respiratory orphan, Essentials of Pediatric Pulmono-
logy, M/s. Siva and Co, II Edn, Chennai 1996.
7. Vijayasekaran D, Subramanyam L. Anaerobic lung
infection. Pediatric Pulmonology update, official bulletin
of Respiratory Chapter of Indian Academy of Pediatrics,
1999;11(3):43-51.
8. Wallace W, Neblett III, Walter M, Morgan III, Tomitta S.
Surgical management of complications of pulmonary
infection. Seminars in Pediatric Infectious Diseases
1995;6:188-200.
 Diseases of Respiratory System 591

12.12 Hemoptysis
Vibha Mangal, Neeraj Jain, Vibhu Kwatra

Definition TABLE 12.12.1: Differentiating features of hemoptysis

and hematemesis
Hemoptysis is defined as the spitting of blood derived
from the lungs or bronchi as a result of pulmonary or Hemoptysis Hematemesis
bronchial hemorrhage. The lungs receive blood from both History
the pulmonary and bronchial arterial systems. The low- Absence of nausea and Presence of nausea and
pressure pulmonary system tends to produce small- vomiting vomiting
volume hemoptysis, whereas bleeding from the Lung disease Gastric or hepatic disease
Asphyxia possible Asphyxia unusual
bronchial system, which is at systemic pressure, tends
to be profuse. Sputum examination
Frothy Rarely frothy
Types of Hemoptysis Liquid or clotted Coffee ground appearance
appearance
Hemoptysis may be frank or spurious. Bright red or pink Brown to black
1. Frank hemoptysis: Expectoration of blood only Laboratory
2. Spurious hemoptysis: Hemoptysis is present secondary Alkaline pH Acidic pH
to upper respiratory tract infection, above the level Mixed with macrophages Mixed with food particles
of larynx. and neutrophils
3. Pseudohemoptysis: It is due to pigment prodigiosin
produced by the gram-negative organism, Serratia
marcescens.
4. Endemic hemoptysis: Present in infection with TABLE 12.12.2: Etiology of hemoptysis
Paragonimus westermani. 1. Infection:
The first task is to confirm the presence of blood • Tracheobronchitis
followed by differentitation between hemoptysis and • Pneumonia
– Bacterial: Mycobacterium tuberculosis, Staphylococ-
hematemesis (vomitting of blood). Some important clues
cus aureus, Pseudomonas aeruginosa
for this are given in Table 12.12.1.
– Fungal: Aspergillosis
• Influenza
Etiology • Parasitic: Echinococcosis
2. Tracheostomy-related
The common causes of hemoptysis in children are listed
3. Bronchiectasis
in Table 12.12.2. 4. Cystic fibrosis
5. Ciliary dyskinesia
DIAGNOSIS 6. Trauma
7. Foreign body
History 8. Congenital heart disease (mainly with pulmonary vascular
obstructive diseases)
History helps to differentiate hemoptysis from hema-
9. Pulmonary A V malformations
temesis and pseudohemoptysis, identify the anatomic 10. Pulmonary thromboembolism
site of bleeding, and narrow the differential disgnosis. 11. Alveolar hemorrhage syndromes
Factors such as age, nutrition status, and comorbid 12. Immunodeficiency
conditions can assist in the diagnosis and management 13. Connective tissue disease vasculitis: Goodpasture’s
of hemoptysis. Some of these are listed in Table 12.12.3. syndrome, Wegener granulomatosis
Details of previous episodes of hemoptysis and 14. Primary pulmonary hemosiderosis: Heiner syndrome
15. Tumors: Bronchial adenoma, metastatic
diagnostic assessments are helpful.
592 IAP Textbook of Pediatrics

TABLE 12.12.3: Diagnostic clues in hemoptysis: History

Clinical clues Suggested diagnosis

Anticoagulant use Mdication effect, coagulation disorder

Dyspnea on exertion, fatigue, orthopnea, paroxysmal Congestive heart failure, left ventricular dysfunction,
nocturnal dyspnea, frothy pink sputum mitral valve stenosis

Fever, productive cough Upper respiratory infection, acute sinus acute bronchitis,
pneumonia, lung abscess

History of chronic lung disease, recurrent lower respiratory Bronchiectasis, lung abscess
tract infection, cough with copious purulent sputum
HIV, immunosuppression Neoplasia, tuberculosis

Pleuritic chest pain, calf tenderness Pulmonary embolism or infarction

Travel history to endemic regions Tuberculosis, parasites (paragonimiasis, schistosomiasis,

amebiasis, leptospirosis), biologic agents (plague, tularemia,
T2 mycotoxin)

Blood from the lower bronchial tree typically induces
cough, whereas a history of epistaxis or expectoration
without cough would be consistent with an upper
respiratory source but does not exclude a lower tract site.
Try to determine the volume and rate of blood loss. This
can be done by observing as the patient coughs or by the
use of a graduated container. Blood-streaked sputum
deserves the same diagnostic consideration as blood
alone.
of the extremities for signs of edema, cyanosis and
tenderness. Clubbing is present in bronchiectasis, lung
abscess and severe chronic lung diseases. Cachexia,
clubbing, hoarseness of voice, hyperpigmentation and
Horner’s syndrome may suggest a primary lung cancer.
Diagnostic Evaluation
After a careful history and examination, a chest radio-
graph should be obtained. Some of the common

Physical Examination TABLE 12.12.4: Diagnostic clues in hemoptysis:

chest radiograph
A good history will narrow the differential diagnosis and
Chest radiograph finding Possible diagnosis
help focus the physical examination. Examination of the
expectoration may helping to localize the source of Cardiomegaly, increased Chronic heart failure, mitral valve
pulmonary vascular stenosis, pulmonary edema
bleeding. The physician should record vital signs,
distribution
including pulse oximetry, and document fever, tachy-
Cavitary lesions Lung abscess, tuberculosis
cardia, tachypnea, weight changes, and hypoxia.
Diffuse alveolar infiltrates Chronic heart failure, pulmonary
Constitutional signs such as cachexia and level of patient
edema, aspiration, toxic injury.
distress should be noted. The skin and mucous mem-
Lobar or segmental Pneumonia, thromboembolism
branes should be inspected for cyanosis, pallor, infiltrates
ecchymoses, telangiectasia, gingivitis, and evidence of
Patchy alveolar infiltrates Bleeding disorders, idiopathic
bleeding from the oral or nasal mucosa. Lymph nodes pulmonary hemosiderosis,
should be examined in the neck, supraclavicular region, Goodpasture syndrome
and axilla. The cardiovascular examination includes an Hilar adenopathy or mass Infectious process, sarcoidosis,
evaluation for jugular venous distension, abnormal heart malignancy
sounds, and edema. The physician should check the chest Mass lesion, nodules, Wegener granulomatosis, septic
and lungs for signs of consolidation, wheezing, rales and granulomas embolism vasculitides
trauma. The abdominal examination should focus on Normal or no change from Upper respiratory infection,
signs of hepatic congestion or masses, with an inspection baseline sinusitis, pulmonary embolism
 Diseases of Respiratory System 593

TABLE 12.12.5: Diagnostic clues in hemoptysis:
Laboratory tests
Test
White blood cell counts
and differential counts
Hemoglobin, hematocrit
Platelet count
Prothrombin time,
International Normalized
Ration (INR) partial
thromboplastin time
Arterial blood gases
d-dimer
Sputum:Gram stain,
culture, acid-fast bacillus
smear and culture
Tuberculin (PPD) skin test
HIV test
Erythrocyte sedimentation
rate (ESR)
Diagnostic findings
Elevated cell count and differential
shifts may be present in upper and
lower respiratory tract infections
Decreased in anemia
Decreased in thrombocytopenia
Increased in anticoagulant use,
disorders of coagulation
Hypoxia, hypercarbia
Elevated in pulmonary embolism
Pneumonia, lung abscess,
tuberculosis
Positive test increases risk for
tuberculosis
Positive test increases risk for
tuberculosis, Kaposi’s sarcoma
Elevated in infection, autoimmune
disorders (Wegener granulomato-
sis, SLE, sarcoidosis, Goodpasture
syndrome)
radiologic findings and possible diagnosis are listed in
Table 12.12.4. If the diagnosis remains unclear, further
imaging with chest computed tomography (CT) or direct
visualization with bronchoscopy is indicated.
Fiberoptic bronchoscopy is used mainly for diagnostic
purpose as it permits tissue biopsy, bronchial lavage or
brushings for pathologic diagnosis. It can provide direct
therapy in cases of continued bleeding. Rigid bron-
choscopy is the preferred in cases of massive bleeding
because of its greater suctioning and airway maintenance
capabilities.
Patient with recurrent or unexplained hemoptysis
may need additional laboratory evaluation to establish
a diagnosis (Table 12.12.5.)
BIBLIOGRAPHY
1. Cahill BC, Ingbar DH. Massive hemoptysis. Assessment
and management. Clin Chest Med 1994;15:147-67.
2. Corder R. Hemoptysis. Emerg Med Clin North Am
2003;21:421-35.
3. Harrison TR, Braunwald E. Hemoptysis. In:Harrison’s
Principles of Internal Medicine.15th edition. New
York:McGraw-Hill, 2001:203-6.
4. Pianosi P, Al-Sadoon H. Hemoptysis in children, pediatr
Rev 1996;17:344-8.
5. Soni PN, Reddy I, Rauff S. Pneumonia and severe
haemptysis. Lancet 1998;352:198.
6. Taskar AD, Flower CD. Imaging the airways. Hemo-
ptysis, bronchiectasis, and small airways disease. Clin
Chest MEd 1999;20:761-73

12.13 Bronchial Asthma

H Paramesh, L Subramanyam, SO Shivbalan

INTRODUCTION interaction, in addition places a strain on health visits

Asthma is a chronic lung disease with airway obstruction,
airway inflammation and airway hyper-reactivity to
various stimuli, often reversible with bronchodilators
and anti-inflammatory drugs. If not treated properly
some of persistent asthmatics end up in irreversible state
due to airway remodelling.
Asthma is a major health concern globally and
causes a great burden on the family and society and
accounts for a large number of lost school days and
interfere with academic achievement and social
to physician and hospital.
EPIDEMIOLOGY
There is substantial evidence that the prevalence of
asthma is increasing worldwide and the likely causes
for the increase or for the variations in prevalence
among countries differ. However, there is general
agreement that the environmental factors, including
increasing exposure to air pollution, tobacco smoke,
allergens, western life style, of living, deviating from
594 IAP Textbook of Pediatrics

traditional food habits and rearing the child in TABLE 12.13.2: Asthma prevalence in schools/density of
extremely hygienic atmosphere, that is devoid of even traffic/affluence
protective germs. Group No. of studied % of asthma
The study in Papua New Guinea showed that intro-
I. School in heavy traffic 3722 19.34
duction of mites in the indoor environment by using
region, children from affluent
blankets had caused increase prevalence of asthma. families
Synergic actions of air pollution, tobacco smoke have II. School in heavy traffic with 273 31.14
been implicated for increase prevalence along with children of low socioeconomic
western life style of living and insulation of houses as an groups (less affluent)
important cause. Polluted cities in Sweden have shown III. School in low traffic region, 2565 11.15
increased prevalence of allergy. Similar observations children from affluent family
have been made in Chile, where school children living groups
in heavily polluted areas present with asthma more than P. Value 1: II < 0.001, II: III < 0.001, 1: III < 0.001
those living in less polluted areas.

PREVALENCE OF ASTHMA IN BANGALORE, INDIA

Based on international guidelines, a two decade study
conducted by a pediatric pulmonologist in a pediatric
OPD children < 18 years of age in a metropolitan cities
revealed asthma prevalence rates every five years since
1979 as follows as shown 9 percent, 1984-10.5 percent,
1989-24 percent, 1989-29.5 percent. The steady rise in
prevalence correlated with demographic changes in the
city like - increase in numbers of industries, increased
density of population from migration of rural population
in search of jobs and increased number of automobiles
to commute, leading to air pollution.
Figure 12.13.1: Prevalence of asthma (1979-2004) (P<0.05)
In continuation of the study we undertook further
study in 12 schools on 5570 urban children and 990 of
prevalence and emergency visits and hospitalization after
rural children in the age group of 6 to 15 years, the
a steady increase over past two and half decade.
prevalence of asthma in this age group is shown in
Our hospital-based study on 6677 children under the
Table 12.13.1.
age of 18 years in the year 2004, in comparison to earlier
studies shows a decrease in the prevalence of asthma as
TABLE 12.13.1: Asthma prevalence Urban /
rural. age 6-15 years in Figure 12.13.1. This decrease in prevalence can be due
to saturation of genetically predisposed population.
Urban Children 5570 16.635 %
However, further analysis revealed that the persistent
Rural Children 990 5.7%
asthma is increased from 20 to 36.3 percent in 10 years
from 1994 to 2004 shown in Figure 12.13.2. It is the
Further we categorized the urban children into three
persistent asthma causes great economic burden to the
groups depending upon the geographical situation of the
society.
schools in relation to vehicular traffic and affluence of
The point prevalence of asthma in 800 adolescents in
the family and the results are shown in Table 12.13.2.
the age group of 16-19 years of age is 10.3 percent.
The admission rate to the hospital from acute severe
Is the Magnitude of Asthma Going to
asthma is reduced from 24.5 percent/year in 1995-97 to
Rise Incessantly?
12.34 percent/year in 1997 to 2003.
Recent Studies in Australia, Hong Kong, Mexico and Italy The emergency room visits of asthma decreased from
show that there is a decreasing trend in asthma 21.35/year to 11.92/year in 3 years. This reflects the good

Figure 12.13.2: Prevalence of persistent asthma
(1994-2004) (P<0.0058)
impact of hands on education of patients and parents in
the outpatients about compliance and technique of
inhalation.
Age of Onset
Asthma may have its onset at any age; 26.3 percent of
patients are symptomatic by one year of age, 51.4 percent
by 1-5 years and 22.3 percent after five years of age. It
was observed that 77.7 percent of asthma cases are in
the age group of less than 5 years.
Distribution of Sex
The male to female ratio is 1.8:1 on par with various other
studies. Contrary to the well-established facts, the recent
observation by the another rural study by the auther on
119 children of agricultural farm workers, in the age
group of 6-15 years of age, who live 6 km away from the
main road has shown that the ratio of male to female is
1:2.3. This change in gender ratio is mainly due to the
fact that girls living in ill ventilated huts, helping the
mother to cook and inhalation of smoke from dirty fuel
(cow dung cakes and agricultural waste) lead to airway
inflammation and asthma.
Genetics
Asthma is a complex genetics disorder influenced by
environment. The current knowledge is, it is inherited
as an autosomal dominant trait. The abnormal loci is on
chromosome 11, and for total IgE (Atopy) it is on
chromosome 5 for specific IgE, it is on chromosome 7.
There are over 51 genes loci are implicated in asthma
Diseases of Respiratory System 595
and atopy. The Adam 33 gene is involved in airway
remodelling and airway hyper reactivity. Often there is
a history of asthma in the close family members. The
monozygotic twins suffer more than dizygotic twins.
Etiology and Triggering Factors
In children the most common trigger for asthma is viral
infections almost 40 percent of the time.
Seasonal variation occurs more in monsoons and
winter but less in summer months. Aeroallergens like
pollens and fungi are present in 7.5 percent of the time.
Indoor allergens are the most common cause for
persistent asthma and include dust mites, cockroaches,
fungi and animal, saliva danders, urine in the bedrooms.
Irritants like cigarette smoke, cologne sprays,
burning of mosquito coils and cooking smell can trigger
asthma. Food as a triggering factor is observed in 19.75
percent by the parental history only. The most blamed
offenders are grapes, banana, guavas, citrus fruits, ice
creams, fried foods and tomato in that order.
Air pollution is both outdoor and indoor. Nitrogen
oxide, sulfur dioxide, ozone and suspended particulate
matters from combustion of fossil fuels sensitize airway
to inflammation and trigger asthma attacks. Polluted
pollens are 50 times more allergenic.
Pets ownership is 5.12 percent in urban locale and
42.3 percent in rural agrifarm workers.It is observed that
where the pet ownership is more the prevalence of
asthma is less. If at all any asthma in children due to pets
it is from their saliva and urine predominantly from cats.
Pathophysiology
Various stimuli can initiate asthmatic symptoms. These
include immunologic IgE mediated type I hypersensiti-
vity reaction to allergens (dust mites, pollens, fungi and
cockroach) and non-immunologic stimuli (viral infec-
tions, physical or chemical stimuli) which acts by
increasing the exposure of airway to cool dry air and
activates the cells and stimulates autonomic nervous
system which releases bronchoactive and vasoactive
mediators like histamine, eosinophilic chemotactic factor
of anaphylaxis (ECF-A), neutrophil chemotactic factor
(NCF-A) and platelet activating factor (PAF). In
individuals with nasal polyps salicylate and non-
steroidal anti-inflammatory drugs (NSAIDs) can trigger
asthma by inhibiting prostaglandins and increasing
leukotriens production via blockage of the cyclo-
596 IAP Textbook of Pediatrics

Flow chart 12.13.1: Pathways of physiology TABLE 12.13.3: Asthma signs in abnormal physiology

1. Increase airway Retraction with increasing

resistance severity
• Over working abdominal muscle
• Subcostal retractions
• Intercostal retractions
• Suprasternal retractions
• Head bobbing anterior flexion of
head during inspiration in infants
• Flaring of nostrils

2. Airway obstruction • Prolonged expiration

• Muscle spasm • Wheeze
• Mucosal edema • Ronchi
• Excess trapping of • Elevated shoulder
air • Hunchback position
• Increase anteroposterior
diameter of chest

3. Excess mucus • Wet sounds (crackles) more

secretion often predominant in infants

4. Hypoxia • Irritability, confusion, refusal to

feed, semi coma, coma

5. Hypercarbia • Bounding pulses, warm hands,

dilated retinal vessels.

of the chest. Wheezing is noticed in 74 percent, vomiting

oxygenase pathways. Gastroesophageal reflux (GER)
triggers asthma possibly by cholinergic mechanisms or
as a direct result of aspiration.
Three major pathologic events contribute to airway
obstruction:
1. Spasm of airway smooth muscles.
2. Edema of mucus membrane.
3. Excess mucus production. This airway obstruction
interferes with mucociliary escalator clearance. The
proposed pathways of pathophysiology are shown
in Flow chart 12.13.1.
Clinical Features
It is a common statement that all that wheezes is not
asthma, however, all asthmatics do not present with
wheeze. Cough is a predominant symptom for asthma
in 90 percent of the time. The cough which persists after
an episode of upper respiratory infection lasting more
than 10 days should be considered as cough variant
asthma unless proved otherwise. The cough has a special
feature like it is more at night or early morning; crying,
running and loud laughing increases cough and patting
on the back of the child produces cough from vibration
in 5 percent (precede by cough), abdominal pain in
3 percent (due to over-activity of abdominal muscles
during expirations) and chest pain in 1 percent of
children.
The signs are related to increased airflow resistance
during expiration, airway obstruction and excessive
mucus production, hypoxia and hypercarbia as shown
in Table 12.13.3.
Diagnosis
The diagnosis of asthma in children under 5 years is
predominantly by clinical features of persistent cough
over one week duration after a bout of cold having more
and wheeze than three episodes per year prolonged
expiration and other signs of airway obstruction. Having
other features of atopy like eczema and allergic rhinitics,
family history of asthma and improvement with
therapeutic trial of bronchodilators is often helpful.
Peripheral blood smear show eosinophilia, total IgE is
elevated in atopic children. In children above 3 years of
age one can measure peak expiratory flow rate (PEF)
before and after inhalation of bronchodilators. If there is
15 percent improvement of peak expiratory flow after

therapy, it is highly suggestive of asthma. In bigger
children spirometric study is beneficial where the ratio
of forced expiratory flow at one second (FEF1) to forced
vital capacity (FVC) ratio is less than 0.8, or less than 80
percent of normal. Forced expiratory flow rates (FEF25-
75) is an effort independent measure and is low in small
airway obstruction. Chest X-ray is not diagnostic of
asthma. It may show only air trapping, but it is needed
if any complication of asthma or any other diagnosis is
suspected. Radio allergosorbent test (RAST), enzyme
linked immunosorbent assay (ELISA) and skin testing
to confirm the specific allergenic causes are not needed
routinely.
Differential Diagnosis
Anyone of the inflammatory or congenital abnormalities
of upper respiratory tract like rhinitis, croup syndrome,
tonsillitis, retropharyngeal abscess, laryngomalacia and
vascular ring and supraglottitis can be mistaken for
asthma. All these upper airway diseases have the
following features in common: (a) inspiratory difficulty,
(b) stridor. Depending on the pitch of the sound one can
make the location of upper airway pathology.
In the lower respiratory tract bronchiolitis is the most
common condition to be differentiated from asthma.
Bronchiolitis is diagnosed clinically if associated with
fever. One can ascertain about bronchiolitis by bronchial
biopsy and decrease in breath nitric oxide, unlike in
asthma (these measures are of academic interest only).
Foreign body aspiration should be suspected in sudden
onset cough and wheeze during play hours in a healthy
child. Non-opaque foreign body aspiration can be
suspected when uneven ventilation of lung is present
and confirmed by inspiratory and expiratory chest
X-rays. Cystic fibrosis, a genetic disease is not uncommon
in our country and is diagnosed by increase in sweat
chloride.
Parenchymal diseases like pneumonias can be
diagnosed by tachypnea, flaring of nostrils and grunting
during expiration. X-ray will be diagnostic.
Complications
The usual complication of asthma is atelectasis observed
more in children under 5 years of age due to lack of
collaterals in that age group which is often mistaken for
recurrent pneumonia and treated with antibiotics.
Pneumonia, middle ear infection, sinusitis, occasionally
Diseases of Respiratory System 597
pneumomediastinum and subcutaneous emphysema
may occur.
Management
While managing the children with asthma, a special
interest to be focussed on children under five years of
age because, the under diagnosis, under treatment are
a major factors. The aims of management of the asthma
in children are: (a) relieve the symptoms, (b) prevent
the relapse of attacks to prevent school absenteeism,
encourage to participate in sports and attain good growth
and development, (c) education of the patients, parents,
grandparents about the disease, need to use the medicine
and proper use of technique of inhalation therapy, (d)
good pharmacological therapy and (e) environment
control.
And in adolescents—the poor compliance is quite
common because they fail to recognize the danger of
poorly controlled asthma, not able to accept the chronicity
of the illness and they feel the therapy will infringe on
their emerging independence. They also fear the stigma
of asthma on their future life style in society and sports.
Especially the adolescent girls try to avoid inhalation
treatment for fear of marriage and mother-in-laws.
Pharmacological Therapy
There are two groups of drugs in the management of
asthma:
1. Quick relievers—Bronchodilators like beta 2 agonists,
salbutamol, and terbutaline are similar in their
efficacy, actions, kinetics and adverse effects. While
inhalation is the method of choice, oral alternative
may be justified in children whose symptoms are mild
and less frequent. Long acting beta 2 agonists like
(salmeterol, formeterol) are not recommended in
acute attacks. Amino-phylline is the second choice
as bronchodilator. In recent days their usage has come
down since better and safer bronchodilators are
available. However, they still find some place in
managing acute severe asthma episodes in ICU
setting as an additive drug for their mild effect of
improved diaphragm contractility, mucociliary
clearance and mild anti-inflammatory effects.
However, caution is exercised while using the
medicine. In addition it has some role to play in
nocturnal asthma as a prophylactic.
598 IAP Textbook of Pediatrics

2. Preventors or anti-inflammatory drugs (mast cell stabilizers): TABLE 12.13.4: Management of acute severe
Cromolyn glycate has mild anti-inflammatory effect; asthma rule of six M’s
but 4 times daily regime is difficult to implement. 1. Metabolic correction Humidified warm oxygen, use of
• Leukotriene inhibitors: These drugs block the sodium bicarbonate in some
synthesis of leukotrienes at various levels. cases as per base excess
Montelukast has been shown to be beneficial for 2. Muscle spasm to be Beta-2 agonists inhalation Methyl
exercise-induced asthma, add-on therapy in relieved Xanthines intravenously
persistent asthma in reducing the steroid dosage 3. Mucosal edema Steroids to be used at the earliest
and in nocturnal asthma. 4. Mucus secretions in Hydration. Stacchato type of
• Steroids: They are the best anti-inflammatory excess coughing
drugs available now. Inhaled steroids are the best 5. Monitor for infections Antibiotics if the mucus is yellow
mode of therapy where adverse steroid effects are or green or evidence of pneumonia
negligible. The available inhaled steroids include 6. Mechanical breathing Ventilators. When ventilator
beclomethasone, budesonide, and fluticasone. failure is established
Fluticasone is the most potent and least bio-
available to produce adverse reactions. Com- during mild exacerbations. Persistent asthma should be
bining with long acting beta-2 agonists will
suspected in children who require bronchodilator
enhance the effect of steroids (seroflo, combitide,
therapy more than 2 times a week and trial of anti-
seretide).
inflammatory drugs can be given.
Treatment of Acute Attack of Asthma After assessing the severity of asthma, signs and
symptoms can be controlled by the use of preventor
The first line of management of an acute attack of asthma
drugs suitable to a grade higher than the patient’s grade
in the emergency room is to administer beta-2 agonists
of severity (step down method). This is preferred as it
through a nebulizer or give epinephrine (1: 1000 dilution)
helps to get quick control of symptoms and gain the
0.1 to 0.3 ml subcutaneously depending on the age. The
confidence of patients and parents, and adherence to the
dose may be repeated two times at 15 minutes intervals
regime of treatment as in Table 12.13.6.
if needed. If there is good response discharge the patient
Children with intermittent asthma but have severe
on oral bronchodilators. If there is no response, the child
exacerbations should be treated as having moderate
should be admitted and treated as a case of acute severe
persistent asthma.
asthma as per guidelines given in Table 12.13.4.
Treatment of Chronic Asthma Selection of Spacers
Chronic asthma is graded as intermittent and persistent The inhalation therapy is the better method in delivering
asthma. Persistent asthma is further graded as mild, the medications, and spacer devices are always
moderate and severe based on clinical features and PEF necessary, in small children who are unable to cooperate,
values as in Table 12.13.5. Children with intermittent a facemask can be attached to the mouthpiece of the
asthma require only inhaled/or oral bronchodilator spacer. The proper selection of the inhalation devices for
therapy to relieve the symptoms and bronchospasm inhalation is shown in Table 12.13.7.

TABLE 12.13.5: Persistent asthma in children—Grading

Grade Frequency Night symptoms with Peak expiratory flow (PEF)

disturbed sleep
Intermittent Less than twice a week Less than twice a month > 80% of personal best
Brief exacerbation < 20% diurnal variation

Mild persistent More than once a week but More than twice a month > 80% personal best
less than once a day 20 to 30% diurnal variation

Moderate persistent Once a day Once a week > 60% < 80 percent of personal best
> 30% diurnal variation

Severe persistent Continuous Frequent < 60% of personal best

> 30% of diurnal variation
 Diseases of Respiratory System 599

TABLE 12.13.6: Selecting the optimal preventer regime Immunotherapy

Severe persistent Inhaled high dose steroids Specific immunotherapy is directed at treating the
+ underlying allergy when avoidance of aeroallergens is
LA beta –2 agonists
not possible and drug therapy is not successful.
Moderate persistent Inhaled low dose steroids + LA beta – Sublingual immunotheraphy (SLIT) is promising in
2 agonists
children.
Or
Inhaled medium dose steroids
Prognosis
Mild persistent Inhaled steroids low dose
Or Although asthma can be a fatal disease, the long-term
Leukotriene inhibitors prognosis is good in children. Most of the children with
Or viral infection triggered asthma will be free of symptoms
Inhaled cromoglycate
by 5 years of age. By 8 years of age some more will be
Note: Low dose = < 400 ug/day symptoms free when airway caliber reaches adult size.
Medium dose = 400 to 800 ug/day By adolescent age almost 90 percent of asthmatics will
High dose = > 800 ug/day of beclomethasone or budesonide.The
corresponding doses of fluticasone is half of the dose.
be free from symptoms. The risk factors for persistent
SA = Short acting, LA = Long acting asthma are: (a) atopic child (b) family history of asthma,
(c) maternal smoking, (d) over-crowded houses with
TABLE 12.13.7: Selection of whatever devices poor indoor air quality (e) poor adherence of medication.
• Nebulizer – Suitable for all ages In patients who are on long-term steroids one has to
observe for cushingoid features, linear growth failure,
• Metered dose inhaler – Children over 10 years.
(MDI) However, a spacer is still
cataracts, osteoporosis and acne.
recommended.
BIBLIOGRAPHY
• MDI with Spacer – Suitable for all ages 1. Consensus guidelines on management of childhood
• MDI with Spacer and mask – Children less than 3 years asthma in India. Indian Pediatrics 1990;157-65.
2. Consensus statement on the diagnosis and management
• Dry Power Inhaler (DPI) – Above 6 years of asthma in children. Asthma by Consensus - National
Guidelines – IAP Respiratory chapter.Update Dec 2003.
Please note whatever be the device a spacer is a must in all
3. GWK Wong, et al. Declining asthma prevalence in Hong
cases.
Kong Chinese School Children. Cli Exp allergy 2004;
Environment Control 34:1550-5.
4. Mario H Varges, Guiltermo S Daz Mejsa, Maria EY
Seventy-five to eighty-five percent of asthma patients Furuya, Jorge Sales, Alejandro Lugo.
have positive skin tests for common inhalants existing 5. Paramesh H. Asthma and the Environment .Indian
inside the house. Avoid big crowds to prevent respiratory Journal of Pediatrs 2006;73:S51-55.
viral infection. Encase the pillow and mattress, sundry 6. Paramesh H. Asthma in children: Seasonal variation.
the bedding weekly, avoid carpets, upholstered Paper read Vienna. Austria in International Conference
furnishing, tobacco smoke, mosquito burning coils, wood on Environment and Child Health; June 2007.
burning smoke, strong odors, and cologne sprays; and 7. Paramesh H. Epidemiology of asthma in India. Indian
avoid air pollution (oxides of nitrogen, ozone, sulfur Journal of Pediatrics 2002;300-12.
8. Paramesh H. Indoor Air Pollution and Child Health. In
dioxide, suspended particulate matters). Cockroach
Anupam Sachdeva, (ed).Pediatric and Adolescent
control measures and avoiding the wet humid and moldy
environment Health,Indian Academy of Pediatrics
places. Stay indoor especially during mid-day and
Presidential Action Plan 2004;1:76-8.
afternoon when pollen and mould counts are high. Wet 9. Paramesh H. Peak flow values in urban and rural
mopping of floors is better. A good cross-ventilation and children, Indian Journal of Pediatrics 2003;70:375-7.
good sunlight inside the house is always better in our 10. Paramesh H, Cherian E. Pediatric allergies. Epide-
country. Avoid suspected food, which increases the miology and management principles and practice of
symptoms during the asthma episodes. Traditional food tropical allergy and asthma In: Wiqar A Shaikh (Ed):
habits are always better. Vikas Medical Publishers, Mubai 2006;603-14.
13.1 Diarrheal Diseases: Ashok K Patwari .................................................................................................................................................... 602
13.2 Persistent and Chronic and Protracted Diarrhea in Children: Gadadhar Sarangi, Jnanindra Nath Behera ................................... 609
13.3 Parenteral Nutrition in Children: Anand N Pandit, Ashish R Bavdekar .............................................................................................. 613
13.4 Parasitic Bowel Diseases: BD Gupta ................................................................................................................................................... 616
13.5 Vomiting in Infants and Children: S Nagabhushana .......................................................................................................................... 620
13.6 Gastroesophageal Reflux in Infants and Children: Neeraj Jain, Vibha Jain, Deepak Seth .............................................................. 622
13.7 Gastrointestinal Bleeding in Infants and Children : Saroj Mehta, Rajiv Chandra Mathur ................................................................ 624
13.8 Constipation: VR Ravikumar ................................................................................................................................................................. 627
13.9 Abdominal Pain: S Srinivas ................................................................................................................................................................... 629
13.9.1 Acute Abdominal Pain in Children ........................................................................................................................................ 629
13.9.2 Chronic Abdominal Pain in Children ..................................................................................................................................... 632
13.10 Helicobacter Pylori Infection in Children: Neeraj K Jain, Vibha Mangal ........................................................................................... 637
13.11 Cystic Fibrosis: Sushil K Kabra, Madhulika Kabra ............................................................................................................................... 639
13.12 Juvenile Tropical Pancreatitis: A Riyaz ............................................................................................................................................... 644
13.13 Liver and Biliary System: B Bhaskar Raju, B Sumathi ........................................................................................................................ 646
13.14 Hepatosplenomegaly: A Practical Diagnositic Approach: Sheila Bhave, Ashish Bavdekar ............................................................ 650
13.15 Differential Diagnosis of Jaundice in Infancy: MK Jain, Sunil Karande ............................................................................................ 653
13.16 Viral Hepatitis: Malathi Sathiyasekaran, Ramaswamy Ganesh ............................................................................................................ 655
13.17 Chronic Hepatitis in Children: BR Thapa ............................................................................................................................................ 667
13.18 Chronic Liver Disorders in Children: VS Sankaranarayanan, S Srinivas .......................................................................................... 672
13.19 Cirrhosis of Liver: VS Sankaranarayanan, S Srinivas .......................................................................................................................... 675
13.20 Neonatal Cholestasis Syndrome: BR Thapa ....................................................................................................................................... 682
13.21 Fulminant Hepatic Failure: Rajiv Chandra Mathur ............................................................................................................................... 692
13.22 Ascites: Balvir S Tomar, Anurag Tomar ................................................................................................................................................ 695
602 IAP Textbook of Pediatrics
13.1 Diarrheal Diseases
Diarrheal diseases constitute a leading cause of morbidity
and mortality among children under five years of age in
developing countries. On an average 3.3. episodes of
diarrhea are experienced per child per year but in some
areas the average exceeds 9 episodes per year. More than
2 million deaths are estimated to result each year as a
consequence of diarrheal disease in under fives. 80% of
these deaths occur in the first 2 years of life, main causes
being dehydration, complications associated with
dysentery, malnutrition and serious infection such as
pneumonia.
Diarrhea is usually defined as passage of 3 or more
loose or watery stools in a 24 hour period, a loose stool
being one that would take the shape of a container.
However, for practical purposes, it is the recent change
in consistency and character of stool and its water content
rather than the number of stools that is important. Infants
who are exclusively breast fed normally pass several soft
or semi-liquid stools each day; for them, it is practical to
define diarrhea as an increase in stool frequency or
liquidity that is considered abnormal by mother.
Types of Diarrhea
Three clinical syndromes of diarrhea have been defined,
each reflecting a different pathogenesis and requiring
different approach to treatment.
Acute Watery Diarrhea
It refers to diarrhea that begins acutely, lasts for less than
14 days, with passage of frequent loose or watery stools
without visible blood. Vomiting may occur and fever may
be present. Loss of large volume of water and electrolytes
can result in dehydration and dyselectrolytemia.
Dysentery
It is the term used for diarrhea with visible blood and
mucus. Dysentery is often associated with fever and
tenesmus. Common clinical features of dysentery include
anorexia, rapid weight loss and complications like renal
failure and encephalopathy.
Ashok K Patwari
Persistent Diarrhea
It represents diarrhea, presumed to be caused by
infectious agents, that begins acutely but is of usually
long duration ( more than 14 days). The episode may
begin either as acute watery diarrhea or as dysentery.
Marked weight loss is common. Diarrheal stool volume
may also be great, with a risk of dehydration. Persistent
diarrhea should not be confused with ‘chronic diarrhea’
which is recurrent or long lasting diarrhea due to non-
infectious causes such as sensitivity to gluten or inherited
metabolic disorder (See section 13.2).
Risk Factors
Most of the diarrheal episodes occur during the first 2
years of life (incidence is highest in 6-11 months), low
socio-economic status, in non breastfed infants, and in
association with measles, severe malnutrition, and
immunodeficiency.
Etiology
In developing countries, the organisms most frequently
associated with acute watery diarrhea include enterotoxi-
genic Escherichia coli (ETEC), enteropathogenic Escherichia
coli (EPEC), Shigella and Campylobacter jejuni. Rota virus
is a common cause of severe diarrhea, vomiting and fever
leading to rapid dehydration. Vibrio cholera is an
important organism in endemic areas and during
epidemics. Non-typhoidal salmonella is a common
organism in areas where commercially processed foods
are widely used and in hospital outbreaks. Most of these
organisms produce watery diarrhea. The main cause of
acute dysentery are Shigella, Campylobacter jejuni and
infrequently enteroinvasive Escherichia coli (EIEC) or
salmonella. Epidemics of dysentery are usually caused
by S. dysentery type 1. Entamoeba histolytica can cause
dysentery in adults but is a less common cause in young
children.
Diarrhea may also be caused by a number of
antibacterial agents like ampicillin, cotrimoxazole,
chloramphenicol, amoxicillin, clindamycin, etc. Pseudo-
 Diseases of Gastrointestinal System and Liver
membranous colitis is the most severe form of antibiotic
associated diarrhea.
Pathophysiology of Infectious Diarrhea
Various mechanisms which have been suggested include:
(i) increased secretion of fluid and electrolytes,
(ii) decreased digestion and absorption of nutrients, and
(iii) abnormal transit due to aberrations of intestinal
motility.
Increased Secretion
Increased secretion of fluid and electrolytes may occur
due to the effect of enterotoxins liberated by micro-
organisms which mediate through cyclic AMP or cyclic
GMP thereby disturbing the sodium pump and leading
to (a) increased secretion from crypt cells, (b) poor
absorption of water and electrolytes from the villi and
(c) increased passive flow of water and electrolytes from
ECF to small bowel lumen through intercellular channels.
Decreased Digestion and Absorption
Decreased digestion and absorption of nutrients parti-
cularly carbohydrates can take place as a consequence
of: (a) disorganized epithelial cell renewal i.e. villus
atrophy and crypt hyperplasia with failure of normal
enterocyte maturation during migration from the crypt
to villus or (b) damage to absorptive surface as a result
of brush border damage, cytotoxin production resulting
in severe epithelial damage and epithelial invasion
leading to patchy micro abscess formation, decreased
mucosal disaccharidase activity and impaired
absorption.
Disordered Transit
Abnormal intestinal myoelectrical activity initiated by
non-invasive organisms and their enterotoxins as well
as by invasive enteropathogens can result in disordered
transit not only as a secondary response to disordered
mucosal transport but may also occur independently as
a primary pathophysiological mechanism.
Clinical Features
Most enteropathogens can cause diarrhea by more than
one mechanism. Hence the clinical presentation depends
upon the underlying pathophysiological changes taking
603
place in the gastrointestinal tract. Three clinical types of
diarrhea have been defined, each reflecting a different
mechanism.
Secretory Diarrhea
It is characterized by acute watery diarrhea with
profound losses of water and electrolytes due to sodium
pump failure as a result of the action of identified toxins.
This group is at risk for rapid development of dehydra-
tion and electrolyte imbalance. Common causes are ETEC
and V. cholerae.
Invasive Diarrhea (Dysentery)
Intestinal mucosal cells are actually invaded by the
microorganisms which set up an inflammatory reaction
clinically presenting with blood and mucus in the stools.
This group is prone to develop other complications like
intestinal perforation, toxic megacolon, rectal prolapse,
convulsions, septicemia and hemolytic uremic syndrome.
Osmotic Diarrhea
Injury to enterocytes may result in brush border damage
and epithelial destruction leading to decreased mucosal
disaccharidase activity. Clinical presentation is characte-
rized by passage of large, frothy, explosive and acidic
stools. High osmolar solutions given orally (e.g.
carbonated soft drinks and ORS with high sugar content)
can also result in osmotic diarrhea. Besides worsening
the hydration status of the child there is a serious danger
of developing hypernatremia.
Consequences of Diarrhea
Dehydration
Dehydration is the commonest and life threatening
consequence of diarrhea. Young children are more
susceptible to develop dehydration due to limited
urinary concentration capacity of the kidneys, more
insensible losses of water through skin and lungs owing
to large surface area and rapid breathing, and their
dependence on adults to replace their fluid losses. Loss
of water and electrolytes in the diarrheal stool results in
depletion of the ECF volume, electrolyte imbalance and
clinical manifestation of dehydration. The first symptom
of dehydration appears after fluid loss of 5% of body
weight. When fluid loss reaches 10% , shock often sets
in, and the cascade of events that follows can culminate
in death unless there is immediate intervention to
rehydrate.
604 IAP Textbook of Pediatrics

TABLE 13.1.1: Assessment of hydration status in a patient with diarrhea

Clinical signs
General condition Well, alert Restless, irritable Lethargic or unconscious
Eyes Normal Sunken Sunken
Thirst* Drinks normally, Drinks eagerly, Drinks poorly,
not thirsty thirsty not able to drink
Skin pinch Goes back quickly Goes back ‘slowly’ Goes back ‘very slowly’

Decide hydration status

The patient has If the patient has If the patient has
no signs of two or more signs, two or more signs,
dehydration there is ‘some there is ‘severe
dehydration’ dehydration’

Treatment Plan Plan A Plan B Plan C

* In a young infant less than 2 months of age, thirst is not assessed and decision regarding ‘some’ or ‘severe dehydration’ is made
if ‘two’ of the three signs are present

Malnutrition Oral Rehydration Therapy

Diarrhea is a major cause of malnutrition in children,
owing to low food intake during the illness (poor
appetite, vomiting, oral thrush/stomatitis, diluting/
withholding of food, etc.), reduced nutrient absorption
in the intestines, and increased requirements as a result
of infection. Repeated and prolonged episodes of
diarrhea have even more deleterious effects and may
eventually result in growth failure, intercurrent infections
and problems associated with severe malnutrition and
even death.
Management of a Child with Diarrhea
Principles of Treatment
• General assessment of the child
• Assessment of hydration status. A number of clinical
signs and symptoms can help in detecting dehy-
dration. However, a simple assessment chart can be
referred for quick assessment of dehydration (Table
13.1.1) and administration of appropriate fluids for
prevention and treatment of dehydration
• Correction of electrolyte and acid base imbalance
• Proper feeding to provide normal nutritional
requirements
• Zinc supplementation
• Treatment of associated problems like dysentery and
persistent diarrhea
• Nutritional rehabilitation
• Health education for prevention of diarrhea
Concept of Oral Rehydration Therapy (ORT) has
revolutionized the management of diarrhea with the
discovery of coupled active transport of glucose and
sodium in the small bowel, resulting in the pas-sive
absorption of water and other electrolytes even during
copious diarrhea. Oral Rehydration Therapy (ORT)
includes:(a) ORS solution of recommended composition,
(b) solution made from sugar and salt (if prepared
correctly), (c) food based solutions with appropriate
concentration of salt, like lentil soup, rice, kanji, butter
milk, etc. and (d) plain water given along with continued
feeding.
Oral Rehydration Salts (ORS) solution: Optimum
absorption of glucose takes place from the intestines
between a glucose concentration of 111-165 mmol/l and
the sodium: glucose ratio between 1:1 to 1:1.4. Therefore,
the standard WHO/UNICEF formula (Table 13.1.2) has
been recommended for rapid rehydration of dehydrated
patients. ORS with this formulation can also be used for
maintenance therapy after correcting dehydration, when
given with equal amounts of plain water or breast-
feeding.
Low Osmolarity ORS: The standard WHO-ORS, used for
over three decades, has saved millions of lives but did
not decrease diarrheal duration or stool output.
Additionally, there was a concern among pediatricians
that there was a risk of hypernatremia with standard
WHO-ORS when given to children with non-cholera
 Diseases of Gastrointestinal System and Liver 605

TABLE 13.1.2: Composition and concentration of WHO/ TABLE 13.1.4: Guidelines for replacement of fluid and
UNICEF recommended oral rehydration salts (ORS) electrolytes in children with ‘No Dehydration’ (Plan A)
Ingredients Composition Ingredients Concentration Age After each loose stool, offer*:
(grams/l) (mmol/l)
< 6 months Quarter glass or cup (50 ml)
Sodium chloride 3.5 Sodium 90 7 months- Quarter to half glass or cup (50 ml–100 ml)
Potassium chloride 1.5 Potassium 80 2 years
2–5 years Half to one glass or cup (100–200 ml)
Trisodium citrate 2.9 Citrate 10
Older children As much as the child can take
(anhydrous)
Glucose (anhydrous) 20 Glucose 111 * Fluids which can be offered include ORS, lemon water, butter
milk, rice kanji, lentil soup, light tea, etc.
Osmolarity 311

Management of ‘Some Dehydration’

TABLE 13.1.3: Low osmolarity ORS formulation
recommended by WHO/UNICEF The objective of treatment is to treat dehydration and
Reduced osmolarity grams/litre Reduced mmol/liter electrolyte imbalance, and to continue feeding. These
ORS osmolarity ORS children should be rehydrated with ORS under super-
Sodium chloride 2.6 Sodium 75
vision in a health facility (Plan B).
Glucose, anhydrous 13.5 Chloride 65
Potassium chloride 1.5 Glucose, anhydrous 75 Correction of Dehydration
Trisodium citrate 2.9 Potassium 20
• For correction of fluid and electrolyte deficit on
Citrate 10
Total osmolarity 245 account of dehydration, administer 50-100 ml/kg
body weight (75 ml/kg) of ORS, over a period of 4
hours. If the child wants more, give more ORS.
diarrhea. Reduced osmolarity of ORS achieved by Breastfeeding should be continued.
reducing the glucose and salt concentrations of the • For infants less than 6 months who are fed on artificial
solution, to avoid possible adverse effects of hyper- milk, and are rehydrated with standard WHO-ORS,
tonicity on net fluid absorption, has been found to be 100- 200 ml of plain water should be given in addition
safe and efficacious in treating children with diarrhea. to ORS
Because of the improved effectiveness of reduced • Older children should have free access to plain water.
osmolarity ORS solution, WHO and Indian Academy of • Acceptance of ORS, purge rate and vomiting should
Pediatrics now recommend use of low osmolarity ORS be closely monitored.
(Table 13.1.3) as the universal solution for treatment and
prevention of dehydration for all causes of diarrhea and Reassess after 4 hours
at all ages. • If still dehydrated, repeat deficit therapy and also
offer milk/food.
Prevention and Treatment of Dehydration
• If rehydrated, treat as ‘no dehydration’ with
Management of ‘No Dehydration’ maintenance therapy with ORS as in Plan A.
The objective of treatment is prevention of dehydration • If ORT is not successful, treat as ‘severe dehydration’
and malnutrition (Plan A). The management can be with intravenous fluids as in Plan C.
successfully carried out at home, by the mother/
caretaker who is advised to: (i) give more fluids than Management of ‘Severe Dehydration’
normal (Table 13.1.4), (ii) continue feeding, and (iii) bring The primary objective is to quickly rehydrate the child
the child back after 2 days, or earlier if he has any of the in a hospital with facilities for IV fluid therapy. Ringer’s
danger signs (thirsty, irritable/restless, fever, high purge lactate is the preferred solution for rehydration given as
rate, repeated vomiting, blood in the stool, eating or 100 ml/kg over 6 hours in infants < 1 year and over 3
drinking poorly, lethargic). hours in older children (Table 13.1.5). If Ringer’s lactate
606 IAP Textbook of Pediatrics

TABLE 13.1.5: Deficit fluid therapy for ‘Severe TABLE 13.1.6: Feeding during diarrhea
Dehydration’ (Plan C)
Stage of hydration Recommended schedule of feeding
Infants (<1 year) Older child (>1 year)
During rehydration phase
Volume of 30 ml/kg body wt. 30 ml/kg body • Breastfed infants • Continue breastfeeding
Ringer’s within first 1 hour, weight within ½ • Non-breastfed infants • Should be preferably given
lactate followed by hour, followed by only ORS till they are
70 ml/kg body 70 ml/kg body rehydrated
weight over next weight over next • Animal milk/food should
5 hours 2½ hours be offered, if rehydration
takes longer than 4 hours
Monitoring Assess for improvement every 1-2 hours: • Severely malnourished • Offer some food as soon as
• If not improving, give IV infusion children possible
more rapidly
• Encourage oral feeding by giving After rehydration phase
ORS 5 ml/kg/hour, along with IV • Breastfed infants • Breastfeed more frequently
fluids, as soon as the child is able to • Non-breastfed infants • Offer undiluted milk as
drink before
Reassess hydration status: • Infants 6–12 months • Give easily digestible energy
• After 6 hours (infants) and 3 hours rich complementary foods in
(Older children) assess hydration addition to breast/animal milk
status and choose appropriate plan • Encourage to eat at least
for hydration (Plan A, B or C) 3 times a day in breastfed
infants and 5 times in non-
breastfed infants
• For older children • Give thick preparation of
is not available, other alternatives like normal saline may
staple food with extra
be used. vegetable oil or animal fats,
rich in potassium (legumes,
Rehydration of Severely Malnourished Children banana), carotene (dark
green leafy vegetables, red
Rehydration of severely malnourished children deserves palm oil, carrot, pumpkin)
special attention owing to certain pathophysiological • Encourage to eat at least
changes in water and electrolyte balance peculiar to 6 times a day
protein energy malnutrition (PEM). Dehydration may
be over or under estimated in the presence of marasmus Zinc Supplementation for Treatment of Diarrhea
or edema. These children are at risk to develop Zinc deficiency is common in children from developing
hypoglycemia and electrolyte imbalance. Rehydration countries because of intake of predominant vegetarian
with ORS solution should be preferred because IV fluids diets and the high content of dietary phytates. Increased
can easily cause overhydration and heart failure. fecal losses during many episodes of diarrhea aggravate
Therefore, it is recommended that severely malnourished pre-existing zinc deficiency. WHO and Indian Academy
children are slowly rehydrated, carefully monitored and of Pediatrics recommends zinc supplementation as an
feeding started early. adjunct to ORS in the treatment of diarrhea. The National
IAP Task Force recommended that all children older than
Feeding During Acute Diarrhea and Dysentery
6 months suffering from diarrhea should receive a
Nutritional management of acute diarrhea and dysentery uniform dose of 20 mg of elemental zinc as soon as
takes optimal advantage of intestinal absorption capacity, diarrhea starts and continued for a total period of 14 days.
which is affected to some extent during diarrhea, by Children aged 2 to 6 months should be advised 10 mg
feeding small, frequent, energy dense food taking in to per day of elemental zinc for a total period of 14 days.
consideration the age, pre-illness feeding pattern and
state of hydration of the child (Table 13.1.6). Feeding is Use of Antimicrobial Agents
continued in children with no dehydration, and resumed Antibiotic therapy should be reserved only for cases of
as early as possible in some dehydration. dysentery and suspected cholera (Table 13.1.7). Every
 Diseases of Gastrointestinal System and Liver 607

TABLE 13.1.7: Antimicrobials used to treat specific causes of diarrhea in children

Causes Drugs of choice Doses

Cholera Doxycycline Single dose of 5 mg/kg (Maximum 200 mg)

or
Furazolidone 5–8 mg/kg/day in 4 divided doses × 3 days
or
Trimethoprim TMP 10 mg/kg and SMS 50 mg/kg in 2 divided
(TMP)-sulfamethoxazole (SMX) doses × 3 days
Dysentery* Trimethoprim TMP 10 mg/kg and SMX 50 mg/kg in 2 divided
(TMP)-sulfamethoxazole (SMX) doses × 5 days
or
Nalidixic acid 60 mg/kg/day in 4 divided doses × 5 days
Amebic dysentery Metronidazole 30 mg/kg/day in 3 divided doses × 5–10 days
Acute giardiasis Metronidazole 15 mg/kg/day in 3 divided doses × 5 days
or
Tinidazole 10–15 mg/kg/day in 3 divided doses × 5 days

In view of wide spread resistance to trimethoprim-sulfamethoxazole (TMP-SMX) and reported resistance to nalidixic acid, Indian
Academy of Pediatrics Task Force recommends ciprofloxacin as first line drug in areas where resistance rates to TMP-SMX
exceeds 30%

case of diarrhea needs to be carefully evaluated for the
presence of blood in the stools which indicates dysentery
and to identify cases of suspected cholera (high purge rate
with severe dehydration in a child above 2 years in an
area where cholera is known to be present). Associated
non-gastrointestinal infections like pneumonia, menin-
gitis, urinary tract infection, etc. should also be carefully
looked for and appropriately treated. In severe malnutri-
tion, the usual signs of infection such as fever are often
absent, yet multiple infections are common in these
children. Therefore, it is assumed that all severely
malnourished children may have an underlying infection
which should be treated with broad spectrum parenteral
antibiotics.
Management of Persistent Diarrhea
Management of persistent diarrhea involves a broad
based therapeutic approach to take care of some of the
problems associated with prolonged episodes which
include: (i) impaired absorption of nutrients, particularly
lactose and other disaccharides; (ii) persistent gut
infection, and (iii) presence of associated non-gastro-
intestinal infections. Broad principles of management of
persistent diarrhea include the following :
• Assess hydration status and manage dehydration as
discussed
• Investigate stool (pH, reducing substances, ova or
cyst, RBC)
• Continue breastfeeding. Offer low lactose diet for non
breastfed babies
• Treat dysentery, if visible blood in stool
• Treat amebiasis or giardiasis, if cysts or trophozoites
of these parasites are detected in the stool.
Hospitalization
Age less than 6 months, dehydration, severe malnutri-
tion, associated infections and severe lactose malabsorp-
tion are indications for hospitalization. Approach to
management of persistent diarrhea in the hospital is
based on following guidelines:
• Investigate and treat for associated infections (ARI,
UTI, Septicemia, etc.)
• Treat persistent infection due to enteropathogens , if
diagnosed
• Dietary manipulations: Offer low lactose diet (kheer,
dalia, phirni, yoghurt, khichri with yoghurt, etc.) if there
is evidence of lactose malabsorption. If there is no
improvement in 2-3 days change over to lactose free
diet (lactose free commercial formula in artificially
fed young infants less than 6 months of age and kichri
with egg in older children). If there is no response to
lactose free diet, change over to disaccharide free
feeding (chicken glucose puree).
608 IAP Textbook of Pediatrics
Nutritional Rehabilitation
Nutritional support to a child following an episode of
acute or persistent diarrhea is of immense importance in
view of the known adverse impact of diarrheal diseases
on the nutrition of a young child. The need for proper
feeding after an episode of diarrhea has even greater
importance particularly because the efforts made by the
mother/caretaker to feed during convalescence are more
rewarding when these children tend to have better
appetite. Therefore, one extra meal at least for 2 weeks
after an episode of acute diarrhea and for at least one
month after persistent diarrhea, stressing the need for
‘catch up growth’, is likely to help in nutritional
rehabilitation of these children.
Diarrhea Training and Training Units and
ORT Corners
Diarrhea case management is very simple and can be
easily carried out at the community level by a health
worker. In fact, the success of the diarrhea case
management lies with the important role played by the
mothers/caretakers who can manage children with
diarrhea at home. However, hospital based referral
facilities are essential for the management of more severe
and complicated cases. Therefore, establishment of
Diarrhea Training and Training Units (DTTUs) in
medical colleges and large referral hospitals will help to:
(i) practice and promote standard case management of
diarrhea (SCMD) on routine basis, (ii) train faculty
members and other health personnel, (iii) train medical
students in SCMD, and (iv) encourage and educate
mothers/caretakers about home management of
diarrhea by providing information and demonstration.
SCMD is an essential component of Integrated Manage-
ment of Neonatal and Childhood Illness (IMNCI)
strategy.
In order to improve case management of diarrhea at
all levels of health care system, treatment areas need to
be identified within the facility to manage patients with
diarrhea. These identified areas serve to shorten the
waiting time of the patients, screen patients with diarrhea
who need to be referred/hospitalized, provide ORS,
practice SCMD on routine basis and educate mothers/
caretakers about home management. Depending upon
the patient load, available space and other facilities, this
identified area may function as a ‘Mini DTTU’ (one room
multi-purpose assessment and treatment area for
mothers and children with all sorts of problems) as in a
District Hospital or ‘ORT Corners’ (extension of
outpatient department with facilities of providing ORS,
rehydration under observation and educating mothers)
as in a Primary Health Centre.
Prevention of Diarrhea
Diarrheal diseases can be prevented to a great extent by
improving infant feeding practices and personal and
domestic hygiene. Some of the interventions which are
feasible and costeffective include: (i) promotion of
exclusive breastfeeding up to 6 months of age;
(ii) improved complementary feeding practices; (iii) use
of clean drinking water and sufficient water for personal
hygiene; (iv) hand washing; (v) use of sanitary toilets;
(vi) safe disposal of the stool of young children and (vii)
measles vaccination.
Rota Virus Vaccines
Recent studies have demonstrated safety and efficacy of
2 new live, oral, attenuated rota virus vaccines (RVV) in
middle and high income countries thereby suggesting a
combined preventive and treatment strategy (vaccine,
low osmolarity ORS and zinc supplementation) to signi-
ficantly reduce child mortality. However, the diversity
of rotavirus strains and high prevalence of mixed
infections are unique features of rota virus epidemiology
in India. Therefore there is a need for uniform,
widespread surveillance for rotaviruses before the
initiation and during the implementation of RVV
immunization programs.
 Diseases of Gastrointestinal System and Liver 609

13.2 Persistent and

Chronic Diarrhea in Children
Gadadhar Sarangi, Jnanindra Nath Behera

PERSISTENT DIARRHEA 2. Moderate form is characterized by several motions/

Definition
Prolongation of acute diarrhea or dysentery for more than
14 days generally with associated weight loss is termed
persistent diarrhea (PD).
When the age of onset is before 3 months, it is often
termed intractable diarrhea of infancy. Persistent
diarrhea with weight loss and extreme malnutrition is
noted as protracted diarrhea or malnourishing diarrhea.
day with marginal weight loss, without dehydration
and non-tolerance to milk and milk products.
3. Severe form of persistent diarrhea is heralded by
dehydration, weight loss and non-tolerance to milk
and cereals. Secondary infection often coexists with
this category (Figs 13.2.1A and B).

Causes of Persistent Diarrhea

The most important causes are:
• Persistent infection with one or more enteric
pathogens.
• Secondary malabsorption of carbohydrates and fat.
• Intestinal parasitosis.
• Infrequently dietary protein allergy/intolerance.

Pathology
Prolonged cell mediated immune form of damage to the
small intestinal mucosa is probably the final common
pathway by which a variety of noxious influences -
nutritional, infective and possibly allergic perpetuate the
syndrome of persistent diarrhea in children in
developing countries. There is impairment and consider-
able delay in the repair of the damaged epithelium of
the gut. Carbohydrate, fat and protein malabsorption
ensues as a result of the damage to the upper small
intestinal mucosal absorptive surface. The loss of brush
border enzymes and direct absorption of macromolecular
foreign proteins result in food intolerance and allergy
(Cow’s milk or wheat protein allergy). Overgrowth of
bacteria in small bowel and altered intestinal flora are
also marked as a consequence.

Clinical Presentation
Three clinical types of persistent diarrhea are recognized:
1. Mild form is characterized by several motions/day Figures 13.2.1A and B: Persistent diarrhea with marasmic
without significant weight loss and dehydration. kwashiorkor, a resultant of infection and malnutrition
610 IAP Textbook of Pediatrics

TABLE 13.2.1: Management guidelines for persistent diarrhea

MILD PERISTENT DIARRHEA

Try low milk formula feeds (Rice, milk, sugar and oil - diet of plan A)
MODERATE PERSISTENT DIARRHEA
Do not try milk. Permit cereal based feeds.
(Rice / wheat / bengal gram/ragi, sugar, oil-diet of plan B)
SEVERE PERSISTENT DIARRHEA
Phase - I Resuscitation<24hours.
Phase - II Partial control of diarrhea, sustained maintenance of vital signs. Electrolyte, metabolic and hemodynamic
balance by partial parenteral nutrition (PPN), intravenous fluids, colloids, parenteral antimicrobials (1-4 days)
Phase - III 5 days onwards (Nutritional rehabilitation)
Monitor weight
Hypo-osmolar, hypoallergenic, home available caloridense nonoffending (lactose free) feeds (plan B) in gradual
increments depending upon tolerance. If it fails - diet of plan - C (chicken / egg white, glucose and oil) along
with PPN to be given. If no response - total parenteral nutrition (TPN)
Criteria for Changing Over from Plan A to B to C
Purge volume and rate >7 stools/day at the end of 7 days
Tendency for dehydration. No weight gain/weight loss despite oral intake of 100 cal /kg/day x 3 days.
Indication for antimicrobials
1. Presence of gross blood in the stool or >10 pus cells/ HPF.
2. Resistant shigella/salmonella in the stool culture.
3. Associated systemic infections.
4. Severe malnutrition.
Antiprotozoals For giardia or Entamoeba histolytica trophozoites in the stool.
Indications for TPN in PD
1. Protracted diarrhea with recurrent dehydration.
2. Intolerance to plan C treatment.
3. Weight loss or no weight gain even after plan C treatment.
Supplemental vitamins and minerals
About twice recommended daily allowance (RDA) of supplemental multivitamins and minerals are to be given
for at least two to four weeks. (Special attention to be given for vit A and zinc).
In severely malnourished infants
Magnesium sulphate IM and oral postassium in recommended doses to be given.
Prevention
Promotion of breastfeeding, active and prompt management of acute dirrhea, and appropriate dietatic
management during diarrhea with judicious administration of drugs will prevent dirrhea of infancy.

Diagnosis CHRONIC DIARRHEA

The emergency risk factors arising out of dehydration, Definition
malnutrition and infection should be assessed. Stool
Chronic diarrhea is defined as diarrhea of at least 2 weeks
examination for culture and reducing sugar with pH will
duration or 3 attacks of diarrhea during the last 3 months,
help in management. The effect of previous treatment
usually with specific conditions like celiac disease,
modalities and diet regimen should be evaluated. The
tropical sprue, cystic fibrosis, congenital, biochemical or
attitude and cooperation of the parents remains the
metabolic disorders.
cornerstone in therapy.

Management Pathophysiology
The management of persistent diarrhea is given in Tables Chronic diarrhea results from brakedown of intraluminal
13.2.1 and 13.2.2. factors responsible for digestion and mucosal factors
 Diseases of Gastrointestinal System and Liver 611

TABLE 13.2.2: Diets for persistent diarrhea

Plan -A (Milk rice diet for persistent Plan -B (Egg based milk free diet for Plan -C (Chicken based diet for
diarrhea) persistent diarrhea) persistent diarrhea)
Ingredient Amount (g) Ingredient Amount (g) Ingredient Amount / Liter
Puffed rice 12.5 Puffed rice 13.5 Chicken 100 g
Milk 40.0 Egg 11.0 Glucose 20 to 40 g
Sugar 2.25 Sugar/Glucose 3.5 Coconut Oil 40 to 50 g
Oil 2.0 Oil 3.5 KCL (15 %) 7.5 ml
Water to make 100.0 Water to make 100.0 NaHCO3 (7.5%) 20 to30 ml

The above will yield following. The above will yield following. Total 1000 ml
Energy density 96 Kcal/100 g Energy density 92.2 Kcal/100 g The above will yield energy 720 Kcal and
Protein 10.0% Protein 9.5% Protein 26 g
Carbohydrate 55.87% Carbohydrate 56.9%
Note: (i) It is prepared by grinding the
Lactose 1.73% Fat 33.29%
precooked boneless chicken stuff in a
Fat 33.9% Amino acid score 1.0%
mixie. Glucose, oil and some water are
Amino acid score 1.0%
Note: Egg white is added to the mixture added to it and the feed is brought to a
Note: Puffed rice is ground and appro- of weighed rice, sugar and oil. Boiled boil. Additional water is added to make a
priate quantities are mixed with sugar and water is added to make a thick gruel final volume of 1 liter. Finally KCL and
oil. Boiled water is then added to make a weighing 100 gm NaHCO3 are added to safe guard against
thick gruel. This feed has a shelf life of spoilage it is stored in a refrigerator.
around 3 hours. (ii) Glucose is initially added in 2%
concentration and then built up to 4% by
increasing 1% every alternate day. To
reduce osmolar load a mixture of Glucose
and sugar may be employed.
(iii) Any vegetable oil may be employed in
place of coconut oil.

responsible for digestion as well as secretion. The
mechanism of diarrhea with the involved intestinal sites
are as follows:
1. Osmotic diarrhea in which the undigested nutrients
get fragmented to short chain fatty acids and increase
the intraluminal osmotic load in colon. It shows good
response to fasting.
2. Secretory diarrhea is one in which due to noxious
agents or exotoxins threre is increase of intracellular
adenosine monophosphate (AMP) or guanosine
monophosphate (GMP) which results in sodium and
fluid secretion.
3. Mutation in apical membrane transport protein like
chlorde bicarbonate exchange transporter which
results in chronic diarrhea from neonatal period with
failure to thrive.
4. Reduction in anatomic surface area of the gut due
to extensive resection in necrotizing enterocolitis,
midgut volvulus or intestinal atresia results in loss of
fluid, electrolyte and nutrients from the gut.
5. Alteration in intestinal motility as in malnutrition
and diabetes mellitus, causes secretory diarrhea.
6. Inflammatory process like regional enteritis and
ulcerative colitis involving a signficant portion of the
gut causes chronic diarrhea.
Causes
The common causes of chronic diarrhea is given in Table
13.2.3.
Evaluation
The evalution should be done in a stepwise manner in
order to avoid confusion in diagnosis (Table 13.2.4).
Treatment
Treatment depennds upon the cause.
Restriction of carbonated drinks or excess fruit juice
will reduce stool frequency in chronic nonspecific
diarrhea. In diarrhea due to secondary carbohydrate
612 IAP Textbook of Pediatrics
TABLE 13.2.3: Common causes of chronic diarrhea
Infancy
• Post-gastroenteritis malabsorption syndrome
• Protein - energy malnutrition
• Cow’s milk / soy protein intolerance
• Secondary / primary disaccharidase deficiencies
• Cystic fibrosis
Childhood
• Excessive consumption of carbonated fluids (Chronic
nonspecific diarrhea)
• Secondary disaccharide deficiency
• Intestinal parasites - Giardia, E. histolytica, Cryptosporidia.
• Post-gastroenteritis malabsorption syndrome
• Celiac disease
• Cystic fibrosis
• Intestinal infection - Enteropathogens, M. tuberculosis
• Tropical sprue
Adolescence
• Irritable bowel syndrome
• Inflammatory bowel disease - Crohn’s disease, ulcerative
colitis
• Giardiasis
• Lactose intolerance
intolerance reduction of lactose or sucrose in the diet will
help. Lactase can be used to aid in digestion of lactose. If
diarrhea persists, elimination of lactose/sucrose
depending upon the situation is indicated.
If stool examination revelas more fat, malabsorption
syndrome remains a distinct possibility. Postgastroente-
ritis malabsorption syndrome needs predigested formula
to which a great proportion responds favorably.
Infants presenting with secretory diarrhea in the 1st
month of life need nutritional support as the likely cause
is congenital defect in transport proteins.
In instances where chronic diarrhea is a minfestation
of a disease, the etiology should be established and
specific treatment instituted.
Nitazoxanide therapy can be instituted where giardia
lamblia or cryptosporidium parvum are suspected or
found.
BIBLIOGRAPHY
1. Bhan MK (Ed). Guidlines for Managment of Diarrhoea
in childen. Task force on diarrhoeal disease.
2. Bhave SY, et al. Common problems faced in diarrhea in
pediatrics. J Gen Med 1993,5:16-24.
TABLE 13.2.4: Evaluation of patients with chronic diarrhea
PHASE- I Clinical history including specific amounts of fluids
ingested per day. Physical examination including
nutritional assessment. Stool exam (pH, reducing
substances, smear for white blood cell count, fat,
ova, and parasites)
Stool culture
Stool for Clostridium difficile toxin
Blood studies (complete blood cell count,
erythrocyte sedimentation rate, electrolytes, blood
urea nitrogen, creatinine)
PHASE- II Sweat chloride
72- hr stool collection for fat determination
Stool electrolytes, osmolality
Stool for phenolphthalein, magnesium sulfate,
phosphate, Breath H2 test
PHASE- III Endoscopic studies
Small bowel biopsy
Sigmoidoscopy or colonoscopy with biopsies
Barium studies.
PHASE- IV Hormonal studies - vasoactive intestinal polypep-
tide, gastrin, secretin, 5-hydroxyindoleacetic
assays.
3. Branski D, Lerner A, Lebenthal E. Chronic diarrhea and
malabsorption. Pediatr Clin North Am 1996;43:307.
4. Donowitz M, Kokke FT, Saidi R. Evaluation of patients
with chronic diarrhea. N Engl J Med 1995;332:725.
5. Fayez K. Ghisshan diarrhea. In: Beharman RE, Kliegman
RM, Jenson HB (Eds): Nelson Textbook of Pediatrics, 18th
edn, 1621-6.
6. Gupte S, Anderson RA. Persistent diarrhea and Chronic
diarrhea, In: Gupte S (Ed): The short text book of
pediatrics, 10th edn, 2004;382-7.
7. IAP Guidelines for management of diarrhea in children,
1994.
8. Kneepkens CM, Hoekstra JH. Chronic nonspecific
diarrhea of childhood: Pathophysiology and Manage-
ment Pediatr Clin North Am 1996;43:375.
9. National child survival and safe motherhood prog-
ramme, integrated clincial skills course for physicians.
Diarrheal disease, module, MCH division, Dept. of
Family Welfare, Ministry of Health and Family Welfare,
Govt. of India, 23-4.
10. Sullivan PB, Marsh MN. Small intestinal mucosal
histology in the syndrome of persistent diarrhoea and
malnutrition: a review. Acta pediatrica 1992;81(s383):
72-7.
11. World Health Organization; Diarrhea managment
training course manual; Guidelines for conducting
clinical training couses at health centers and small
hospital, 1990.
 Diseases of Gastrointestinal System and Liver
13.3 Parenteral Nutrition in Children
Nutritional therapy is now increasingly recognized as
an important component of pediatric intensive care. In a
number of illnesses (both surgical and medical), the
nutritional demands of the child cannot be met
adequately through the enteral route for prolonged
periods. Nutritional support however, is critical not only
to minimize negative nitrogen balance but also to
promote growth and development, which, during early
childhood is at its peak velocity. The concept of providing
all the required nutrients like proteins, carbohydrates,
fats and vitamins via the intravenous route, is called
parenteral nutrition (PN).
The advent of successful parenteral nutrition (PN) has
indeed reversed the prognosis of many such illnesses,
which were hitherto fatal. The popularity of PN is now
fast growing in our country too, despite the constraints
of cost and infrastructure. Although widespread
availability is very much desired, it is important that the
technique is developed with considerable expertise and
used judiciously with full knowledge of it’s indications,
limits, danger and benefits.
INDICATIONS
PN is required in any situation in which the baby should
not be fed, will not feed, or cannot be fed adequately for
prolonged periods. The range of indications of PN has
grown considerably in recent years. It is usually indicated
when oral intake has been or is likely to be inadequate
for more than 5 to 10 days. Other deciding factors are
age, underlying malnutrition, nature of concurrent
therapeutic measures (e.g. ventilation) and the expected
outcome of the disease. In our setup, social and monetary
background also are important considerations. Some
common indications are discussed below.
Surgical Conditions
PN has dramatically changed the outcome in extensive
resections of the small intestine, entero-cutaneous fistulae
and proximal enterostomies (short gut syndrome). At our
center too, the most gratifying results with PN were in
surgical neonates with successful corrections, e.g.
tracheoesophageal fistula, duodenal atresia, omphalo-
613
Anand N Pandit, Ashish R Bavdekar
cele, and Hirschsprung’s disease. The need for PN in such
conditions can be predicted early and therapy can be
started immediately after corrective surgery.
Low Birth Weight Infants (LBWS)
The numerous feeding difficulties, the poor intestinal
function, and the greatly increased requirements make
PN a logical choice in very LBWs. Though routine
supplementation of VLBWs with PN is controversial,
its critical role in conditions such as necrotizing entero-
colitis, and surgical anomalies is undoubted.
Malabsorption Syndrome
One of the commonest indications for PN has been severe
protracted diarrhea in children irrespective of the
etiology: infectious diarrheas, milk protein or lactose
intolerance, or immune deficiency. The recent use of
special enteral diets have definitely reduced the need of
PN in these cases. However, a few with severe small
intestinal mucosal pathology like intractable diarrhea
often require long-term PN as gastrointestinal losses of
fluids, electrolytes and proteins continue even after
stopping all enteral feedings. A judicious combination
of enteral and parenteral nutrition will obviously allow
restoration of normal nutritional status while
maintaining gastrointestinal function.
Non-gastrointestinal Indications
An increasingly common indication of PN today is in
management of children with malignant diseases, as
chemotherapy and radiation may impair intestinal
mucosa, damage circulatory vessels and lymphocytes and
interfere in gastrointestinal motility. PN is also increasingly
used in a host of other conditions such as end stage liver
disease (waiting for liver transplants), renal failure (with
appropriate amino acids) and multiple trauma or extensive
burns (to combat excessive nitrogen losses).
NUTRIENT SOURCES
The basic solutions comprise a protein source, a lipid
source, and a carbohydrate source to be mixed with
614 IAP Textbook of Pediatrics

electrolytes, vitamins and trace metals, all appropriate

to the age, body weight and energy requirements of the
child.

Proteins
These solutions are mixtures of crystalline amino acids
(AA), at least 40 percent of which are essential amino
acids. Neonates and young infants are particularly
sensitive to imbalance in amino acids solutions. The
amino acids of particular concern are methionine,
phenylalanine and glycine, which are not fully metabo-
lized by infants. Caution should, therefore, be exercised
while using AA solutions primarily designed for adults.

Lipids
Parenteral lipid emulsions are available in 10 percent or
20 percent strengths. They are calorie dense, rich in
essential fatty acids and have a protein sparing effect.
Being isotonic and low in osmotic activity, lipids can be
given through peripheral veins for prolonged periods.
Tolerance to lipids is, however, reduced in VLBWs and
should therefore, be introduced cautiously. Figure 13.3.1: Parenteral infusion: assembly

Carbohydrates
TABLE 13.3.1. Guidelines for parenteral nutrition doses
Glucose is the carbohydrate of choice, as it is an energy
Nutrient Starting Advance by Goal Maximum
substitute with ubiquitous utilization by all tissues of the
dose % of total
body. Glucose substitutes such as sorbitol, fructose, and cals
xylitol, have also been tried although they are
Proteins 1 gm/kg/ 1 gm/kg/ 3 gm/kg/ 15
metabolized only in the liver and tend to cause osmotic
day day day
diuresis.
Lipids 1 gm/kg/ 1 gm/kg/ 3 gm/kg/ 30–50
Electrolytes, Vitamins, day day day
Minerals and Trace Elements Carbo- 5–7 mg/ 2–4 mg/ 10–12 mg/ 50–60
Daily estimated requirements of electrolytes, vitamins
hydrates kg/min kg/min kg/min
and minerals (Na, K, Ca, P and Mg) must be added to
PN. Intravenous preparation for phosphorus is not easily
available in India and has to be supplied orally. provide accurate steady flow rates (Fig. 13.3.1).
Progressive build up regimens for neonates, infants and
PN ASSEMBLY AND REGIMENS
older children have been described (Table 13.3.1).
PN is introduced gradually over a period of 2 to Proteins/fat/dextrose should not be decreased until
4 days depending on size and age of child. The calculated enteral feeds exceed 50 ml/kg/day. However, do not
quantities of amino acids, dextrose and electrolytes are exceed total (enteral + parenteral) proteins 3.5 g/kg/day
mixed in the same bottle under laminar air flow. This and fat 5 g/kg/day. Stop PN when three-fourth of daily
mixture and the lipid emulsion are administered by enteral intake has been achieved. Parenteral nutrition is
separate IV sets and the two lines coupled by a Y to be given preferentially by peripheral veins. Central
connector just before entry into the vein. Both the catheters should be used as sparingly as possible because
solutions should be regulated by infusion pumps to of high rate of complications.
 Diseases of Gastrointestinal System and Liver
COMPLICATIONS
The provision of parenteral nutrition is associated with
significant and sometimes life-threatening complications.
These need to be considered before starting PN to any
child. These complications can be classified as:
Technical
Complications of peripheral access are thrombosis,
perforation of vein, with necrosis of tissue, and
thrombophlebitis. Central venous access has potential
for more serious complications, pneumothorax, arterial
hemorrhage, air embolism and cardiac arrhythmias.
Infections
Sepsis associated with PN is life-threatening. Sources are
multiple and include entry site of catheter, connections,
PN fluids, etc. The common organisms are Staph.
epidermidis, Staph. aureus and occasionally gram negative
and fungal sepsis. Therapy is determined by the organism
involved and antibiotic sensitivity. Most catheters can be
preserved using appropriate antibiotics with heparin or
urokinase. Prevention of catheter related sepsis is of
paramount importance and strict asepsis during catheter
insertion, preparation and administration of PN, use of
laminar flow system and training of staff dealing with PN
will go a long way in reduction of sepsis.
Metabolic
i. Complications of protein metabolism: The use of
crystalline amino acids has significantly reduced
the risk of hyperammonemia. Amino acid infusion
may have to be reduced till ammonia levels
normalize. Metabolic acidosis is more frequent
when a large infusion of amino acids is given to
preterm infants.
ii. Complications of carbohydrate metabolism: Hyper-
glycemia is usually a problem in central venous
administration when dextrose is delivered directly
into the central venous flow. Other causes to be
considered are hypokalemia, sepsis are steroid use.
Hyperglycemia could lead to glycosuria, osmotic
diuresis and dehydration.
iii. Complications of fat metabolism: Hypertrigly-
ceridemia and high free fatty acid levels are
associated with PN. These can be prevented by
either using mixed solution of MCT and LCT or
regular monitoring of serum triglyceride levels.
615
iv. Complications related to electrolytes and minerals:
Hyponatremia, hypo/hyperkalemia hypocalcemia,
hypomagnesemia and hypophosphatemia are
commonly associated with PN. These are often
iatrogenic and preventable by monitoring. Trace
element and vitamin deficiencies are common on
long-term PN. They need to be supplemented
especially in LBW infants.
Hepatobiliary Complications
These include steatosis, cholestasis, fibrosis, cirrhosis or
cholelithiasis. Abnormal LFT is seen in quite a few
children on PN for more than two weeks. In most
patients, these liver enzymes improve with initiation of
partial enteral feeds. Fatty infiltration of the liver occur
due to excess carbohydrate calories or inappropriate non-
protein calorie nitrogen ratio. This is readily reversible
by reducing the carbohydrate infusion.
The fear of PN related complications has always been
a deterrent in the institution of this potentially life-saving
technique. However, the complication rates have shown
a marked decline with experience and expertise the
world over. Specially designed, locally manufactured
intravenous sets, use of a laminar flow workstation for
compounding and other such adaptations have
contributed further.
MONITORING
Meticulous monitoring is necessary not only to detect
complications, but to document clinical benefit. Most
septic and metabolic complications can be prevented or
detected before they cause serious consequences, if the
biochemical monitoring protocol is followed rigidly.
Monitoring should be more frequent in the initial stages
of PN and perhaps, less frequent once PN is well
established. The monitoring protocol at our hospital is
given in Table 13.3.2. It is mandatory to develop micro-
method systems for biochemical monitoring in newborns
and young infants. In absence of these, blood sampling
volumes should be carefully recorded and replenished
when indicated. Adjustments in daily electrolytes,
nutrients and fluid orders are based on biochemical
monitoring.
COST ANALYSES
Cost saving may be achieved by (i) reducing wastage by
sharing solutions and preventing over prescription; (ii)
616 IAP Textbook of Pediatrics

TABLE 13.3.2. Suggested monitoring protocol for A reduction in cost should not be attempted by
parenteral nutrition (i) repeated use of solutions; (ii) compromise on bio-
chemical monitoring; (iii) compromise on disposables;
Serum electrolytes 3 times/week initially, then weekly
(iv) compromise on infusion pumps; and (iv) substituting
Serum urea nitrogen 3 times/week initially, then weekly
hypertonic glucose for lipids.
Calcium, magnesium, 3 times/week initially, then
phosphorus weekly
BIBLIOGRAPHY
Glucose 2 times/day
Serum proteins Weekly 1. Arnold WC. Parenteral nutrition, and fluid and electro-
lyte therapy. Pediatr Clin North Am 1990;37:459–61.
Liver function tests Weekly
2. Arthur CD. Fundamentals of Parenteral Nutrition, 2nd
Hematocrit Weekly edn. London, Smith and Smith, 1985.
Urine glucose Daily 3. Ball PA, Booth IW, Puntis JWL. Pediatric Parenteral
Serum triglycerides 4 hours after a dose increase of Nutrition. Bourne End. Kabi Vitrium 1989;16–19.
lipids initially, then weekly 4. Bhave SA, Bavdekar AR. Pediatric parenteral nutrition
in India. Indian J Pediatr 1999;66(1 Suppl):S141–9.
5. Cochran EB, Phelps SI, Helms RA. Parenteral nutrition
decreasing complications by using peripheral lines, in pediatric patients. Clin Pharmacy 1988;7:351–65.
preventing metabolic complications, and strict asepsis 6. Zlotkin SHM, Stallings VA, Pencharz MB. Total
and (iii) indigenization of equipment. parenteral nutrition in children. PCNA 1985;32:381–400.

13.4 Parasitic Bowel Diseases

BD Gupta

Parasitic bowel diseases. are group of infectious diseases ETIOPATHOGENESIS

due to protozoa and helminths, and are a major cause of
morbidity in infants and children in many parts of the
world.
Parasitic bowel diseases may be classified according
to their etiological agents as under:
I. Protozoal diseases: Entameba histolyica, Giardia
lamblia, Balantidium coli, Cryptosporidium parvum.
Blastocystis, Isospora belli, Cyclospora cayetanensis and
Microsporidia.
II. Helminthic diseases:
A. Nematodes: Ascaris lumbricoides, Enterobius
verrmicularis, Hookworms, i.e. Ankylostoma
duodenale and Necator americanus, Trichinella spiral
is, and Trichuris trichura.
B. Trematodes: Fasciolopsis buski, Nanophyetus
salmincola, and Heterophyes heterophyes.
C. Cestodes: Taenia solium, Taenia saginata,
Diphyllobothrium laturn, Hymenolepis nana, and
Echinococcus granulosus.
Parasitic bowel diseases are endemic in areas of world
with poor sanitation and low socioeconomic standards.
Two distinct modes of transmission are known, namely
faeco-oral route and cutaneous route.
1. Protozoa like E. histolytica, G. lamblia and B. coli infect
humans by ingestion of cysts while nematodes like
A lumbricoides, T. trichura, E. vermicularis and
cestodes like T. saginata, T. solium and D. latum spread
by ingestion of contaminated food and water with
eggs of respective parasites.
2. Hookworms like A. duodenale and N. americanus alter
the human body through skin penetration by their
larvae. These larvae undergo extraintestinal
migration through the venous circulation and lungs
before they are swallowed to reach intestine.
Various parasites localize themselves at various sites
in small as well as large intestine as per their suitable
environment, e.g. E. histolytica dwell in colon, G. lamblia
colonize in the lumen of duodenum and proximal
 Diseases of Gastrointestinal System and Liver 617

jejunum, B. coli infests the large intestine, A. lumbricoides
in small intestine, T. trichura in caecum and ascending
colon, and E. vermicularis typically inhabits caecum,
appendix and adjacent areas of ileum and ascending
colon.
Various parasites cause symptoms due to invasion
(E. histolytica), obstruction (A. lumbricoides), reduced
absorptive surface (G.lamblia) and blood sucking
(Hookworms).
CLINICAL FEATURES
Parasitic bowel disease is associated with wide variety
of clinical manifestations ranging from asymptomatic
carrier stage to various intestinal and extraintestinal
manifestations. The clinical features depend largely on
the parasite, site of involvement, mechanical factors and
interference with host’s nutrition.
General Symptoms
Most of parasites present with diarrhea which can be
acute, chronic or recurrent; bloody or nonbloody;
associated or not associated with tenesmus, abdominal
cramps, bloating, flatulence etc. Other symptoms include
nausea, vomiting, anorexia, weight loss, fever, abdo-
minal distension, malaise, myalgia, headache, etc.
Various other clinical features caused by different
parasites are summarized in Table 13.4.1.
LABORATORY DIAGNOSIS
Parasitic bowel diseases can be diagnosed by examination
of stool samples by direct microscopy. Repeated fresh
samples may be required to reach the diagnosis of
clinically suspected organisms. The stool examination may
be supported by blood examination for evidence of
eosinophilia and various serological tests specifically
designed for the organism under consideration. Stool
examination along with endoscopically obtained smears
and tissue biopsy helps a lot in diagnosis of parasites.
Ideally fresh stools should be examined within 30 minutes
of passage for evidence of trophozoites/cysts in case of E.
histolytica or G. lamblia. Stool samples preserved in
polyvinyl alcohol (PVA) helps in diagnosis of these
organisms. Serological tests like Indirect hemagglutination
are available for E. histolytica. Enterotest on duodenal fluid
for giardiasis is another alternative.
Stool examination and demonstration of oocysts helps
in diagnosis of spore forming intestinal protozoa like
Cryptosporidium, Isospora, Cyclospora etc. Other tests for
parasites are enzyme immunoassay, indirect immuno-
fluorescence and PCR.

TABLE 13.4.1: Clinical manifestations

Clinical manifestation Parasitic bowel disease(s)

Nutritional Deficiency Ascariasis, giardiasis, and infection by intestinal flukes
(Vitamin A deficiency)

Anemia
Iron deficiency Hookworm disease
B12 or folic acid deficiency D. latum (Diphyllobothriasis), Trichuriasis

Malabsorption Syndrome Giardiasis, ascariasis, hookworm diseases and infection by intestinal flukes
Weight loss Giardiasis, hookworm disease, diphyllobothriasis and spore forming protozoa like
cryptosporidiasis, isosporiasis and cyclosporiasis

Intestinal obstruction Ascariasis, taeniasis

Rectal prolapse Giardiasis, trichuriasis

Extraintestinal involvement:
Liver Amebiasis, intestinal flukes
Muscles Trichinosis, flukes, spore forming protozoa, e.g microsporidia
Skin Cutaneous larva migrans-hookworm, Strongyloides stercoralis
Brain Amebiasis, trichinosis, microsporidiasis, taeniasis-neurocysticercosis
Lungs Amebiasis, ascariasis, hookworm disease Strongyloides stercoralis

Immunodeficiency states Associated parasites-Cryptosporidium parvum, Isospora belli, Cyclospora

cayetaeniasis, Microsporidium (AIDS), Giardiasis, Amebiasis
618 IAP Textbook of Pediatrics

TABLE 13.4.2: Common parasitic infections and their treatment

Etiological agent Major clinical features Treatment Alternative Drug (s)

Entamoeba Diarrhea Metronidazole 30-50 mg/kg/day orally Omidazole 30-50 mg/kg/day orally
histolytica Dysentry in 3 doses for 10 days in 2 dose
Liver abscess Diloxanide furoate 20 mg/kg/day Nitazoxanide 7.5 mg/kg twice daily
orally in 3 doses for 10 days for 3 days
Dehydroemetine 1 mg/kg/day sc or im daily
for 7-10 days
Giardia lamblia Diarrhea Metronidazole 5-10 mg/kg tid orally for Quinacrine 2 mg/kg tid orally for
Malabsorption 5 days 5 days
Furazolidone 6 mg/kg/day q 6 hrs. Albendazole 400 mg OD for 5 days
for 10 days
Nitazoxanide 7.5 mg/kg twice daily for 3 days Tinidazole 50 mg/kg once
Balantidium coli Diarrhea/dysentery, Metronidazole 45 mg/kg/day q 8 hrs. Tetracycline 40 mg/kg q 6 hrs.
pain abdomen orally for 5 days for 10 days (>=8 yrs)
Iodoquinol 40 mg/kg/day q 8hrs
PO (10 days)
Crytosporidium Severe diarrhea with Nitazoxanide 100 mg bid orally for Paromomycin 1 gm bid orally +
malabsorption in 3 days azithromycin 600 mg/day orally
AIDS patients for 4 week followed by paromomycin
1 gm bid oral 8 weeks
Isospora belli As above Trimethoprim 5 mg/kg/dose +
sulphamethoxazole 25 mg/kg/
dose 8 hourly for 10 days
then bid for 3 weeks
Ciprofloxacin or pyrimethamine +/-
folinic acid in sulpha-intolerant patients
Cyclospora As above Trimethoprim 5 mg/kg/dose + Ciprofloxacin
sulphamethoxazole 25 mg/
kg/dose bid orally for 7 days
Microsporidium As above Albendazole 400 mg bid for Nitazoxanide 7.5 mg/kg
3 weeks bid for 3 days
Atovaquone
Ascaris lumbricoides Abdonimal pain, cough, Albendazole 400 mg orally Piperazine citrate 150
nausea once Mebendazole 100 mg mg/kg orally initially
bid orally for 3 days or 500 followed by 65 mg/kg/
mg once Pyrantel pamoate dose 12 hourly for 6 doses
11 mg/kg once
Ivermectin 200 mcg/kg
day od orally for 1-2 days
Strongyloides Loeffler like syndrome Ivermectin 200 mcg/kg/day Thiabendazole 50 mg/kg
stercoralis abdominal pain, once orally for 1-2 days bid orally for 2 days
diarrhea malabsorption Albendazole 400 mg
once for 2 days
Enterobius Pruritus ani, Pyrantel pamoate 11 mg/kg Ivermectin 200 mcg/kg/day
vermicularis sleeplessness once Mebendazole 100 mg bid orally for 1-2 days
PO for 3 days Albendazole
400 mg/kg once (Therapy to
be repeated after 2 weeks)
Trichuris trichiura Chronic dysentery Mebendazole 100 mg bid Albendazole 400 mg once
Rectal prolapse, anemia orally for 3 days or 500 mg
once

Contd...
 Diseases of Gastrointestinal System and Liver 619

Contd...

Etiological agent Major clinical features Treatment Alternative Drug (s)

Hookworm infection Abdominal pain, loss of Albendazole 400 mg/day Pyrantel pamoate 11 mg/kg/day
(A.duodenale, appetite, diarrhea, orally once Mebendazole once for 3 days
N.americanus) anemia, hypoalbuminemia 100 mg bid for 3 days

Hymenolepis nana Abdonimal pain, Praziquantel 25 mg/kg orally once Albendazole 400 mg/day for 3 days
discomfort (if available)
Nitazoxanide 7.5 mg/kg bid orally for 3 days

Trichinella spiralis Diarrhea, fever, Mebendazole 200-400 mg tid orally for Albendazole 400 mg bid orally for
periorbital edema, 3 days then 400-500 mg tid for 10 days 8-14 days
myalgia
Diphyllobothrium Megaloblastic anemia, Praziquantel 5-10 mg/kg orally once Niclosamde 50 mg/kg once
latum leukopenia,
thrombocytopenia

Demonstration of eggs of helminths in stool is the BIBLIOGRAPHY

mainstay of diagnosis of most of the parasites. For
ascariasis, Kato’s thick smear examination of stool is easy
and sensitive method. Fertilized eggs signify infection
with both male and female worms while unfertilized
eggs show infection with female worm only. Enterobiasis
can be diagnosed by examining cellophane tape imprint
from perianal area. For trichinosis serologic tests like
Bentonite flocculation test, muscle biopsy levels of muscle
enzymes like creatine kinase and LDH help in diagnosis.
PREVENTION AND CONTROL
Parasitic bowel diseases essentially are much more
prevalent in areas of poor sanitation and environmental
conditions. Hence, these diseases can be prevented by
following measures viz. safe disposal of human excreta”
safe water supply, proper food hygiene, personal and
community hygiene, health education, and early
diagnosis and treatment of symptomatic and asympto-
matic cases.
Treatment
Treatment for various parasitic diseases is outlined in
Table 13.4.2.
1. Chen X M, Keithly JS, Paya CV, et al. Cryptosporidiasis.
N Engl J Med 2002;346:1723-31.
2. Chandler AC. Indian J Med Res 1927;15:695-743.
3. Chowdhary AB, Sehad GA, Am J Trop Med and hyg
1972; 21: 300-301.
4. Conteas CN, Berlin OG, Ash LR, Pruthi JS. Therapy for
human gastrointestinal microsporidiasis. Am J Trop Med
Hyg 2000;63:121-7.
5. Franzen C, Muller A. Cryptosporidia and micro-
sporidia—waterborne diseases in the immunocompro-
mised host. Diagn Microbiol Infect Dis 1999; 34:245-62.
6. Gardener TB, Hill DR. Treatment of giardiasis. J Clin
Microbiol 1997;35:1526-29.
7. Kliegman RM, BehrnIan RE, Jenson HB and Stanton BF
(Eds). lnfectious diseases. In: Nelson Textbook of
Pediatrics. 18th atition. New Delhi, Saunders Elsevier
Indian Edition 2008;1448-1519.
8. Park K. Intestinal infections. In: Park’s text book of
Peventive and Social Medicine. 17th edition. Ed Park K.
Jabalpur, Banarsidas Bhanot 2002;166-70.
9. Park K. Intestinal infections. In: Park’s textbook of
Peventive and Social Medicine. 19th edition. Ed Park K.
Jabalpur, Banarsidas Bhanot 2007;167-205.
10. Patel SS, Kazura JW. Helminthic diseases. In: Nelson Text
book of Pediatrics. 17 th edition. Eds Behrman RE,
Kliegman RM, Jenson HB. Saunders, Philadelphia 2004;
1155-73.
11. Tripathi KD. Antiamoebic and other antiprotozoal drugs
and anthelmintic drugs. In: Essentials of medical
pharmacology. 6th edition. Ed Tripathi KD. New Delhi,
Jaypee Brothers Medical Publishers (P) Ltd 2008;797-816.
12. WHO. Tech Rep Ser 1969:421.
620 IAP Textbook of Pediatrics

13.5 Vomiting in Infants and Children

S Nagabushana

Vomiting is a coordinated motor response of the Flow Chart 13.5.1: Mechanism of vomiting in children
gastrointestinal and respiratory tracts that results in
increased salivation followed by forceful expulsion of the
stomach contents. It occurs in three phases, i.e (a)
nausea,(b) retching and (c) emesis. In very young
children and in those with raised intracranial pressure,
vomiting is induced without nausea.
Regurgitation (Possetting), on the other hand is a
nonforceful, effortless expulsion of gastric contents
through the mouth, It is common in neonates and infants,
is often a developmental process and does not need
therapy; the symptoms resolve with age and the child
thrives well. In contrast, Gastroesophageal reflux disease
(GERD) is abnormal as in addition to vomiting it is
usually associated with complications like aspiration,
pneumonia and esophagitis and the child may not thrive
well. It therefore needs early recognition and prompt
therapy.

Pathophysiology
The causative mechanisms can be depicted as in the Flow
Chart 13.5.1.
The common causes of vomiting in different age
groups are as illustrated in Table 13.5.1
Approach to Management
Enquire about the duration, frequency, presence of blood
or bile in the vomitus. Ask about associated abdominal
pain, recent changes in feeding pattern, changes in
urinary color, drug consumption and presence of
associated fever or sensorial alteration. Look out for
symptoms and signs attributable to the respiratory,
gastrointestinal, urinary and central nervous system in
that order. Assess the child for signs of dehydration.
Remember that parental perception of how sick their
child is in between episodes of vomiting helps us to
determine the seriousness of the illness and the measures
to be adopted. In neonates and infants with acute
vomiting the possibility of serious infections like sepsis,
meningitis or urinary tract infection needs to be
considered and ruled out, i.e. the Cause of vomiting may
be outside the gastrointestinal tract. Further, vomiting
due to benign non-organic causes does not lead to
significant dehydration or weight loss.
The clinical features that indicate common organic
causes of vomiting are given in Table 13.5.2.
Investigations
The history of the child and the clinical features on
presentation most often guide the diagnosis.
a. Urine for evidence of infection (pus cells, granular
casts, bacteria, Gram stain, culture and sensitivity),
proteinuria and abnormal metabolites.
b. Blood for evidence of systemic infection (leucocytosis,
toxic granules, band forms, C reactive protein,
appropriate cultures, etc.)
c. Liver function tests
d. Renal function tests, electrolyte studies and metabolic
screening tests (e.g. Lactate, Organic acids, Ammonia,
etc.)
e. Stool for blood, pus cells, evidence of parasitic
infestations
f. Radiological studies: Plain and Contrast X-rays of
abdomen, ultrasound or endoscopy.
g. Lumbar puncture and CSF analysis in children with
clinically suspected intracranial infection.
h. CT or MRI Scan of skull or abdomen or sinuses as
and when indicated.
 Diseases of Gastrointestinal System and Liver 621

TABLE 13.5.1: Common causes of vomiting by age of Management

presentation
The principles of management include recognition and
Newborn Infant and child treatment of the primary causes of vomiting in addition
Infections Sepsis Gastroenteritis to symptomatic therapy and correction of dehydration.
Meningitis Meningitis Steps of symptomatic treatment include stomach wash
Respiratory in neonates and infants, with holding oral fluids for a
infections
few hours and gradually restarting in sips. If a child
Anatomic Atresias and webs Pyloric stenosis
has persistent vomiting, dehydrated or electrolyte
Duplications Intussusception
Malrotation/ imbalances, IV fluids are necessary. The preferred fluid
volvulus is normal saline or 5 percent dextrose saline.
Gastrointestinal Overfeeding/ Gastroesophageal Persistent vomiting due to simple gastroenteritis is
Possetting reflux relieved by a single dose of antiemetic. If vomiting is not
Gastroesophageal Gastritis relieved, look out for other causes like intestinal
reflux Hepatitis obstruction, raised ICT, infection, etc. It is always prudent
Gastritis–swallowed Appendicitis to remember that organic causes of vomiting do not
meconium
satisfactorily respond despite adequate doses of
Renal Urinary tract Urinary tract
antimetics. In clinical practice, hasty use of an antiemetic
infection infection
without definite diagnosis of the cause has to be avoided.
Neurologic Birth trauma Subdural
Antiemetics like Metaclopromide or Domperidone
hematoma
Increased intra- hasten stomach emptying and are useful if used
cranial tension judiciously. Ondonsetron, a serotonin antagonist is
Migraine effective in the treatment of chemotherapy induced and
Metabolic Uremia refreactony causes of vomiting.
Endocrine Congenital
Cyclic vomiting is a syndrome of recurrent vomiting
adrenal
hyperplasia (about 9 episodes per month) with onset in children aged
Diabetes mellitus 3 to 5 years. It occurs periodically, lasts 3 to 4 days, with
Acute intermittent four or more episodes per hour it is usually due to a
porphyria combination of psychogenic factors (excitement and
Others Cyclical vomiting stress) and a liability to Ketone formation. Abdominal
Toxin ingestion migraine may present as idiopathic cyclic vomiting.
Treatment consistes of rest, IV rehydration with dextrose
saline administration and Ondonsetron. Preventive
TABLE 13.5.2: Features indicating organic causes
treatment with drugs like Amitryptaline or Cypro-
heptidine is possible.
I. Persistent forceful vomiting
Recurrent vomiting (> 3 episodes in 3 months) needs
II. Abdominal distension
prompt investigations to identify the cause.
III. Palpable mass/abdomen or visible peristalsis
IV. Failure to gain weight/loss of weight
BIBLIOGRAPHY
V. Altered sensorium/ failure to accept/demand feeds
VI. Bulging fontanelle/persistent headache 1. Approach to a child with acute, chronic or cyclic
vomiting. Rudolph AM, Hoffmann JIE, Rodolph CD
VII. Sudden onset in a well child/vomiting in an ill child (Eds): Rudolph’’s Pediatrics, 20th end. 1991>Prentice hall
with fever. International Inc. USA, 2;303:1523-24.
VIII. Persistent irritability in an infant with vomiting 2. Behrman, Kliegmenn, Jensonand Stanton (Eds): Nelson
IX. Persistent copious bilious vomiting Textbook of pediatrics 18th edn. Elsevier Saunder’s
2004;1199-1200.
622 IAP Textbook of Pediatrics
3. Flake ZA, Sca1ley RD, Bailey AG. Practical selection of
antiemetics. Am Fam Physician 2004;69:1169-74,1176.
4. Illingworth RS (Ed). Common symptoms of disease in
children. Oxford ‘University press (9th edn) 69-82.
5. John W Graef (Ed). Manual of Pediatric therapeutics.4th
edn. Little Brown company: Boston l988;33-34.
13.6 Gastroesophageal Reflux in
Infants and Children
The term gastroesophageal reflux (GER) implies a
functional or physiologic process in a healthy infant with
no underlying systemic abnormalities. GER is a common
condition involving regurgitation, or “spitting up,”
which is the passive return of gastric contents retrograde
into the esophagus.
The prevalence of GER peaks between 1 to 4 months
of age and usually resolves by 6 to 12 months of age. No
gender predilection or definite peak age of onset beyond
infancy has been established. Regurgitation has been
reported in 40 to 65% of healthy infants, but decreases to
1 % by one year of age.
Gastroesophageal reflux disease (GERD) is a pathologic
process in infants manifested by poor weight gain, signs
of esophagitis, persistent respiratory symptoms, and
changes in neurobehavior. Abnormal signs and symp-
toms that warrant a diagnosis of GERD occur in
approximately 1 in 300 infants. A higher prevalence of
GERD is present in children who have the following: a
history of esophageal atresia with repair; neurologic
impairment and delay; hiatal hernia; bronchopulmonary
dysplasia; asthma; and chronic cough. GERD is also
associated with pulmonary aspiration, chronic bronchitis,
and bronchiectasis. All infants with GERD, therefore, do
not visibly regurgitate, and the majority of infants who
regurgitate do not have GERD.
Clinical Manifestations
Infants with GER regurgitate without any secondary
signs or symptoms of inadequate growth, esophagitis,
or respiratory disease. Infants with GER are thriving and
represent the majority of infants who present to the
physician with this condition.
6. Judith M Sondheimer (Ed). Current Pediatric diagnosis
and treatment. 16th edn 1919;614-15.
7. MK Bhan, et al. Consensus statement of IAP taskforce:
Report on management of Acute Diarrhea. Indian
Pediatrics 2004;41:335-48.
Neeraj Jain, Vibha Jain, Deepak Seth
Patients with GERD may manifest persistent
regurgitation with secondary poor weight gain and
failure to thrive. Failure to thrive occurs when caloric
intake is less than ongoing losses. Infants may manifest
signs of esophagitis, including persistent irritability, pain,
feeding problems, and iron deficiency anemia. A subset
of infants may demonstrate significant reflux by
esophageal pH monitoring but will not have symptoms
of regurgitation, known as “silent” GERD.
A variety of respiratory symptoms occur in infants.
Apnea and cyanotic episodes may arise secondary to
upper airway stimulation by pharyngeal regurgitation.
Instead of a pure obstructive apnea pattern, a mixed
pattern of both obstructive and central types generally
predominates. Symptoms include belching, refusal to eat,
abdominal pain, vomiting, hiccups, gagging, choking,
frequent cough, coughing fits at night, wheezing and
frequent upper respiratory infections. However, each
child may experience symptoms differently.
After infancy, more classic symptoms of esophagitis
predominate, including lower chest pain, heartburn
(pyrosis), odynophagia, dysphagia, and signs of anemia
and esophageal obstruction from stricture formation.
With the exception of apnea, older children experience
respiratory symptoms similar to infants. Complications
of reflux esophagitis may be seen, including signs of
peptic stricture and Barrett’s esophagus, which is the
progressive replacement of distal eroded squamous
mucosa with metaplastic gastric epithelium. Barrett’s
esophagus may increase the risk of esophageal adeno-
carcinoma in adulthood, but the risk is much lower in
children.
 Diseases of Gastrointestinal System and Liver 623

Differential Diagnosis of GERD Management

Other gastrointestinal and systemic disorders must first Conservative
be excluded before considering GERD as the main cause 1. Thickened feedings and positional changes in infants,
of an infant’s or child’s symptoms of silent or visible and dietary modification in children.
regurgitation or vomiting (Table 13.6.1). 2. Avoidance of foods and behaviors that decrease lower
esophageal sphincter tone: This includes excessive
Diagnostic Evaluation intake of caffeinated, acidic, and alcoholic beverages
Diagnostic procedures for evaluation ofGERD include in children and cigarette smoking in adolescents.
chest x-ray, barium swallow with fluoroscopy of the 3. Completely upright and prone positioning is
upper gastrointestinal tract, radio-nuclear (technetium) beneficial in infants with GERD.
scan, endoscopy, esophageal manometry, esophageal pH 4. Weight reduction.
studies and gastric emptying studies. In most cases of 5. H2receptor antagonist: Ranitidine 1-2 mg/kg/dose.
GER, no invasive diagnostic studies are required. 6. Prokinetic agents: Metoclopramide 0.1 mg/kg/dose or
lisapride 0.2mg/kg/dose. Cisapride is not used
because of bradycardia and nodal dysrhythmias
TABLE 13.6.1: Differential diagnosis of GERD associated with its use.
7. Proton pump inhibitors: Omeprazole 1.0-3.3 mg/kg/
Gastrointestinal tract
day; lansoprazole 0.8-4 mg/kg/day; rabeprazole 10-
Pyloric stenosis
Malrotation 20 mg/kg/day and pantoprazole 20- 40 mg /kg/day.
Cow’s milk allergy
Peptic ulcer disease Surgery
Hepatitis
Viral gastroenteritis In severe cases of reflux, a surgical procedure called
Urinary tract fundoplication may be performed. This procedure is
Infection usually done laparoscopically.
Obstruction
Central nervous system BIBLIOGRAPHY
Hydrocephalus
1. Glassman M, George D, Grill B. Gastroesophageal reflux
Meningitis
in children: clinical manifestation, diagnosis, and
Metabolic disorders
therapy. Gastroenterol Clin North Am 1995;24:71-98.
Renal tubular acidosis
2. Hill SL, Evangelista JK, Pizzi AM, Mobassaleh M, Fulton
Urea cycle defects
DR, Berul CI. Proarrhythmia associated with cisapride
Hypocalcemia
in children. Pediatrics 1998;101:1053-6.
Drugs/toxins
3. Khoshoo V, Edell D, Clarke R. Effect of cisapride on the
Respiratory disorders
QT interval in infants with gastroesophageal reflux.
Functional rumination
Pediatrics 2000;105:E24.
624 IAP Textbook of Pediatrics
13.7 Gastrointestinal Bleeding in
Infants and Children
UPPER GASTROINTESTINAL BLEEDING
Upper Bleeding denotes bleeding from any site in the
gastrointestinal tract proximal to the ligament of Treitz.
It can present as hematemesis (coffee ground vomitus)
and/or Malena (tarry black stools). Massive upper
gastrointestinal bleeds can present as hematochezia
(frank bleeding per rectum), however occult bleeding is
a rare presentation of upper gastrointestinal bleeding.
Etiology
The common of upper gastrointestinal bleeding are given
in Table 13.7.1.
Clinical Features
Acute gastrointestinal bleed leads to hypovolemia and
shock whereas, chronic gastrointestinal bleed usually
produces severe anemia. Hematemesis (or acute
hematochezia or melena with positive NG aspirate for
blood) may result from swallowed blood, upper GI
mucosal lesions, variceal bleeding, or rarely, hemobilia
(hemorrhage into the biliary tract). Swallowed blood may
be seen in conjunction with epistaxis, sore throat, or
breast feeding or may follow dental work or
TABLE 13.7.1: Common causes of upper
gastrointestinal bleeding
Newborn:
• Swallowed blood
• Hemorrhagic disease of the new born
• Septicemia and DIC
• Reflux esophagitis
• Reactive gastritis
• Stress ulcers
• Necrotizing Enterocolitis
Infants and Children
• Variceal bleed—esophageal, gastric varices
• Drug induced—erosive gastritis
• Viral hemorrhagic fever
• Reflux esophagitis with hiatus hernia
• Mallory Weiss esophageal tear
• Gastric, Duodenal ulcers.
Saroj Mehta, RC Mathur
tonsillectomy. Mucosal lesions include esophagitis,
Mallory Weiss tear, reactive gastritis, stress ulcer and
peptic ulcer. A history of chronic heart burn, chest pain,
vomiting, oral regurgitation, or dysphagia suggests reflux
esophagitis or ulcer disease.
A Mallory Weiss tear is an acute mucosal laceration
of gastric cardia or gastroesophageal junction. The classic
presentation is hematemesis following repeated forceful
retching, vomiting, or coughing. Abdominal pain is
uncommon and if present more likely to be musculo-
skeletal in origin due to forceful emesis. Such vomiting
episodes usually are linked to a concurrent viral illness.
Reactive gastritis may be diffuse or localized in the
stomach. Significant hemorrhage may be seen with
diffuse hemorrhagic stress gastritis associated with
trauma, surgery, burns or severe medical problems
requiring hospitalization in an intensive care unit.
Associated coagulopathy is not uncommon. Localized
reactive gastritis is more common and may be associated
with non-steroidal anti-inflammatory drugs (NSAID
gastropathy), ingestion of caustic substances, Helico-
bacter pylori infection, viral infection, Crohns disease,
vasculitis (Henoch Schonlein purpura) radiation
exposure, bile reflux, bezoars, hiatus hernia, prolapse of
the gastroesophagial junction, or congestive gastropathy
(associated with portal hypertension). Reactive gastritis
may coexist with duodenal erosive lesions. Bleeding from
localized gastritis usually manifests as coffee ground
emesis. Peptic ulcer is rare in children. A more common
cause of gastric mucosal erosion is due to stress and
trauma from tips of NG tubes.
Upper gastrointestinal bleeding may be the initial
presentation of esophageal varices. Variceal bleeding
caused by portal hypertension should be considered in
any child who has hepatomegaly, spenomegaly, ascites,
and jaundice.
Clinical Examination
Vital signs should be evaluated first in every child. Most
previously well children who present with hematemesis
 Diseases of Gastrointestinal System and Liver
are hemodynamicaly stable and describe hematemesis
as a coffee ground like or bright red tinged vomitus,
indicating a low rate of bleeding. Bleeding from mucosal
lesions usually stops spontaneously. The initial labo-
ratory evaluation should be a hematocrit, MCV, platelet
count, coagulation profile, liver function tests, blood
grouping.
Upper GI endoscopy is the test of choice for
evaluating upper GI bleeds. The goal is to identify the
site of bleeding, diagnose the specific cause and initiate
therapeutic interventions when indicated. Push enteros-
copy has shown to have a higher diagnostic yield as the
scope goes beyond jejunum. Wireless capsule endoscopy
is also useful for diagnosis.
Epigastric pain and tenderness are seen in gastric
mucosal lesions.
Management of a Massive Upper
Gastrointestinal Bleed
1. Vital signs to be assessed and look for signs of
hypovolemia (Tachycardia, hypotension/postural
hypotension). There is intravascular and extra-
vascular volume reduction resulting in shock.
Resuscitation should be done with intravenous
normal saline/ringer lactate or blood transfusions.
2. Nasogastric intubation, aspiration for diagnostic
purposes.
3. Parenteral somatostatin or its analogue octreotide to
arrest the bleed.
4. Upper GI endoscopy (within 12 hr) for diagnosis and
treatment.
5. Further management depends on the cause and is
discussed under three categories:
a. Variceal bleed
b. Reflux esophagitis, hiatus hernia, Mallory Weiss
tear
c. Acid peptic disease, stress ulcers, erosive gastritis.
Variceal Bleed
i. Emergency endoscopic sclerotherapy(EST) or band
ligation.
ii. Parentral somatostatin or its analogue for three more
days to prevent early rebleeds. If early rebleeds
persist IV vasopressin or esophageal balloon
tamponade with Sengstaken Blackmore or Linton
tubes.
iii. Management of late rebleeds (bleeding after 2 weeks
of therapy)
625
a. Periodic EST or banding
b. TIPS (Transjugular intrahepatic portasystemic
shunt) in older children
c. Surgery (shunt surgery and non-shunt)
d. Prevention of bleeds: acid suppression by proton
pump inhibitors, sucralfate, beta blockers.
Gastro-esophageal Reflux Disease (GERD)
i. Head up position after meals and low fat diet.
ii. H2 receptor antagonist, proton pump inhibitors and
pro kinetics constitute the medical line of manage-
ment.
iii. Surgery—Fundoplication.
Acid Peptic Disease
i. Screen for H. pylori. If positive, treat with metroni-
dazole + amoxicillin/clindamycin + proton pump
inhibitors.
ii. If negative treat with either antacids H2 antagonists,
proton pump inhibitors or sucralfate.
iii. Laser photocoagulation for immediate control of
ulcer bleed.
LOWER GASTROINTESTINAL BLEEDING
Lower gastrointestinal bleeding is defined as bleeding
distal to the ligament of Treitz. Bloody diarrhea and
bright red blood mixed or coated normal stool are classic
presentations of lower GI bleed.
Etiology
The common causes of lower gastrointestinal bleed are
given in Table 13.7.2.
Clinical Features
Swallowed maternal blood either from the vagina or
breast is confirmed by a positive Apts test. Hemorrhagic
disease of the newborn responds well to vitamin K
therapy. NEC occurs in premature/low birth weight
babies and presents as rectal bleeding, abdominal
distension and sepsis.
Acute hematochezia in an ill appearing child who
has acute abdominal pain and tenderness suggests
intestinal ischemia as a complication of intussusception,
mid gut volvulus, incarcerated hernia or mesenteric
thrombosis. The sudden onset of colicky abdominal pain
and vomiting in the setting of an antecedent viral illness
626 IAP Textbook of Pediatrics

TABLE 13.7.2: Common causes of lower or pneumotosis intestinalis (gas in bowel wall seen in
gastrointestinal bleed NEC). Intussusception can be diagnosed by barium
Newborn enema study (shows coiled spring appearance) and this
• Swallowed maternal blood can also be therapeutic. Ultrasound and CT scan of the
• Hemorrhagic disease of newborn abdomen can also be used. Meckel’s diverticulum can
• Anal fissure
be diagnosed by Meckel’s scan (99Tc -pertectenate
• Necrotizing Enterocolitis(NEC)
• Malrotation and midgut volvulus nuclear can).
Infants and older children Anal fissure can be seen by direct anorectal exami-
• Anal fissure nation. Polyps are most commonly found in the recto
• Intussusception, gangrenous bowel due to volvulus sigmoid region and can be identified by direct rectal
• Polyp and polypoid disease
examination or colonoscopy. AV malformations are
• Gastroenteritis-Salmonella, Shilgella, Yersinia, Campylobacter,
Ehe. coli, Ete. coli, Clostridium difficile, CMV, Entamoeba
diagnosed by radioisotope tagged RBC scans using
histolytica, Trichuris trichuria technetium 99m sulfur colloid if there is bleeding or by
• Colitis colonoscopy/capsule endoscopy.
• Meckel’s diverticulum
• Inflammatory bowel disease Management
• AV malformations
Lower GI bleeding is rarely life threatening. Anal fissure
should be treated with stool softeners, sitz bath and rectal
dilatation. Nonoperative management has a high
followed by passage of currant jelly stool is indicative of recovery rate in NEC. Malrotation with midgut volvulus
an intussusception. should be treated by exploratory laprotomy and Ladd
Painless passage of blood per rectum suggests procedure. If enema reduction is unsuccessful or the child
Meckel’s diverticulum, polyp, intestinal duplication or is very sick operative manual reduction or resection of
A V malformation. Anal fissure occurs in constipated the intussusception should be done. Colonoscopy can be
children and presents as painful passage of streaks of used to treat polyps, telangiectasias and small heman-
blood in stool. giomas. Meckel’s diverticulum should be surgically
resected.
Clinical Assessment
BIBLIOGRAPHY
Stools in children with bloody diarrhea should be 1. Gastrointestinal bleeding in infants and children. Boyle
examined for polymorphonuclear leukocytes and JT. Pediatr Rev 2008;29(2):39-52.
2. Lower gastrointestinal bleeding in children. Leung AK,
cultures should be done to identify the organism. All
Wong AL. Pediatr Emerg. Care 2002;18(4):319-23.
infants who experience acute hematochezia should 3. Upper gastrointestinal bleeding in children. Chawla S,
undergo abdominal flat plate/upright or cross table Seth D, Mahajan P, Kamat D. Clin Pediatr 2007;46(1):
lateral radiography to screen for intestinal obstruction 16-21.
 Diseases of Gastrointestinal System and Liver 627

13.8 Constipation
VR Ravikumar

Constipation is passage of firm or hard pellet like stools dilated rectum filled with hard fecal masses. Children
at infrequent and long intervals with difficulty to expel. adopt peculiar postures during defecation and many
Frequency of stooling varies in different age groups and children cross their legs and push back the fecal mass. A
only the hard consistency is the important factor. vicious cycle follows and there is fecal retention and
Obstipation refers to the absence of passage of both impaction. The child starts soiling the under clothes due
feces and flatus. Encopresis is fecal soiling in the presence to the seepage of liquid fecal material around the
of functional constipation due to fecal retention and impacted mass.
overflow, whereas fecal incontinence is due to anatomic In chronic constipation a cycle of events take place.
or organic cause. Fecal retention → rectal distension → decreased
The common causes of constipation are given in Table sensory perception → hard stool → fissure in ano →
13.8.1. pain and with holding evacuation → impaction →
Other rare causes of constipation are neuronal fecaloma formation.
intestinal dysplasia, Chaga’s disease, small left colon
syndrome, neurofibromatosis, and intrinsic myopathy HIRSCHSPRUNG’S DISEASE
leading on to pseudo-obstruction. The common differential diagnosis of habitual consti-
pation in older children is with Hirschsprung’s disease,
Functional Constipation (Habitual constipation) which is due to aganglionosis of rectum and colon. It
It is the most common cause of constipation in children usually involves the rectum and distal sigmoid but the
aganglionosis may extend to variable length. Total
beyond 4 years. However, it can happen in younger age
colonic aganglionosis is less common and rarely the small
period during weaning, or more commonly during toilet
training or at the time of joining a school. intestines may be affected. The diagnosis is usually made
by barium enema, which will show the dilated rectum,
Many present with chronic recurrent abdominal pain.
transition zone and the narrow portion. Rectal biopsy
Enuresis may be the presenting feature.
Unlike Hirschsprung’s disease the abdomen is only either full thickness or the suction biopsy of the mucous
membrane of rectum will show absence of ganglion cells,
mildly distended with hard stool felt in the left lower
hypertrophy of nerve bundles and increased acetyl-
quadrant of the abdomen. Rectal examination reveals a
cholinesterase staining in hypertrophy of nerve bundles
in Hirschsprung’s disease. Anal manometry is valuable
TABLE 13.8.1: Common causes of constipation especially for ultra short segment of Hirschsprung’s
disease.
Newborn Infants and children
This disease presents with progressive abdominal
1. Preterm infant under- Bad dietary habits and lack distension, constipation and vomiting not responding to
feeding of fiber in the diet
laxatives.
2. Hypothyroidism Hypothyroidism
3. Hirschsprung’s disease Hirschsprung’s disease Ultra short Hirschsprung’s disease is where internal
4. Anorectal anomalies Functional or psychogenic sphincter achalasia is difficult to differentiate from
5. Spinal abnormalities Cerebral palsy chronic constipation (Table 13.8.2). The rectal biopsy is
6. Meconium plug Drugs: Antispasmodics, not helpful. Anal manometry will be diagnostic. A
syndrome antimotility drugs, posterior myomectomy is usually curative (Figs 13.8.1
phenothiazines, codeine
containing cough mixtures,
and 13.8.2).
vincristine and vinblastine
Treatment
7. Anterior perineal anus,
anal stenosis, presacral Treatment of constipation depends on the cause. Anal
masses stenosis and incomplete covered anus get corrected by
628 IAP Textbook of Pediatrics

TABLE 13.8.2 Difference between habitual constipation and

Hirschsprung’s disease

Clinical features Habitual constipation Hirschsprung’s

disease
Age of onset 2 to 3 years Birth onwards
Meconium Normal Delayed passage
history
Rectal Loaded rectum Empty rectum
examination
Perineal soiling Perineal soiling Perineal soiling is
present absent
Nutrition Thriving well Failure to thrive
Barium enema Dilated rectum Dilated segment
without transition with narrow
zone aganglionic rectum
Manometry Internal sphincter Internal sphincter
relaxation present relaxation absent
Rectal biopsy Ganglion cells are Ganglion cells are
present absent

Figure 13.8.2: Classical Hirschsprung’s disease

segment can be corrected by posterior myomectomy. A

Figure 13.8.1: Short segment HIrschsprung’s disease
anoplasty. Acute fissures in ano respond to local
application of local anesthetic agents and stool softeners.
Hirschsprung’s disease needs surgical removal of
aganglionic colon and bringing the ganglionated colon
to the anal region by different techniques. Ultra short
small percentage of children with history of meconium
plug syndrome may develop constipation and need
investigation to exclude Hirschsprung’s disease.
A separate group of children have idiopathic mega
rectum and do not respond to conservative measures and
need excision of the redundant rectum.
Constipation due to hypothyroidism responds to
thyroxine replacement. Drug induced constipation needs
identifying the drug and withdrawal of the offending
drug.
Treatment of functional constipation is difficult and
needs patience and perseverance and include the
following:
1. Proper toilet training.
2. Avoidance of precipitating factors.
3. Diet rich in residue and fiber like bran, pop corn,
fruits, green vegetables and reduced milk intake.
The parents need to be educated on the long-term
safety of laxatives and the need for prolonged treatment.
The change in dietary habits is stressed upon. The rectum
need to be emptied regularly with stool softeners, enemas
 Diseases of Gastrointestinal System and Liver
and laxatives. The idea is to promote regular evacuation
at fixed timings so that the distended rectum slowly
regains its normal tone and sensory perception. The
treatment may be prolonged upto six months to one year
and may relapse if there is interruption in the training.
The common drugs that promote softening the stool
and promote evacuation are:
1. Milk of magnesia at doses of 0.5 ml per kg per day in
children less than two years and 5 to 15 ml in children
between 2 to 5 years and 15 to 30 ml above 6 years.
2. Biscodyl can be used as a suppository 5 mg or
10 mg.
3. Liquid paraffin is not generally used in children less
than 3 years of age. 10 to 30 ml can be given at bed
time in toddlers. However it seeps by the side of the
fecal bolus and stains the undergarments, but it is
one of the effective stool softeners.
4. Lactulose is a syrupy solution: 2.5 ml to 10 ml per
day for infants can be given in divided doses.
5. Senna preparations are stimulant laxatives and can
be given for a short period of time at 10 to 20 mg per
kg at bedtime.
13.9 Abdominal Pain
Abdominal pain is a very common symptom in
childhood. It can be present in acute and chronic or
recurrent manner. In acute abdominal pain, it is
important to distinguish between medical and surgical
causes of abdominal pain. On the other hand, in children
with recurrent abdominal pain, the distinction has to be
made between organic and nonorganic (or psychogenic)
pain abdomen.
13.9.1 ACUTE ABDOMINAL PAIN IN
CHILDREN
Abdominal pain is one of the most common reasons for
a parent to bring his or her child to medical attention.
The evaluation of a “tummy ache” can challenge both
parents and the physician.
629
6. Dietary fiber increases the bulk and increases the
amount of water in the stool and is a natural stool
laxative. Various commercial preparations are
available.
7. Prokinetic agents like cisapride has also been used
but carries the danger of inducing cardiac arrhyth-
mias and hence not routinely recommended now in
children.
8. Biofeed techniques to condition to relax the external
anal sphincter has been tried with success.
The ultimate goal is to achieve normal bowel
movements without the need for laxatives. This will need
proper training to evacuate at fixed timings daily with
judicious use of stool softeners and other non-punitive
measures.
Children with intractable constipation especially
those with neurological weakness of the sphincters and
following surgery for anorectal anomalies and mega
rectum are most difficult to treat and may benefit by
antegrade continent enema procedures using either the
appendicular stump or a Monti’s tube connected to colon.
S Srinivas
Numerous disorders can cause abdominal pain (Table
13.9.1.1) and it must be remembered that causes of
chronic abdominal pain can have an initial acute
presentation. The most common medical causes are
gastroenteritis and constipation, and the most common
surgical cause is appendicitis.
In most instances, abdominal pain can be diagnosed
through the history and physical examination
HISTORY
Age is a key factor in evaluating the cause; the incidence
and symptoms of different conditions vary greatly over
the pediatric age spectrum. Infantile colic occurs in
infants. It is not important to inspect genitalia and not
miss an incarcerated hernia in a crying and irritable
infant. Intussuception and volvulus tend to occur in
infants and younger children below five years of age.
630 IAP Textbook of Pediatrics

TABLE 13.9.1.1: Causes of acute abdominal pain in children

Gastrointestinal causes Liver, spleen, and biliary tract Genitourinary causes

Reflux esophagitis disorders Urinary tract infection
Gastritis/ Gastroenteritis Hepatitis Urinary calculi
Food poisoning Liver abscess Perinephric abscess
Constipation Cholecystitis Ovarian/ testicular torsion
Peptic ulcer Cholelithiasis Dysmenorrhea
Mesenteric lymphadenitis Splenic infarction Mittelschmerz
Lactose intolerance Rupture of the spleen Pelvic inflammatory disease
Inflammatory bowel disease Pancreatitis Hematocolpos
Irritable bowel syndrome Ectopic pregnancy

Surgical causes Metabolic disorders Hematologic disorders

Appendicitis Diabetic ketoacidosis Henoch Schönlein purpura
Abdominal trauma Acute intermittent porphyria Sickle cell crisis
Intestinal obstruction Hemolytic uremic syndrome
Intussusception
Peritonitis

Miscellaneous
Infantile colic, Functional pain, Worm colic, Lead poisoning, Venoms
Pharyngotonsillitis, Basal pneumonia, Familial Mediterranean fever,
Vascular causes like mesenteric ischemia or dissecting aneurysm of abdominal aorta

Pharyngotonsillitis and Henoch Schonlein purpura are
more common in preschoolers and children below 12 yr
of age whereas dysmenorrhea, ectopic pregnancy,
inflammatory bowel disease and irritable bowel
syndrome are more common in adolescents.
Pain history Pain from foregut structures (e.g., lower
esophagus, stomach) generally is felt in the epigastrium.
Midgut structures (e.g., small intestine) cause peri-
umbilical pain, and hindgut structures (e.g., large
intestine) cause lower abdominal pain. Pain in the right
hypochondrium may either be due to acute stretching of
the capsule of the liver as in acute viral hepatitis,
cholecystitis or rarely peptic ulcer disease. Pain in
pancreatitis is epigastric or central and may be referred
to the back. Pain in cystitis or dysmenorrhea is usually
suprapubic in location. Appendicitis classically is
described to start with periumbilical pain and vomiting;
then slowly gets localized to the right iliac fossa. In
infants, appendicitis progresses quickly to perforation
and peritonitis because of the lack of an adequate omental
barrier to limit peritoneal spread.
Younger children who do not verbalize and older
children may have a poor sense of onset or location of
pain. Thus, inquiry into the location, timing of onset,
character, severity, duration, and radiation of pain are
all important points but must be viewed in the context
of the child’s age.
Recent trauma: A history of recent blunt abdominal
trauma might suggest pain due to parietal wall injury or
internal organ injury to bowel or pancreas causing
pancreatitis.
Precipitating or relieving factors: Parietal pain is aggravated
by movement. Relief of pain after a bowel movement
suggests a colonic source, and relief after vomiting
suggests a source in the more proximal bowel.
Associated symptoms: In the acute surgical abdomen, pain
generally precedes vomiting, and the reverse is true in
medical conditions. Any child presenting with bilious
vomiting should be presumed to have a bowel obstruc-
tion. Diarrhea often is associated with gastroenteritis or
food poisoning but may be associated with other
conditions including retrocaecal appendicitis. Bloody
diarrhea is much more suggestive of inflammatory bowel
disease or infectious enterocolitis. The typical ‘red currant
jelly stool’ is seen in intussusception. Failure to pass flatus
or faeces may suggest intestinal obstruction.
 Diseases of Gastrointestinal System and Liver
Urinary frequency, dysuria, urgency, and malo-
dorous urine suggest a urinary tract infection. Cough,
shortness of breath, and chest pain point to a thoracic
source. Polyuria and polydipsia suggest diabetes
mellitus. Joint pain and skin rash suggest Henoch-
Schönlein purpura.
Gynecologic history: In adolescent girls, a thorough
gynecologic history is essential.
Past health: All previous hospitalizations or significant
illnesses such as sickle cell anemia and porphyria should
be noted. Previous surgery can increase the risk of
intestinal obstruction from adhesions. Nephrotic
syndrome predisposes to bacterial peritonitis. A
Mediterranean background along with fever and
abdominal pain could suggest Familial Mediterranean
Fever.
PHYSICAL EXAMINATION
General appearance: In general, children with visceral pain
tend to writhe during waves of peristalsis, while children
with peritonitis remain quite still and resist movement.
The hydration status of the child should be assessed.
Vital signs: Fever indicates an underlying infection or
inflammation. Tachycardia and hypotension suggest
hypovolemia. If a postmenarcheal girl is in shock, ectopic
pregnancy should be suspected. Hypertension may be
associated with Henoch-Schönlein purpura or hemolytic
uremic syndrome. Kussmaul’s respiration indicates
diabetic ketoacidosis.
Abdominal examination: The breathing pattern should be
observed, and the patient should be asked to distend the
abdomen and then flatten it. After the child is asked to
indicate, with one finger, the area of maximal tenderness,
the abdomen should be gently palpated, moving toward
(but not palpating) that area. The physician should
examine for Rovsing’s sign (when pressure on the left
lower quadrant distends the column of colonic gas,
causing pain in the right lower quadrant at the site of
appendiceal inflammation), then gently assess muscle
rigidity. Gentle percussion best elicits rebound tender-
ness. Deeper palpation is necessary to discover masses
and organomegaly. It is important to include examination
of genitalia and hernial orifices. A rectal examination may
provide useful information about tenderness that might
suggest pelvic appendicitis or pelvic abscess and the
presence of masses/stool/blood.
631
Associated signs: Pallor and jaundice point to sickle cell
crisis. A positive iliopsoas test (passive extension of the
right hip and flexion of the right thigh against resistance)
or obturator test (rotation of the right flexed hip) suggests
an inflamed retrocaecal appendix, a ruptured appendix,
or an iliopsoas abscess. A positive Murphy’s sign
(interruption of deep inspiration by pain when the
physician’s fingers are pressed beneath the right costal
margin) suggests acute cholecystitis. Cullen’s sign (bluish
umbilicus) and Grey Turner’s sign (discoloration in the
flank) are unusual signs of internal hemorrhage. Palpable
purpura and arthritis suggest Henoch-Schönlein
purpura.
LABORATORY STUDIES
Laboratory studies should be tailored to the patient’s
symptoms and clinical findings. Initial tests may include
a complete blood cell count, urinalysis, liver function
tests, and serum amylase. A low hemoglobin level
suggests blood loss or underlying hematologic abnor-
malities, such as sickle cell disease. However, a normal
hemoglobin level does not exclude an acute massive
hemorrhage for which the body has not yet compensated.
Leukocytosis, especially in the presence of a shift to the
left and toxic granulations in the peripheral smear,
indicates an infection. Urinalysis can help identify
urinary tract pathology, such as infection or stones. A
pregnancy test should be considered in postmenarcheal
girls.
Plain-film abdominal radiographs are most useful
when one suspects intestinal obstruction or perforation.
It may however occasionally detect ascariasis or reveal a
loaded colon as the cause of abdominal pain. Chest
radiographs may help rule out pneumonia. Ultrasono-
graphy is a very useful investigation and aids in the
diagnosis of intussusception, gallstones, renal stones,
appendiceal pathology and gynecologic pathology such
as ovarian cysts with torsion or hemorrhage. CT involves
significant radiation exposure and may require the use
of contrast agents.
MANAGEMENT
Treatment should be directed at the underlying cause.
The indications for surgical referral are listed below in
Table 13.9.1.2.
632 IAP Textbook of Pediatrics

TABLE 13.9.1.2: Indications for surgical referral
• Bile-stained or feculent vomitus
• Involuntary abdominal guarding/rigidity
• Rebound abdominal tenderness
• Marked abdominal distension with diffuse tympany
• Signs of acute fluid or blood loss into the abdomen
• Significant abdominal trauma
• Suspected surgical cause for the pain
In many patients, the key to diagnosis is repeated
physical examination by the same physician over an
extended time after judicious use of analgesics, which
may enhance diagnostic accuracy by permitting detailed
examination of a more cooperative patient.
BIBLIOGRAPHY
1. Davenport M. Acute abdominal pain in children. BMJ
1996;312:498-501.
2. Leung AK, Sigalet DL. Acute abdominal pain in children.
Am Fam Physician 2003;67:2321-6.
13.9.2 CHRONIC ABDOMINAL PAIN IN
CHILDREN
The traditional definition of recurrent abdominal pain
used over the last 50 years has used Apley and Naish’s
criteria of at least three pain episodes over a three month
period interfering with daily function. This has been
replaced by the term chronic abdominal pain which
refers to pain present continuously or occurring on a
weekly basis for a minimum period of 2 months. It is a
description and not a diagnosis, and can be due to organic
disease or functional causes.
A child with chronic abdominal pain poses a
formidable challenge as the parents may be terribly
worried; child may be distressed and the practitioner
may be concerned about ordering multiple tests to avoid
missing occult disease. Yet only in a small number of
children is the pain caused by organic disease and in the
majority the pain is functional — i.e. without demons-
trable evidence of a pathologic condition.
The differential diagnosis of abdominal pain in
children varies with age, sex, genetic and environmental
factors. Besides organic and functional components are
not mutually exclusive, since psychological compli-
cations of organic disease are common in children. Hence
the diagnostic approach to abdominal pain in children
relies heavily on the history provided by the parent and
child to direct a step-wise approach to investigation
rather than multiple “exclusionary” investigations.
ETIOLOGY
Table 13.9.2.1 lists the common causes of chronic
abdominal pain in children.

TABLE 13.9.2.1: Causes of chronic abdominal pain in children

Functional disorders (as classified by Rome III criteria)

1. Functional dyspepsia
2. Irritable bowel syndrome
3. Abdominal migraine
4. Childhood functional abdominal pain
5. Childhood functional abdominal pain syndrome

Gastrointestinal causes Liver, spleen, and biliary tract Genitourinary causes

Reflux esophagitis disorders Urinary tract infection
Helicobacter pylori gastritis Hepatitis Urinary calculi
Peptic ulcer Liver abscess Hydronephrosis
Lactose intolerance Cholelithiasis Dysmenorrhea
Giardiasis Recurrent or chronic pancreatitis Pelvic inflammatory disease
Inflammatory bowel disease

Surgical causes
Malrotation with intermittent volvulus
Chronic appendicitis

Miscellaneous
Infantile colic, lead poisoning, familial mediterranean fever,
Vasculitis, angioneurotic edema, acute intermittent porphyria
 Diseases of Gastrointestinal System and Liver
HISTORY
The location of the pain is important and the child may
indicate the location of the pain by pointing with one
finger or with the whole hand. Apley’s observation that
“the further the pain from the umbilicus, the greater the
likelihood of organic disease” has held up reasonably
well and most children with functional abdominal pain
present with pain around the region of the umbilicus.
Night pain or pain on awakening suggests a peptic
origin, while pain that occurs in the evening or during
dinner is a feature of constipation. Children often deny
heartburn, but other features of peptic disease include
early satiety, nausea and the complications of gastro-
oesophageal reflux.
A diary that lists diet, symptoms and associated
features for three to seven days is invaluable since it will
indicate potential causes of the symptoms, such as
exposure to lactose or the failure to have a normal bowel
movement.
A history of abdominal distension, involuntary
weight loss, deceleration of linear growth, prolonged
fever, bile stained or persistent vomiting, chronic
diarrhea, dysphagia, nocturnal symptoms, family history
of inflammatory bowel disease and pain persistently
located away from the central abdominal area are the
‘red flag’ symptoms and should trigger a search for
organic disease.
History of recent medications is important as
antibiotics may predispose the patient to intestinal
bacterial overgrowth; acne medications may induce
esophagitis and tricyclic antidepressants may cause
constipation.
Family history of peptic disease, irritable or infla-
mmatory bowel disease, pancreatitis, biliary disease or
migraine should be determined.
The influence of pain on the child’s daily activity is
assessed through questions about school attendance,
athletic endeavours and peer relationships. Whenever
possible, a few minutes should be taken alone with
adolescents to address concerns in the absence of parents
and to elicit honest answers about sexual issues,
psychological fears and the disruptions to lifestyle caused
by the parents’ interventions.
EXAMINATION
Anthropometric data of weight, height and growth
velocity are documented. Blood pressure is recorded and
the weight-for-height is plotted to assess malnutrition
633
or obesity. The physician should percuss the liver span,
document the spleen and kidney size and determine the
influence of leg motion (psoas sign). Examination for pain
should be performed with gentle and deep pressure as
well as with rebound.
Abdominal and rectal examinations will identify
constipation, perianal inflammatory lesions of Crohn’s
disease, abdominal tumors such as neuroblastoma or
Wilms’ tumor and the presence of umbilical or abdominal
wall hernias. The pelvic examination may suggest
gynecologic problems, such as endometriosis, ectopic
pregnancy or ovarian cysts or torsion.
The ‘red flag’ signs of organic disease include
localized tenderness in right upper or lower quadrants,
localized fullness or palpable mass, hepatomegaly,
splenomegaly, costo-vertebral angle tenderness or
perianal abnormalities.
LABORATORY TESTING
The routine screening laboratory evaluation of abdo-
minal pain in children includes the complete blood cell
count with differential and erythrocyte sedimentation
rate to evaluate for anemia, leukocytosis and chronicity.
Platelet counts and CRP are frequently elevated in
inflammatory diseases. Urinalysis and routine urine
culture are indicated. A sample to check the stool for
blood is obtained during the rectal examination and the
result is often confirmed with three additional outpatient
samples. Additional laboratory investigations are chosen
on the basis of the history and physical examination.
These investigations include stool culture, stool testing
for parasites or Giardia antigen, a chemistry profile to
evaluate liver enzymes, serum amylase, lipase and
serology testing for coeliac disease and Helicobacter pylori.
Carbohydrate breath testing for lactose intolerance is
indicated if empiric dietary interventions are incon-
clusive.
Imaging Investigations
Sonography of the abdomen and pelvis is usually
performed first to exclude non-intestinal origins of the
pain which include gallstones and renal stones. Pelvic
sonography is indicated because of its sensitivity for free
fluid, the frequency of retroperitoneal disease and the
visualization of the ileum for Crohn’s disease, lymph-
adenopathy and chronic features of abscess from fistulas
or Meckel’s diverticulum. It also provides information
about possible pelvic/ovarian disease in adolescent girls.
634 IAP Textbook of Pediatrics
Barium swallow is not a sensitive test for gastro-
esophageal reflux disease. A barium contrast of the upper
gastrointestinal tract may be useful to rule out malro-
tation especially if episodes of colicky abdominal pain
are associated with vomiting. Barium enema is indicated
primarily in the context of obstruction or chronic
intussusception. Abdominal computed tomographic
(CT) scan with contrast allows evaluation of the pancreas,
extraintestinal mass lesions, abscess and retroperitoneal
disease.
Endoscopy
Upper endoscopy is rarely indicated as a first-line
investigation. The yield is maximal in patients with
epigastric pain, symptoms of gastrooesophageal reflux
or positive coeliac screen. Biopsies of the esophagus,
gastric antrum and duodenum may be indicated even
in the absence of macroscopic disease to identify
microscopic diagnostic features of reflux esophagitis, H.
pylori, eosinophilic gastritis, granuloma of Crohn’s
disease and villous injury with enteropathy. Colonoscopy
has replaced barium enema in the evaluation of pain with
chronic diarrhea or bleeding.
MANAGEMENT
Empiric Intervention
The child’s response to empiric intervention is also part
of the diagnostic evaluation. This may include:
• Addition of a fiber supplement to rule out consti-
pation
• A trial of H 2 blocker in children with gastro-
esophageal reflux disease or peptic ulcer disease prior
to confirmatory investigations or
• A trial of lactose elimination
Empiric trials of antispasmodic, anxiolytic or
antidepressant medications are not indicated.
SOME SPECIFIC DISEASE STATES
Functional Abdominal Pain
Functional abdominal pain is the most common cause
of chronic abdominal pain. It was previously referred to
as ‘recurrent abdominal pain syndrome’ and has
traditionally remained a diagnosis of exclusion. This
trend is changing and a positive diagnosis of functional
abdominal pain can be made in most circumstances
without the need for extensive investigations when there
are no alarm symptoms or signs, physical examination
is normal and stool sample is negative for occult blood.
Tests are sometimes performed to reassure the patient,
parent or physician especially when pain diminishes
quality of life.
Functional abdominal pain is uncommon under
5 years of age. The typical presentation is a child aged
5-10 years of age with vague, peri-umbilical pain which
can be quite severe, interrupt normal activities and be
associated with nausea, pallor and headache. Epigastric
pain is also described. The pain occurs during daytime
and is unrelated to food intake, activity levels or stool
pattern. The episodes resolve spontaneously and the
child functions normally in between bouts of pain. The
physical examination is striking for its normality, and
the screening laboratory investigations are by definition
normal. The family history is often positive for functional
bowel disease such as irritable bowel syndrome.
Although there is a high rate of spontaneous remission
(30-70%) of chronic abdominal pain in children there is
also evidence that some children with chronic abdominal
pain can progress to have irritable bowel syndrome as
in adults.
The pathophysiology of functional abdominal pain
is thought to involve abnormalities in the enteric nervous
system. The enteric nervous system is also referred to as
‘the little brain in the gut’ and has bi-directional
interaction with the central nervous system. It is now
believed that adults and children with functional bowel
disorders may have abnormal reactivity to physiologic
stimuli (meal, gut distension), stressful stimuli (infla-
mmatory or psychological). There is also growing
evidence of association of functional bowel disorders
with visceral hyperalgesia.
The management of functional abdominal pain
begins with the acknowledgement that the pain is real,
that extensive investigations are not warranted.
Education of the family in simple understandable
language is an important part of treating a child with
functional abdominal pain - likening the abdominal pain
to a headache and giving examples of hyperalgesia like
a healing scar. The primary goal of therapy is not
eradication of pain but resumption of a normal lifestyle
with regular school attendance, extracurricular activities
and a normal sleep pattern. Parents must be discouraged
from reinforcing the symptoms by allowing the child to
miss school and paying too much positive attention to
the pain.
 Diseases of Gastrointestinal System and Liver
It is important to identify, clarify and reverse possible
physical and psychological stress factors that may
exacerbate or maintain pain.
Dietary interventions that have been tried with
variable benefit include increasing dietary fibre intake.
Psychological approaches including cognitive
behavioural therapy and gut-directed hypnotherapy are
increasingly being used with success in children with
functional abdominal pain.
Drug therapy for pain related FGIDs has generally
been directed at symptoms alleviation rather than at
precise pathophysiological abnormalities. However with
increased understanding on the etiology of visceral
hypersensitivity and dysmotility, newer strategies are
being developed which include 5 HT3 antagonists.
Since pain related FGIDs tend to be chronic, waxing
and waning - a quick cure is unlikely. As they have a
high rate of spontaneous remission - a stepwise approach
is necessary with the initial step being education,
alleviation of stress factors and diet modifications.
True irritable bowel syndrome occurs infrequently
before late adolescence. It is best characterized as an
intestinal dysmotility with intervals of nuisance diarrhea
or constipation. The pain is dull, crampy and located in
the left lower quadrant or periumbilical region.
Autonomic symptoms may be associated. Stress is
implicated in the flare-up of symptoms, and a positive
family history is common. Management includes dietary
factors such as exclusion of contributory lactose
intolerance and the addition of fiber to the diet and stress
management techniques.
Cyclic Vomiting Syndrome (CVS)
Gee’s original description of a syndrome with “fits of
vomiting.... with disease-free intervals” in 1882 has held
up well in the clinical definition of periodic syndrome,
which is now called cyclic vomiting syndrome. CVS is a
severe form of functional vomiting syndrome - consi-
dered to be a brain-gut disorder. The typical patient is a
5-8 year old girl, who has repeated episodes of severe
vomiting (median 6 emeses per hour and 15 emeses per
episode) typically beginning during the night or early
morning hours and lasting from six to 48 hours, with
intervening intervals of 2-4 weeks with no symptoms or
findings at all. The episodes are stereotypic within
individuals as related to time of onset, duration and
symptomatology including pallor, listlessness, nausea,
retching and abdominal pain. Typical migraine symp-
635
toms of headache and photophobia affect 30-40%. More
than half require intravenous hydration. The diagnosis
remains clinical and a positive response to anti-migraine
therapy supports the diagnosis. Treatment is empiric and
includes lifestyle changes (e.g. regimenting sleep,
avoiding triggers). In the acute phase – early use of nasal
anti-migraine medication like sumatriptan may abort the
episode in progress. Other supportive therapies include
nursing the child in a dark and quiet environment,
intravenous rehydration, anti-emetics, sedation and
analgesia for pain relief. NASPGHAN guidelines
recommend prophylactic anti-migraine medications
(cyproheptadine, amitriptyline, and propranolol) for
frequent or prolonged episodes.
Constipation
Constipation is a major cause of chronic abdominal pain
in children from toddler age to the preteen years. The
etiology of constipation in most children is a combination
of improper toilet training and a diet low in fiber
producing a dilated lower colon, painful defecation,
erratic stool patterns and frequent encopresis. The
parents usually do not understand what is causing the
child’s discomfort. The child avoids passing the hard
stool. Aside from complicating encopresis and bleeding
from rectal fissures, symptoms include crampy pain that
occurs during large meals, reduction in appetite and
distention of the abdomen (from stool and gas) that
occurs in the evening.
The management goal is complete evacuation of the
lower colon on a nearly daily basis. This is achieved by
using stool softeners like lactulose until muscle tone can
be restored over two to six months. These are combined
with “motivation to go,” which can be achieved in some
children with behavior-modification sticker charts but
usually requires stimulant laxatives. The child is
encouraged to establish the “habit” of toilet use especially
after a meal to make use of the gastro-colic reflex, the
use of a daily calendar, rewards for attempting defecation
and rewards for absence of encopresis. Dietary efforts
begin with reducing intake of constipating foods and
eventually including increased fiber.
If there is fecal impaction, the initial management
may require use of an enema or suppository. Manual
disimpaction is rarely needed. Both softening and
stimulant medications are then initiated and adjusted to
the response of averaging two soft stools a day for six to
eight weeks. At that point, most children can tolerate a
636 IAP Textbook of Pediatrics
transition to increased dietary fiber and habitual toilet
use.
Peptic Disorders
The peptic disorders causing chronic abdominal pain
include reflux esophagitis, antral gastritis, gastric and
duodenal ulcer, and H. pylori infection.
The signs and symptoms of peptic disease include
early morning pain, early satiety, night arousal and a
positive family history. The pain may be epigastric or
periumbilical and is remarkably consistent in character.
Occult bleeding is frequent with ulceration and less
common in gastritis.
Gastro-esophageal reflux disease can present with epigastric
or retro-sternal pain of a ‘burning’ nature with associated
symptoms of sour eructations or ‘water brash’. These
symptoms are more common in older children and
younger children often present with vomiting and
irritability as the predominant symptom. Some children
may have associated minor upper GI bleeding secondary
to oesophagitis.
Stress ulcers usually present with acute, relatively
painless, dramatic upper gastrointestinal bleeding,
features shared with gastric ulceration resulting from use
of nonsteroidal anti-inflammatory drugs (NSAIDs).
Antral gastritis following a viral infection is not
uncommon in children. Children present with chronic
epigastric pain, early satiety with nausea, modest weight
loss and a low frequency of family history of peptic
disease. Gastric emptying is impaired, and reflux
symptoms may be prominent.
Helicobacter pylori gastritis In 1984, Marshall and Warren
demonstrated the role of a gram-negative aerophilic
bacterium, H. pylori, in chronic gastritis and peptic ulcer
disease in adults. This bacterium produces a cytotoxin,
urease, mucinase and superoxide dysmutase, which act
in concert to produce gastric and/or duodenal injury.
Recognizing the limitations of a positive serology result
and the research status of the C-13 -urease breath test,
the diagnosis in children has been dependent on
documentation of the bacterium in endoscopic biopsies
of the stomach and duodenum. Most children receive
triple therapy with continued acid suppression combined
with a two week course of amoxicillin and clarithromycin
or metronidazole. Children who fail to eradicate H. pylori
and remain symptomatic would need quadruple therapy
with addition of bismuth subsalicylate. Antibiotic
resistance is an increasing concern, so empiric treatment
for possible Helicobacter infection is discouraged.
Endoscopic confirmation of healing is indicated with
recurrent or persistent symptoms.
Inflammatory Bowel Disease
Abdominal pain is frequently reported in children with
ulcerative colitis and Crohn’s disease. The pain, which
typically occurs in the lower abdomen, is cramping in
nature and increases after meals or activity. The pain is
reduced by eating smaller meals, which contributes to
the anorexia and growth impairment that occur in
children with inflammatory bowel disease. The diagnosis
is relatively easy when the child has bloody diarrhoea,
the need to defecate during the night, perianal disease
or an ileal mass on abdominal examination. More subtle
features include delayed puberty, anemia that is
unresponsive to iron therapy, recurring oral aphthous
ulcers, chronic liver disease, or large joint synovitis or
arthritis. The diagnosis is established by small bowel
barium contrast x-ray and colonoscopy with biopsies.
Once the etiology of chronic abdominal pain is
established, the process of patient and family education
has just begun. Careful follow-up is necessary to monitor
compliance with treatment, restoration of normal
activities and appropriate family interventions.
BIBLIOGRAPHY
1. American Academy of Pediatrics and North American
Society of Pediatric Gastroenterology, Hepatology, and
Nutrition Subcommittee on Chronic Abdominal Pain.
Chronic abdominal pain in children. Pediatrics 2005;
115:812-15.
2. Arine M Vlieger, Marc A Benninga. Chronic Abdominal
Pain including Functional Abdominal Pain, Irritable
Bowel Syndrome, and Abdominal Migraine. In:
Kleinman G, Mieli-Vergani S, Sherman S, eds. Walker’s
Pediatric Gastrointestinal Disease, Volm 1,5th edition.
BC Decker Inc, Hamilton. 2008;715-26.
3. Chronic abdominal pain in children: a clinical report of
the American Academy of Pediatrics and the North
American Society for Pediatric Gastroenterology.
Hepatology and Nutrition. J Pediatr Gastroenterol Nutr
2005;40:245-48.
4. Lake A. Chronic abdominal pain in childhood: diagnosis
and management. Am Fam Physician 1999;59:1823-30.
5. Rasquin A, Di Lorenzo C, Forbes D, et al. Childhood
functional gastrointestinal disorders: child/ adolescent.
Gastroenterology 2006;130:1527-37.
 Diseases of Gastrointestinal System and Liver
13.10 Helicobacter Pylori Infection in Children
INTRODUCTION
Helicobacter pylori, first cultured and identified as
Campylobacter pylori in 1982 by Warren and Marshall, is
a spiral gram-negative bacillus, which produces urease,
catalase and oxidase and is associated closely with antral
gastritis and duodenal ulcers in adults and children. It is
highly motile with multiple unipolar flagella. It inhabits
the muscus adjacent to the gastric mucosa and can live
in the stomach and in the duodenum for long.
Epidemiology
Worldwide, H. pylori prevalence in children ranges from
10 to 80%. At least half of the world’s population is
infected by H. pylori. However, most infected people
(>70%) are asymptomatic. Man is the only known
reservoir of H. pylori. The infection is transmitted mainly
through feco-oral route in developing countries and poor
water supply are major risk factors. Thus prevalence of
infection is higher in developing countries than
developed nations. Up to 50% of children living in poor
socio-economic conditions are infected. Around 80% of
children under the age of 10 years are infected in
developing countries. Prevalence of infection in India is
about 22%, 56% and 87% in 0-4, 5-0 and 10-19 years age
groups respectively. Re-infection rate after treatment of
H. pylori is higher in under five-age group of children.
Pathogenesis
H. pylori is almost always acquired in childhood, and if
untreated infection is usually lifelong. Colonization of
H. pylori depends on virulence factors of the organism,
host factors and environmental factors. H. pylori produces
disease-inducing factors including urease, vacuolating
cytotoxin, catalase, and lipopolysaccharide (LPS). Urease,
a potent antigen, induces increased IgG and IgA
production. Vacuolating cytotoxin induces inflammatory
cytokines leading to more pronounced inflammation.
Catalase helps H. pylori to survive in the host by
preventing the formation of oxygen metabolites from
hydrogen peroxide in neutrophils. The LPS outer
membrane of H. pylori is a less potent inducer of the host
637
Neeraj K Jain, Vibha Mangal
complement cascade and enhances the ability of H.pylori
is a less potent inducer of the host complement cascade
and enhances the ability of H.pylori to colonize the
stomach.
The microbial virulence factors identified so far
include the H. pylori cytotoxin associated gene A (cagA),
its related pathogenicity island (cag PAI), vacuolating
toxin A (vacA) and factors involved in adherence of H.
pylori to gastric epithelial cells. The immunoreactive 120-
145 KDa protein cagA is encoded by cagA of H. pylori.
Some of the gene in the cagPAI region encode a type IV
bacterial secertion apparatus, which can translocate cagA
into host target cells. Phosphorylation of cagA may
activate host signaling pathways and subsequently
influence host cellular functions, including proliferation,
apoptosis, cytokine release, and cell motility. VacA
expression is determined by variations in the signal
sequence and mid-region of the vacA gene.
Host genetic factors might affect H. pylori colonization
and development of diseases. Genetic polymorphism of
the cytokines and other related ligands, receptors and
enzymes might influence H. pylori infection. Interleukin
1-B is a pro-inflammatory cytokine and a powerful
inhibitor of gastric acid secretion. Host genetic factors
that affect IL-1 B may determine why some individuals
infected with H. pylori develop gastric cancer or ulcers
while others do not.
Interactions between host, environment and H. pylori
in the development of peptic ulcer diseases have been
proposed. A two-way interaction might exist between H
pylori and gastric acid that determines pattern of gastritis
and hence clinical outcome. Infection in infancy leads to
pangastritis (low acid secretion status), whereas in latter
childhood it may lead to a predominantly antral gastritis
(high acid load). Environmental factors (smoking,
malnutrition, high salt intake and vitamin deficiency)
and host factors associated with low acid secretion status
favor the colonization of H. pylori with intense infla-
mmation and further reduction in acid secretion. The
resultant hypochlorhydria promotes H. pylori coloni-
zation, more intense inflammation leading to gastric
atrophy, gastric ulcer and cancer.
638 IAP Textbook of Pediatrics
Clinical Manifestations
H. pylori associated duodenal ulcers are seldom seen in
children below 10 years of age. The spectrum of clinical
manifestations infection in children is not well defined.
Primary infection appears to be mainly asymptomatic.
Histologic changes of gastric inflammation generally
occur after several years and signs of gastric injury are
more frequently found in older children. Infection with
H. pylori in childhood apparently does not last a lifetime
but is often spontaneously cleared, although children
frequently become re-infected.
In symptomatic H. pylori infection in children, one of
the most frequent clinical symptoms is chronic, recurrent
abdominal pain; however, most recurrent abdominal pain
in children is not associated with H pylori infection. The
infection in young infants can present as an acute illness
characterized by protracted vomiting that can be
confused with upper gastrointestinal tract obstructive
disorders. Three clinical entities have been associated
with H. pylori infection: asymptomatic gastritis; acute
active gastritis; and chronic gastritis, duodenitis, and
peptic ulcer.
Asymptomatic gastritis: The frequency of asymptomatic
gastritis is not known, but according to seroepidemiologic
studies in general population, it is not a rare event,
particularly in older children. The reason for absence of
symptoms is not known.
Acute active gastritis: Symptoms may begin with epigastric
pain, nausea, and vomiting that may last for a few days.
Patients may improve rapidly and remain asymptomatic.
The pH of gastric juice usually is neutral or alkaline as a
result of a decrease in gastric acid output. This
hypochlorhydria may persist for several weeks and may
present with halitosis and mild gastrointestinal tract
disturbances.
Chronic gastritis, duodenitis, and duodenal ulcer: The triad
of antral gastritis, duodenitis, and duodenal or gastric
ulcer seen by endoscopy is associated with chronic and
more severe gastrointestinal tract symptoms. Children
may present with severe chronic and recurrent abdo-
minal pain, anorexia, and failure to thrive or with
persistent vomiting. Occasionally, hematemesis may be
the first symptom. If H. pylori infection is associated with
chronic gastritis alone, the only symptom may be
recurrent abdominal pain or symptoms of non-ulcerative
dyspeptic syndrome and occasionally, chronic diarrhea.
No pediatric cases with H pylori-associated gastric
cancer have been reported so far. However, precancerous
lesions including mucosal atrophy can develop in the
infected children. Infected persons also have a 2 to 6-
fold increased risk of developing mucosa-associated
lymphoid tissue (MALT) lymphoma, and gastric cancer
compared with uninfected counterparts. The extra-
intestinal manifestations of H. pylori infection in children
include iron deficiency anemia, growth retardation and
migraine.
Diagnosis
1. Endoscopy: The histology test is the gold standard of
diagnosis of H. pylori infection can be performed on
the tissue sample taken from the lining of the stomach.
The culture is however performed in very few
laboratories and is helpful in the choice of antibiotics.
2. Urea breath test (UBT): This is a rapid diagnostic test
for H. pylori infection. Infection can be detected in
the exhaled breath. This test is positive only if the
person has a current infection. Sensitivity and
specificity of this test ranges from 94 to 98%.
3. Serologic test (IgG antibody): Detection of antibodies
to H. pylori denotes past infection as it remains
positive for years after infection and also for several
months after H. pylori has been successfully treated.
It has limited clinical value.
4. H. pylori antigens in feces: Recently, a test that detects
H. pylori antigens in feces has been proposed as a
pretreatment diagnostic tool and, especially, as post-
treatment control. It is still awaiting full confirmation
before the test is recommended widely.
Treatment
Since H. pylori is colonizes a large number of people who
are asymptomatic, there is a debate whether patients
need treatment. It is recommended in those with peptic
ulcer disease. Eradication of H. pylori is difficult as the
lining of the stomach protects them from antibiotics.
Several therapeutic regimens have been shown to be
effective. In general, the use of single agents has been
found to be ineffective for curing infection in the majority
of patients. Two or three drugs for 14 to 21 days are
recommended for treatment. At least two effective
antibiotics along with either an acid-lowering agent
(proton-pump inhibitor or histamine H2 receptor blocker)
 Diseases of Gastrointestinal System and Liver
or bismuth subsalicylate are prescribed. The following
combination therapies are currently in use:
1. Amoxicillin 50 mg/kg/day twice daily for 14 days +
clarithromycin 15 mg/kg/day twice daily for 14 days
+ one proton pump inhibitor for 1 month.
2. Amoxicillin 50 mg/kg day twice daily for 14 days +
metronidazole 20 mg/kg day twice daily for 14 days
+ one Proton pump inhibitor for 1 month.
3. Metronidazole 20 mg/kg/day twice daily for 14 days
+ clarithromycin 15 mg/kg/day twice daily for 14
days + one proton pump inhibitor for 1 month.
Proton pump inhibitors commonly use are:
1. Omeprazole 1.0-3.3 mg/kg/day
2. Lansoprazole 0.8-4 mg/kg/day
3. Rabeprazole 10- 20 mg/kg /day
4. Pantoprazole 20- 40 mg /kg/day.
Those who relapse are treated with a repeat course
and metronidazole for 4 weeks. Compliance with such
regimens is a problem and shorter treatment courses that
are equally effective in children have been tried. There
may be a need for whole family eradication therapy for
removal of the intrafamilial reservoir of H. pylori infection
in cases with relapse after treatment.
13.11 Cystic Fibrosis
Cystic fibrosis (CF) is the most common life limiting
recessive genetic disorder in Caucasians with an
incidence of approximately 1 in 2500 children born in
the United Kingdom. It is less common in African
Americans (1 in 15000) and in Asian Americans (1:31000).
It also affects other ethnic groups such as black
population with an incidence of 1 in 17,000 and the native
American population with an approxi-mate incidence of
1 in 80,000.
CF was thought to be extremely rare in India.
However recent review of CF in Indian children suggests
that CF does occur in Indian children and frequency is
unknown. The incidence in migrant Indian populations
in the UK and USA has been estimated to be 1 in 1000 to
1 in 40000. The precise incidence of CF among Indians is
unknown. As a result of the widespread belief that CF
does not occur in Indians, the disease is rarely suspected
and even if it is suspected the diagnosis is not confirmed
due to the poor availability of facilities for diagnosis.
639
BIBLIOGRAPHY
1. Chan FKL, Leung WK. Peptic ulcer disease. Lancet
2002;360:933-941.
2. Das JC, Nazir MFH. Helicobacter pylori infection in
children: Diagnosis and treatment -A Review.
Bangladesh. J Child Health 2005;29:22-30.
3. Hocker M, Hohenberger P. Helicobacter pylori virulence
factors -one part of a big picture. Lancet 2003;362:
1231-3.
4. Malaty HM. Helicobacter pylori infection and eradication
in paediatric patients. Paediatr Drugs 2000;2:357-65.
5. Obata Y, Kikuchi S, Miwa H, Yagyu K, Lin Y, Ogihara
A. Diagnostic accuracy of serological kits for Helicobacter
pylori infection with the same assay system but different
antigens in a Japanese patient population. J Med
MicrobioI 2003;52:889-92.
6. Siberry GK, Iannone R, Eds: Formulary: drug doses. In:
The Harriet Lane Handbook. 15th edition. Mosby-Year
Book; 2000;622,630,645-6,674-5,772-3,795,837.
7. Sotudehmanesh R, Malekzadeh R, Fazel A, Massarrat S,
Ziad-Alizadeh B, Eshraghian MR. A randomized
controlled comparison of three quadruple therapy
regimens in a population with low Helicobacter pylori
eradication rates. J Gastroenterol Hepatol. 2001;16:
264-8.
Sushil K Kabra, Madhulika Kabra
Molecular Genetics of Cystic Fibrosis
The basic defect in CF is a mutation in the gene for
chloride conductance channel i.e. cystic fibrosis
transmembrane conductance regulator (CFTR). The
failure of chloride conductance by epithelial cells leads
to dehydration of secretions that are too viscid and
difficult to clear.
Till now more than 1400 mutations in the gene have
been recognized. The commonest mutation is delta F 508
which constitutes about 70% of the total cases. The
frequency of this mutation in Indian children has been
reported between 19 to 44%.
Pathogenesis
Due to mutations in CFTR there is defective chloride
channel leading to thick and viscid secretions. This leads
to impaired airway clearance. Airways get colonized with
bacterial agents. Over a period of time it airways gets
colonized with pseudomonas spp. After colonization
640 IAP Textbook of Pediatrics

there may be release of proteolytic enzymes leading to

TABLE 13.11.1: Common clinical features of cystic fibrosis
progressive destruction of airways resulting ultimately
in bronchiectasis. Similarly due to blockade of pancreatic 0-2 years %
ducts enzyme do not reach to intestine and cause
Meconium ileus 10-15
destruction of remaining pancreatic tissue resulting in Obstructive jaundice
steatorrhoea and failure to thrive. Hypoproteinemia/anemia
Bleeding diathesis
Clinical Manifestations Heat prostration /hyponatremia
The clinical features of CF are variable. The clinical FTT
Steatorrhoea 85
features depend on age of diagnosis, supportive care
Rectal prolapse 20
received and treatment. The common clinical presenta- Bronchitis/Bronchiolitis
tion includes meconium ileus in neonatal period, Staphylococcal pneumonia
recurrent bronchiolitis in infancy and early childhood, 2-12 years
recurrent lower respiratory tract infections, chronic lung Malabsorption 85
disease, bronchiectasis, steatorrhoea and with increasing Recurrent pneumonia 60
Nasal polyposis 6-36
age, pancreatitis, and azoospermia. Pancreatic insuffi- Intussusception 1-05
ciency is present in > 85% of CF patients (Table 13.11.1). >13 years
Chronic Pulmonary disease 70
Diagnosis Clubbing
The diagnosis of CF should be suspected by the presence Abnormal GTT 20-30
DM 7
of a typical phenotype or family history and confirmed
Chronic intestinal obstruction 10-20
by the demonstration of a high sweat chloride (> 60 mEq/ Focal biliary cirrhosis
L) on repeated measurements and/or by identifying two Portal hypertension 25
CF causing mutations. Nasal potential difference Gall stones 4-14
measurements can be used as an adjunct to sweat test Azoospermia 98%
but is not widely available.
In the absence of sweat chloride estimation and the number of infecting organisms and suppressing the
mutation analysis at most centers in India, CF may be inflammatory process and hyperreactivity of airways.
suspected by supportive investigations. An algorithm The principle components of care used to achieve this
based on clinical features and laboratory investigations includes airway clearance techniques, antibiotics and anti
is given in Figure 13.11.1 for making a diagnosis of inflammatory agents
suspected CF.
Airway Clearance Techniques
Management
The airway secretions are very viscid in CF. They are
The treatment of cystic fibrosis in children includes very difficult to clear and lead to secondary infections
respiratory management, nutritional care, anticipation and damage to respiratory tract. Airways can be kept
and early diagnosis of liver disease, diabetes and other clear by adequate hydration, chest physiotherapy,
organ dysfunction. judicious use of antibiotics and mucolytic agents. To keep
the secretions less viscid it is important to maintain good
Respiratory Management hydration by ensuring intake of plenty of liquids and
Respiratory manifestations are important cause of extra salt.
morbidity during childhood in children with CF. In
Chest Physiotherapy
majority respiratory illness is main cause of mortality.
Lung damage in cystic fibrosis is caused by excessive Chest physiotherapy techniques for keeping airways
poorly effective inflammatory processes in response to clean includes following methods:
bacterial infection of normally sterile airways. Respi- 1. Postural drainage and chest clapping
ratory therapy aims to limit lung damage by decreasing 2. Active cycles of breathing
 Diseases of Gastrointestinal System and Liver 641

Figure 13.11.1: Suggested algorithm for diagnosis and management of cystic fibrosis in resource limited setting

3. Positive expiratory pressures (PEP) Mucolytic Agents

4. High pressure PEP
5. Flutter therapy
6. Autogenic drainage
7. High frequency chest wall oscillation (HFCWO)
The method can be selected for an individual on the
basis of age of patient, clinical status, experience of
physiotherapist, personal preference of patients, social
issues including level of support etc. They can be used
under supervision of physiotherapist.
Various mucolytic agents have been used by oral as well
as in-halation route. N-acetyl cystein breaks the
sulphydryl bonds of the mucous glyco-protein thereby
reducing the viscosity of airway secretions. Because of
its offensive odor and propensity to cause bronchospasm,
hemorrhagic tracheitis and impaired ciliary clearance, it
is not used. Recombinant human DNase (rhDNase): In CF
patients, there is inordinately high concentration of DNA
642 IAP Textbook of Pediatrics
in respiratory secretions that is released by disintegrating
inflammatory cells. DNAse, given as aerosol, increases
mucociliary clearance and reduces incidence of
respiratory infections; it also decreases rate of
hospitalization, number of days missed from work or
school and the frequency of CF related symptoms.
Hypertonic saline (7% saline) inhalation is relatively
inexpensive and may be used in place of DNAse which
is very expensive.
Antibiotic Therapy
The commonly encountered microbial agents causing
pulmonary exacerbation in children with CF include
Staphylococcus aureus, Haemophilus influenzae b, Pseudo-
monas spp, Burkholderia cepacia etc. Different viruses,
mycoplasma, Mycobacterium spp, and aspergillus are
other important pathogens responsible for pulmonary
exacerbation. It is important to select an antibiotic on
basis of organisms isolated from respiratory secretions.
The organisms can be isolated by obtaining cough swab,
sputum or deep throat swabs after physiotherapy
(DTSP). Periodic cough swab cultures may help in
empirical treatment of acute exacerbation.
The treatment of acute exacerbation of infection if the
patient is known to be colonized with Pseudomonas
include ceftazidime, or cefoperazone or piperacillin or
imipenam or meropenam in combination with an
aminoglycoside. If the colonization status is not known
then a combination of drugs effective against Pseudo-
monas and Staphylococcus are used empirically. These
drugs may be started early and given for 2-3 weeks.
Aerosolised antibiotics: The airways of CF patients get
colonized with Pseudomonas spp. and may be responsible
for frequent exacerbation. Use of prolonged use of
aerosolised antibacterials by nebulizer has shown to
improve pulmonary function and decrease pulmonary
exacerbation. The drugs commonly used are tobramicin
or colistin.
Bronchodilator and Inhalation Steroid Therapy
Bronchial hyper-responsiveness occurs in 25-50% patient
particularly during intercurrent infections and in those
with poor baseline lung function. Some patient may have
atopic asthma as well as cystic fibrosis. These patients
should be treated for asthma on usual guidelines.
Nutritional Management of CF
The main aim of nutrition management is to achieve
normal growth and development of children. Nutritional
management of CF can be discussed as follows:
i. Increasing caloric intake
ii. Supplement fat soluble vitamins
iii. Replace pancreatic enzymes.
Increase Caloric Intake
The caloric need increases in situations with persistent
chest infection or frequent pulmonary exacerbations.
Caloric demand may increase up to 50% during acute
pulmonary exacerbation. Caloric intake can be increased
by encouraging the child to eat energy rich food
throughout day e.g. – full fat dairy products and fried
food. Parents should be told not to restrict fat in the child’s
diet.
Oral Caloric Supplements
In addition to caloric needs, supplementary feeds by
using commercial preparations or home made feeds can
be used. It should be kept in mind that the caloric
supplements are given in addition to the regular meals.
Nasogastric and Gastrostomy Feeding
In some patients short term/long term nasogastric or
gastrostomy feeding is required. Indications for
nasogastric feeding are (1) no weight gain for 6 months
even with adequate caloric intake, (2) acute pulmonary
exacerbation with poor oral intake, (3) consistently poor
appetite and inability to maintain caloric intake, (4) before
major surgical procedures, (5) during periods of
increased caloric requirement e.g. puberty and preg-
nancy.
Supplementation of Fat-Soluble Vitamins and Minerals
Children with pancreatic insufficiency are at risk of
developing deficiency of fat-soluble vitamins. Children
should receive 2 times the daily recommended doses of
vitamin A, D and E. Vitamin K is given in presence of
clinical manifestation of deficiency and those having liver
disease.
 Diseases of Gastrointestinal System and Liver
Increased sweating in hot weather may result in
clinical manifestations of hyponatremia. Sodium
supplement is recommended in hot climate. They may
be allowed to take extra salt in their meals during hot
and humid climates.
Pancreatic Enzyme Supplement
Regular enzyme supplement in form of enteric-coated
spherules has improved nutritional management
significantly. The enzyme preparation is given with
meals. The pancreatic supplements can be given in form
of capsules or the spherules can be sprinkled over small
amount of food and given before meals in infants and
young children who are not able to swallow capsules.
Doses can be adjusted by observing stool consistency and
weight gain in the child.
Management of other GIT Manifestations
The common GI manifestations in CF include pain
abdomen, abdominal distention, meconium ileus
equivalent, intussusception, meconium peritonitis and
liver disease.
Pain abdomen in CF may be due to pancreatic
insufficiency, rectal prolapse, gastroesophageal reflux,
or intestinal obstruction. Pain and abdominal distention,
rectal prolapse due to pancreatic insufficiency respond
after increasing doses of enzymes.
For gastroesophageal reflux prokinetic agents along
with H-2 receptor antagonist are required. Pain abdomen
secondary to constipation can be treated with oral
lactulose in doses of 1 ml/kg/day in 2 divided doses.
Management of Liver Disease in CF
With improved survival, liver involvement in CF is
recognized more frequently. Early administration of
ursodeoxycholic acid (UDCA) may improve outcome
of liver disease in children with CF. It is speculated that
ursodeoxycholic acid may prove to affect the natural
history of cystic fibrosis-related liver disease.
Assessment and Monitoring
CF is chronic illness and require regular follow-up at
centers that have experience in managing these patients.
They should visit CF clinics every 2-3 months for clinical
assessment. The assessment includes clinical monitoring,
643
spirometry and anthropometry. All children need a detail
clinical and lab assessment annually.
Gene Therapy
CF is caused by mutations of the cystic fibrosis
transmembrane conductance regulator (CFTR) gene.
Consequent to mutations in parental genes; airway
epithelial cells have insufficient CFTR function. Because
this can be corrected in vitro by transfer of the normal
CFTR gene into airway epithelial cells, it is reasonable to
hypothesize that the respiratory manifestations of CF
could be prevented by transfer of the normal CFTR cDNA
to airway epithelium in vivo. Studies with experimental
animals demonstrated that inhalation of gene with a
vector in the airways, CFTR cDNA could be transferred
to the airways epithelium, with expression of the human
CFTR cDNA for at least 6 weeks. This is still experimental
and details of ongoing trial are awaited eagerly. Till now
no major success has been reported.
Prognosis
The median life expectancy for cystic fibrosis is now over
30 years, and it is projected that in newborn infants it
will become more than 40 years. With the identification
of the cystic fibrosis gene and its product, cystic fibrosis
transmembrane conductance regulator (CFTR), it has
been possible to discover the wide-spectrum of the
disease from the classical case of the infant with cystic
fibrosis to the elderly childless man with unexplained
bronchiectasis. There is increasing evidence of the
advantages of newborn screening for cystic fibrosis and
subsequent specialist care. Management concentrates on
optimizing nutritional status and preventing lung
infection and inflammation. Survival analysis of Indian
children with CF suggest that early mortality was
associated with early onset (below 2 months) of
symptoms, severe malnutrition at the time of diagnosis,
more than four episodes of pulmonary exacerbations in
a year and colonization with pseudomonas.
Prenatal Diagnosis
As of today there is no cure for CF. It is an autosomal
recessive disease there are 25% chances of affected child
644 IAP Textbook of Pediatrics
in each pregnancy. With the identification of genetic
mutations in a child and parents, now it is possible to
make a prenatal diagnosis by chorionic villous (CV)
biopsy around 10-12 weeks or amniotic fluid cell culture
at 15-16 weeks of gestation in future pregnancies, in
addition pre implantation diagnosis that is also possible.
BIBLIOGRAPHY
1. Kabra SK, Kabra M, Lodha R, Shastri S. Cystic fibrosis in
India. Pediatric Pulmonology 2007;42:1087-94.
13.12 Juvenile Tropical Pancreatitis
Juvenile tropical pancreatitis (JTP) is a form of chronic
calcific non-alcoholic pancreatitis. It is the commonest
cause of pancreatitis in children in the tropical countries.
Some of its synonyms are nutrititional pancreatitis,
tropical pancreatitis, Afro-Asian pancreatitis and
fibrocalculous pancreatic diabetes.
Epidemiology
JTP was first reported by Zuidema from Indonesia in
1955. Subsequently it was reported from other Asian
countries like India, Bangladesh, Sri Lanka, Malaysia and
Thailand, and African countries like Uganda, Nigeria,
Congo, Zambia and Ghana. A few cases have been
reported from Brazil also.
In India, the highest incidence is in the south eastern
part of Kerala, the prevalence being 125/100000
population. A few cases have been reported from the
other southern states like Tamil Nadu, Karnataka and
Andhra Pradesh and also from the eastern state of Orissa.
It is very rare in the northern and western parts of India.
As it is restricted to a belt between latitudes 30 degrees
north and south of the equator, the term tropical
pancreatitis is appropriate.
Etiopathogenesis
The exact pathogenesis is not known, but the following
factors may predispose to it:
2. Kabra SK, Kabra M, Shastri S, Lodha R. Diagnosing and
managing cystic fibrosis in the developing world.
Paediatr Respir Rev 2006;7 Suppl 1:S147-50.
3. Kabra SK, Kabra M. Cystic fibrosis in India. Natl Med J
India 2003;16:291-93.
4. Kabra SK, Kabra M, Lodha R, Shastri S, Ghosh M, Pandey
RM, Kapil A, Aggarwal G, Kapoor V. Clinical profile and
frequency of delta f508 mutation in Indian children with
cystic fibrosis. Indian Pediatr 2003;40:612-19.
5. Taccetti G, Campana S, Neri AS, Boni V, Festini F.
Antibiotic therapy against Pseudomonas aeruginosa in
cystic fibrosis. J Chemother 2008;20:166-69.
A Riyaz
PEM and Free Radicals
JTP is almost exclusively seen in the poor children of
developing countries with severe PEM. PEM also leads
to increased production of free radicals, which also may
cause pancreatic damage. The deficiency of free radical
scavengers like vitamin C, E, beta-carotene, zinc,
selenium etc in PEM also contributes to pancreatitis.
However, the incidence of JTP is very low in some
poor countries with a high incidence of PEM like
Ethiopia. Besides, kwashiorkor is not associated with
pancreatitis and pancreatic stones are not seen even in
advanced stages of kwashiorkor. PEM thus very well
could be the effect rather than the cause of the disease.
Cassava Toxicity (Cyanogen Toxicity)
Cassava (tapioca, Manihot esculenta) is a tuber rich in
carbohydrates but very poor in proteins (0.4 g%)
especially methionine and cysteine. It is the staple food
of about 400 million people in the developing countries,
where JTP is common. It is very popular in the south
eastern belt of Kerala, from where most of the cases of
JTP are reported.
It contains toxic cyanogenic glycosides like linamarin
and methyl linamarin (Iotaustralin). These react with
gastric hydrochloric acid to form the toxic hydrocyanic
acid. The enzyme rhodanase detoxifies hydrocyanic acid
to thiocyanate in a reaction requiring sulphur containing
amino acids like methionine and cysteine. As these amino
 Diseases of Gastrointestinal System and Liver
acids are essential for the proper functioning of pancreas,
pancreatitis results. Besides, these toxins can also injure
the pancreas directly. Sorghum, which is the staple diet
of the people of the rural belt of Karnataka, is also rich in
cyanogenic glycosides. This may be responsible for JTP
in this state.
However, the cassava hypothesis lacks experimental
support.
Familial Aggregation
JTP sometimes affects several members of the same
family. This suggests, but does not necessarily prove a
hereditary etiology for JTP, since several members of a
family could be exposed to the same toxic or other
environmental factors.
Genetic Factors
SPINK 1 is a potent protease inhibitor which is a major
protective mechanism preventing inappropriate
activation of pancreatic enzyme cascade by inhibiting up
to 20% of trypsin activity. The absence of SPINK 1 gene
may predispose to chronic pancreatitis in general and
JTP in particular.
Pathology
The pancreas is markedly atrophied and may be as small
as the little finger in advanced stages of the disease. There
is extensive intralobular and interlobular fibrosis.
Immunohistochemistry has shown paucity of alpha cells
and beta cells. There are advanced fibrosis and calculi of
varying shapes and sizes. They are composed of 95.5%
calcium carbonate and small amounts of calcium
phosphate and traces of magnesium, urate and oxalate.
Clinical Features
The clinical features of JTP can be aptly summarized as
recurrent abdominal pain in childhood, diabetes mellitus
and pancreatic calculi by adolescence and death in the
prime of life, due to severe malnutrition, complications
of uncontrolled diabetes and carcinoma of pancreas.
Abdominal Pain
Recurrent severe abdominal pain that radiates to the back
is the chief complaint. It may be associated with vomiting.
The child may get up in the middle of the night with
645
severe pain that disturbs his sleep. The pain is increased
by food and hence he refuses to eat. This aggravates PEM.
Thus, a vicious cycle is produced causing persistent
damage to the pancreas. As the disease progresses, the
severity of pain tends to decrease and it usually
disappears with the onset of exocrine pancreatic
insufficiency
Unfortunately, abdominal pain is usually passed off
as functional pain by the parents and doctors, and hence
the diagnosis is very much delayed.
Diabetes Mellitus
Diabetes is an inevitable consequence of JTP and occurs
one or two decades after the first episode of abdominal
pain. It is referred to as fibrocalculous pancreatic diabetes
(FCPD). It is brittle with episodes of hypo and hyper-
glycemia, with or without insulin therapy.
One of the characteristic features of FCPD is that
despite requiring insulin for control, ketosis is rare unlike
type I diabetes. .However, microvascular complications
do occur.
Exocrine Pancreatic Insufficiency
Steatorrhoea is seen in only 20% of patients with JTP.
This is only because these children consume very little
fat due to the poor appetite. If a high fat diet is given
most of them will develop steatorrhea.
Diagnosis
The association of diabetes mellitus and recurrent
abdominal pain in a young patient suggests the diagnosis
of JTP. Extreme emaciation, a peculiar cyanotic hue of
the lips, bilateral painless parotid gland enlargement,
retarded growth and development, potbelly and
hepatomegaly are seen in most of the patients.
Complications
1. Severe malnutrition.
2. Both microvascular and macrovascular complications
may occur in FCPD. However, macrovascular
complications are relatively rare as the patients are
young, lean and have lower lipid levels.
3. Complications due to chronic pancreatitis like
pseudocysts, pancreatic abscess and ascites may
rarely occur.
4. Carcinoma of pancreas is the most sinister compli-
cation of JTP. The risk factors for cancer remain
unknown.
646 IAP Textbook of Pediatrics

Investigations Endoscopic and Surgical Treatment

1. Plain radiograph of the abdomen shows pancreatic
calculi, usually to the right of L 1 and L2 vertebrae.
They are most numerous in the head of the pancreas.
2. Ultrasound and CT scan detect smaller pancreatic
calcifications not evident on radiographs and also
complications like carcinoma of pancreas.
3. Endoscopic retrograde cholangiopancreatography
shows a dilated main pancreatic duct with radio
opaque and lucent calculi.
4. Endoscopic ultrasonography is an exciting new tool
for the diagnosis of chronic pancreatitis.
Management
Medical
Therapy is directed towards repletion of nutritional
deficits and the management of chronic pain. Diabetes
is managed with insulin or at times with oral hypo-
glycemic agents. Pancreatic enzymes may be given if the
child has steatorrhoea. It may also decrease abdominal
pain because suppression of pancreatic secretion reduces
intraductal pain. Antioxidant supplementation may also
help to decrease pain.
Exploration of the pancreatic duct and removal of stones
or endoscopic papillotomy and removal of stones are
useful procedures. Severe pain is an indication for
surgical treatment
Puestow-Gillesby operation: Ductal decompression and side
to side pancreaticojejunostomy.
Duval’s procedure: here, distal pancreaticojejunostomy is
done.
Ablative procedures like partial or subtotal pancrea-
tectomy are done in those with intractable pain.
BIBLIOGRAPHY
1. Barman KK, Premalatha G, Mohan V. Tropical chronic
pancreatitis. Postgrad Med J 2003;79:606-15.
2. Narendranathan M. Chronic calcific pancreatitis of the
tropics. Trop Gastroenterol 1981;2:40-45.
3. Pitchumoni CS. Juvenile tropical pancreatitis. Walker
WA, Durie PR, Hamilton RJ, Smith JAW, Watkins JB
(Eds). Paediatric gastrointestinal disease patho-
physiology, diagnosis and Management. 2nd edn. Mosby
St. Louis: Missouri 1996;1502-10.
4. Schneider A, Suman A, Rossi L, et al. SPINK 1/PSTI1
mutations are associated with tropical pancreatitis and
type 2 diabetes in Bangladesh. Gastroenterology
2002;123:1026-30.

13.13 Liver and Biliary System

B Bhaskar Raju, B Sumathi

EMBRYOLOGY
The hepatobiliary system consists of the liver, gallbladder
and bile ducts. It develops from an endodermal
outgrowth that arises from the ventral aspect of the gut
at the junction between foregut and midgut called the
hepatic diverticulum during fourth week of embryo-
genesis. The hepatic diverticulum divides into two parts:
pars hepatica (larger cranial part, the primordium of the
liver) and pars cystica (smaller ventral invagination, the
primordium of gallbladder) (Fig. 13.13.1). The endo-
dermal cells of the hepatic diverticulam form the hepatic
parenchyma and bile capillaries. The mesenchyme of
septum transversum forms the capsule, fibrous tissue of
the liver and Kupffer cells. Umbilical and vitelline veins
are broken up to form the sinusoids of the liver and they Figure 13.13.1: Embryology
 Diseases of Gastrointestinal System and Liver
are also formed from the mesenchyme of the septum
transversum. The pars cystica of the hepatic bud forms
the gallbladder, the cystic duct and extra-hepatic bile
ducts.
ANATOMY
Liver is the largest organ in the body and is relatively
larger in infancy comprising one–eighteenth of the birth
weight. It is apparently divided into right and left lobes
by the falciform ligament. Right lobe contains the caudate
and quadrate lobes. Actually, the principle plane which
divides the liver into functional lobes passes through the
bed of the gallbladder. Anatomical variations include
accessory lobes, Riedl’s lobe (downward tongue like
projection of the right lobe of the liver, occasionally
palpable per abdomen, more common in girls). The
biliary system comprises of biliary canaliculi which
combine to form bile ductules, bile ducts, right and left
hepatic ducts which unite to form the common bile duct
(CBD) at porta hepatis. The common bile duct enters the
second part of duodenum, along with the main
pancreatic duct at the ampulla of Vater. The distal end
of the common bile duct contains the sphincter of Oddi
which prevents bile flow during fasting (Fig. 13.13.2).
Blood Supply
The liver has a dual blood supply. 75% of the blood
supply to the liver is from the portal vein which carries
nutrient rich but oxygen-poor venous blood to the liver
from the intestines and spleen. The hepatic artery (a
branch of the celiac axis) carries well-oxygenated arterial
blood to the liver (50 to 80% of the liver’s oxygen supply)
and accounts for the remaining 25% of the blood supply.
Figure 13.13.2: Hepatobiliary system
647
The venous drainage is by three main hepatic veins
which drain directly into the inferior vena cava(IVC)
except the caudate lobe which has independent drainage
to IVC. The cystic artery and vein, perfuse the gallbladder
and biliary apparatus.
Lymphatic Drainage
Lymphatics from both lobes drain into the nodes at the
porta hepatis, celiac axis, mediastinal nodes and those
along the intra thoracic portion of IVC. Lymphatics of
the gallbladder drain into the cystic node, nodes along
the CBD and head of pancreas.
Morphology
The hepatic lobules form the basic liver architecture. The
lobules are separated from the portal tract by limiting
plates (Lamina Limitans) (Fig. 13.13.3).
• At the center of each lobule run the tributaries of the
hepatic veins carrying back venous blood from the
liver.
• At the junction of three hepatic lobules run the portal
tracts, consisting of the branches of the portal vein,
hepatic artery, and the bile duct.
Columns of liver cells and sinusoids extend between
these two systems. The microscopic spaces between the
hepatocytes and the bordering sinusoids—are the ‘Spaces
of Disse’ and they contain tissue fluid, flowing into the
hepatic lymphatics.
FUNCTIONS OF THE LIVER
• Production of bile that excretes bilirubin, the end
product of hemoglobin metabolism and Copper. Bile
Figure 13.13.3: Structure of the liver lobule
648 IAP Textbook of Pediatrics
is also rich in phospholipids (predominantly
phosphatidylcholine) that form mixed vesicles and
micelles with bile salts and thereby provide a means
for the disposal of highly lipophilic endogenous and
exogenous compounds, such as cholesterol, from the
body.
• Production of plasma proteins (Albumin, Globulin,
Fibrinogen); transport proteins; coagulation factors
(fibrinogen, prothrombin, V, VII, IX, X, XIII) and
components of the complement system.
• Production of cholesterol and special proteins which
help to carry lipids throughout the body.
• Conversion of excess glucose into glycogen for storage
(This glycogen can later be converted back to glucose
for energy).
• Regulation of blood levels of amino acids, which form
the building blocks of proteins.
• Processing of hemoglobin for use of its iron content
(The liver stores iron).
• Conversion of poisonous ammonia to urea (Urea is
one of the end products of protein metabolism that is
excreted in the urine).
• Storage of vitamins A, D, E, K, B12, Iron and Copper.
• Detoxification of drugs and other poisonous sub-
stances.
• Resisting infections by producing immune factors and
removing bacteria from the portal blood stream.
SIGNS AND SYMPTOMS OF LIVER DISEASE
Jaundice, nausea, dark urine, light-colored stools, pain
in the upper right part quadrant of abdomen, pruritus,
varicose veins in the esophagus, fatigue, hypoglycemia,
low grade fever, muscle aches and pains, unusual weight
loss or weight gain, vomiting, diarrhea, loss of sex drive
in adolescents, depression, malaise, or a vague feeling of
illness, loss of appetite, fluid retention, neuropsychiatric
symptoms and hepatomegaly are some of the important
signs and symptoms of liver disease.
Liver span: It is the distance between upper and lower
borders of the liver, estimated by percussion in the right
mid-clavicular line. The liver span increases linearly with
body weight and age in both sexes. Normal values in
infants are about 5-7 cm, in 5 yrs old it is 7-8 cm and in
10-12 yrs old it is 9-10 cm. A decreased liver span is seen
in cirrhosis (shrunken liver). Acute hepatocellular
necrosis also shows rapid reduction in liver span. If a
rapid increase in liver span is seen, we should exclude a
space occupying lesion.
1. Jaundice (icterus) is yellowish discoloration of skin
and mucus membranes- especially, elastin rich
tissues like sclera due to hyperbilirubinemia. It is
clinically detectable when serum bilirubin is >2.5
mg/dl. Hyperbilirubenemia may be due to (1)
Excess production of bilirubin, e.g. hemolytic
anemia, (2) Decreased uptake of bilirubin into
hepatic cells, (3) Disturbance in conjugation, (4)
Obstruction to bile flow.
2. Pruritus or itching is due to deposition of bile salt
or similar pruritogenic factor/factors produced in
the liver in the skin and is seen in cholestatic
jaundice.
3. Abdominal pain in the epigastrium/right hypo-
chondrium is due to distended liver causing
capsular stretch, caused by viral hepatitis, con-
gestive hepatomegaly, liver abscess, perihepatitis
and or cholangitis.
4. Pale or clay colored stools seen in cholestatic
conditions indicates the absence of bile in the
intestines due to obstruction to flow and usually
leads to fat malabsorption.
5. Dark colored urine is seen in all types of jaundice
except hemolytic jaundice (acholuric jaundice) due
to excretion of conjugated bilirubin in the urine.
6. Symptoms due to vitamin deficiencies include night
blindness (vitamin A); bone deformities (vitamin D);
bleeding tendencies (vitamin K and clotting factors)
7. Fluid retention. The presence of ascites, pedal edema
and bilateral hydrothorax suggests hypoalbumi-
nemia. Fluid retention due to Portal hypertension
is usually localised to the abdomen.
8. Abdominal distension in liver disease may be due
to ascites and or hepato/hepatosplenomegaly.
9. Neuropsychiatrist symptoms like confusion,
drowsiness, altered sleep rhythm, may be due to
hepatic encephalopathy.
10. Symptoms like anorexia, nausea, vomiting, malaise
constitute the usual prodrome in acute hepatitis.
SYMPTOMS OF LIVER FAILURE
An enlarged and tender liver which rapidly shrinks,
altered sensorium, coagulopathy, encephalopathy,
ascites and aplastic anemia may be evidence of acute liver
cell failure.
 Diseases of Gastrointestinal System and Liver
AIM OF THE INVESTIGATIONS
A single liver function test is of little value in screening
for liver disease as some serious liver diseases may be
associated with normal levels of individual tests.
Selective combination of tests may be required to identify
liver disease and diagnose the etiology. Tests of liver
function and disease are done for:
a. To detect hepatic abnormality
b. Measure severity of liver damage
c. Identify the specific cause of the liver disease
d. Investigations to diagnose possible complications
INVESTIGATIONS FOR LIVER DISEASE
1. Baseline investigations: Complete hemogram, ESR,
smear study.
2. Serum bilirubin (normal< 1 mg/d1. 80% uncon-
jugated). If the conjugated fraction is >20% of total
bilirubin, it may suggest cholestasis.
3. Serum aspartate transaminase (AST) or (SGOT):
Normal-5-35 IU/L. Serum alanine transaminase
(ALT) or (SGPT) normal-5-35 IU/L. Elevated levels
indicate hepatocyte injury. AST (SGOT) is sensitive
but ALT (SGPT) is more specific for liver disease.
(SGOT is also present in heart, skeletal muscle and
kidney).
4. Serum alkaline phosphatase (ALP) (Normal 3-13 KA
units/dl or 21-100 IU/L) is raised in liver disease
and cholestasis.
5. Gamma glutamyl transpeptidase (GGTP) (Normal
7-30 IU/L) is also raised in cholestasis. Its activity is
induced by drugs like phenobarbitone, rifampicin
and also by alcohol and they may elevate its blood
levels.
6. Serum proteins: Albumin (normal 4.5-5.5 g/dl). Low
levels indicate poor synthetic function. Low albumin
suggests poor prognosis in fulminant hepatic failure.
It is usually low in decompensated chronic liver
disease (<3 g/dl). Globulin (Normal 1.5 g/dl) may
be raised in cirrhosis. Reversal of albumin/globulin
ratio occurs when raised gamma globulins are
accompanied by fall in serum albumin levels. That
occurs in cirrhosis and similar inflammatory chronic
liver diseases
7. Prothrombin time (PT): (Normal 10-14 sec).
Prolonged PT indicates severe liver damage or poor
absorption of Vit K. If uncorrected by parenteral Vit
K, it indicates poor prognosis in liver disease
649
8. Activated partial thromboplastin time (PTTa):
Prolonged PTTa suggests coagulopathy. It is usually
accompanied by prolonged Prothrombin time
9. Antimitochondrial antibody (AMA); Elevated levels
are seen in primary biliary cirrhosis and auto-
immune chronic active hepatitis.
10. Viral markers for Hepatotrophic viruses A to E.
11. PCR (Polymerase chain reaction) can be used to
confirm viral etiology.
12. Ultrasonogram of abdomen to assess the liver
echotexture, splenoportal axis, collaterals in portal
hypertension, presence of ascites, space occupying
lesions.
13. CT scan of abdomen.
14. Liver biopsy is used to confirm the tissue diagnosis.
It is also useful in follow up of chronic liver disease
and for the assessment of effect of therapy.
15. Hepatobiliary radioisotope scan is used to asses the
excretory capacity of the liver and delineate the
extrahepatic biliary passages.
16. Splenoportovenogram is no longer preferred for
diagnosis. Some hepatologists however still consider
it as the “gold standard test” for delineating portal
anatomy, but it has been mostly replaced by non
invasive imaging techniques now.
17. Procollagen III: Serum concentration of procollagen
III peptide is used as surrogate marker for hepatic
fibrosis. It may also be raised in chronic infla-
mmation in the liver. It is useful in follow up of
chronic liver disease.
BIBLIOGRAPHY
1. BR. Thapa and Anuj Walia, Liver Function Tests and their
Interpretation. Indian Journal of Pediatrics 2007;74.
2. Daniel S, Pratt, Marshall M. Kaplan. Evaluation of liver
function; Harrison’s Principles of internal medicine; 16th
edition; McGraw Hill Medical publishing division
2005;2:1813-16
3. Inderbir Singh, GP Pal. Human embryology, Chapter 14
Liver, Pancreas, Spleen; Respiratory system; Body
cavities, Seventh edition 2001;187-88.
4. Sheila Sherlock, James Dooley. Disease of the Liver and
biliary system, Eleventh Edition 2002; Blackwell Science
publications, 1-17.
5. Sleisenger, Gastrointestinal and Liver Disease; Patho-
physiology/Diagnosis/Management 7th Edition,
Saunders Publications 2002;2.
6. William F.Ganong, Review of medical physiology,
Regulation of Gastrointestinal Function Chapter 26;
Twenty second edition. International edition 2005;
500-503.
650 IAP Textbook of Pediatrics

13.14 Hepatosplenomegaly: A Practical

Diagnostic Approach
Sheila Bhave, Ashish Bavdekar

Hepatomegaly is a common clinical problem in infants

and children. Many disease processes, which may or may
not be primarily hepatic, cause liver enlargement. The
pathophysiological mechanisms causing hepatomegaly
are:
• Infection, inflammation (hepatitis, fibrosis)
• Kupffer cell hyperplasia
• Venous congestion
• Storage of glycogen, fat and other metabolites (inborn
errors)
• Infiltrations
• Tumors, neoplasia.
Figure 13.14.1: Assessment of hepatosplenomegaly
CLINICAL EVALUATION
Practical Clues
Is it a Primary Liver Disorder or a Part of
Is the Liver Really Enlarged? Generalized Disease?
In infancy and early childhood, the liver may be felt Common pediatric conditions such as protein energy
normally upto 3 cm below the costal margin. In chest malnutrition, anemia and tuberculosis can cause
diseases, such as pneumothorax, bronchiolitis and significant hepatomegaly. History and general clinical
emphysema and in chest deformities such as in rickets, examination can give important clues to these diseases.
the liver may be pushed down giving an ‘apparent’ Primary liver disorders usually present with signs of liver
hepatomegaly. Hence, percussion for the upper border cell failure (e.g. jaundice, ascites) and abnormal liver
of the liver is important in the assessment of hepato- function tests (See chapter 13.13 – Liver and biliary system).
megaly. Age of the Child
Size, Margin, Contour, and Consistency of Liver The age of onset is an important clue to the etiology of
pediatric liver disease (Table 13.14.1). Neonatal
Size of the liver is better assessed by ‘liver span’, i.e.
cholestasis syndrome presents in early infancy; Indian
height of the liver in right mid clavicular line (superior
childhood cirrhosis occurs typically in preschool children
border by percussion and inferior border by palpation
whereas Wilson’s disease affects older children and
Fig. 13.14.1).
adolescents.
Epigastrium should always be palpated for the left
lobe. Firm to hard consistency with sharp margin, usually
Other Clues in History and
implies cirrhosis or fibrosis. Soft, enlarged and tender
General Physical Examination
livers occur in inflammatory and congestive processes
such as viral hepatitis and congestive heart failure (CHF). Helpful clues are:
An isolated mass felt in an otherwise normal liver or an • Onset: acute (viral hepatitis) or chronic (as in cirrhosis,
asymmetric enlargement may suggest tumor or cyst. chronic hepatitis)
 Diseases of Gastrointestinal System and Liver 651

TABLE 13.14.1: Common causes of hepatosplenomegaly according to age

Neonates and infants Children and adolescents

Intrauterine infections (TORCH) Infection-Acute

Neonatal cholestasis syndrome (NCS) Viral hepatitis A-E
Biliary atresia Dengue, typhoid, leptospirosis
Neonatal hepatitis Infection: Chronic
Erythroblastosis (Rh, ABO incompatibility) Tubercular, malaria, kala azar
Congestive heart failure (CHF) Liver cirrhosis
Sepsis, systemic viral infections Indian childhood cirrhosis
Metabolic liver disease Budd Chiari, veno-occlusive disease
Galactosemia Chronic active hepatitis
Tyrosinemia, Alpha 1 AT deficiency Wilson’s disease
Hemochromatosis Extra hepatic portal hypertension
Secondaries Hepatic fibrosis
Wilms’ tumor, Neuroblastoma Cystic fibrosis
Metabolic liver disease
Glycogen storage disease
Gaucher’s, Niemann-Pick disease
Mucopolysaccharidosis
Hematological disorders
Hemolytic anemias
Leukemia, lymphoma
Cysts (congenital, hydatid)
Abscesses (amebic, pyogenic)

• Fever: typhoid, dengue, malaria, tuberculosis TABLE 13.14.2: Associated clinical manifestations which
• Family history and consanguinity: Wilson’s disease, aid in diagnosis of hepatomegaly
thalassemias
Clinical features Clues to diagnosis
• Hepatotoxic drugs: anti-tubercular, anti-epileptic,
anti-cancer drugs Microcephaly/ Intrauterine infections (e.g. Rubella,
• Anemia: hemolytic anemias, leukemias Hydrocephalus Toxoplasmosis, CMV)
• Lymphadenopathy: disseminated tuberculosis, Cataracts Galactosemia, Wilson’s disease
malignancy (some other clinical clues to diagnosis are KF rings Wilson’s disease
given in Table 13.14.2). Tremors, dysarthria Wilson’s disease
Mental retardation Galactosemia; lipid storage
Important Associated Features in Engorged neck veins- Congestive heart failure, constrictive
Differential Diagnosis of Hepatomegaly pericarditis
Jaundice: Obstructive/ Hemolytic/ Hepatocellular. Each Rickets Wilson’s disease, Tyrosinemia
type is associated with different group of diseases (See Cystic kidneys Congenital hepatic fibrosis
Chapter 13.15 on Jaundice). Skin rashes Histiocytosis
Splenomegaly is commonly associated with hepato-
megaly because of common pathogenetic mechanisms.
Causes of predominant and massive splenomegaly are Scheme of Investigations
seen in Table 13.14.3.
The scheme of investigations should be directed
Ascites, edema and bleeding tendencies are signs of
liver damage. Drowsiness (precoma, coma) and judiciously at detecting the etiology and the mechanism
gastrointestinal hemorrhage (hematemesis, malena) are of hepatomegaly as also the extent and severity of the
ominous signs of impending hepatic failure (see chapter disease. (see Chapter 13.13 Liver and Biliary Tract). Special
13.21 on Fulminant Hepatic Failure). additional tests are given in Table 13.14.4.
652 IAP Textbook of Pediatrics

TABLE 13.14.3 Causes of massive hepatosplenomegaly TABLE 13.14.4 Special tests in diagnosis of
hepatosplenomegaly
Predominant enlargement of

Liver
Glycogen storage disease
Congenital hepatic fibrosis
Tumor (Hepatoma,
secondaries)
Cyst (hydatid, abscess)
Chronic extrahepatic
cholestasis
}
Spleen Hemogram, ESR, rectic count,
Urine routine, culture
Gaucher’s disease
Liver function tests (See chapter 12.12 Liver and
Hemolytic anemias Liver biopsy Biliary System)
USG abdomen, CT scan
Extra hepatic portal Radioisotopic scanning – esp. for Neonatal cholestasis syndrome
hypertension
Additional Special Tests
Chronic myeloid leukemia • Viral markers Hepatitis A-E Dengue
(juvenile) • Autoimmune markers Autoimmune hepatitis
• TORCH titres for intrauterine infections
Myelofibrosis
• Metabolic studies
Chronic malaria, kala azar
• Metabolic screen (urine) Metabolic liver disease
Hypersplenism, tropical
and confirmatory tests
splenomegaly
• Enzyme estimations Galactosemia, Gaucher’s
disease, Niemann-Pick
• Urine succinylacetone Tyrosinemia

}
• Copper studies
Progress of Liver Disease/Hepatomegaly
• Ceruloplasmin, urinary
Important conclusions can be based on careful follow- Cu
• Cu stains on liver biopsy ICC, Wilson’s disease
up of hepatomegaly. Benign hepatomegaly associated
• Hepatic Cu
with common febrile illnesses of children usually recedes • Alpha fetoprotein Hepatoblastoma, tyrosinemia
completely within a few weeks. So also most cases of • Sweat chloride Cystic fibrosis
acute viral hepatitis resolve within 3 to 6 weeks. On the
other hand continued hepatomegaly with signs of
progressive liver failure must be evaluated for chronic 2. Kelly DA. Diseases of the liver and biliary system in
children. Oxford, U.K. Replika Press Pvt. Ltd., Blackwell
liver diseases and cirrhosis (see Chapter on 13.18 and
Science Limited, 1999.
13.19 on Chronic Liver Disorders and Cirrhosis). 3. Scriver CR, Beaudet AL, Sly WS, Valle D. (Eds) The
metabolic and molecular bases of inherited disease. 7th
BIBLIOGRAPHY edn. New York, USA Vol. II. McGraw Hill. 1996.
4. Walker-Smith JA, Hamilton JR, Walker WA (Eds).
1. Bhave SA, Bavdekar AR, Pandit AN. Neonatal cholestasis Practical Pediatric Gastroenterology. (2nd edn). New
syndrome in India: A diagnostic and therapeutic Delhi, India. Jaypee Brothers Medical Publishers (P) Ltd.,
challenge. Indian Pediatr 1996;33:753–62. 1996.
 Diseases of Gastrointestinal System and Liver 653

13.15 Differential Diagnosis of

Jaundice in Infancy
MK Jain, Sunil Karande

COMMON CAUSES OF JAUNDICE IN INFANCY • Dubin-Johnson syndrome

Unconjugated • Rotor syndrome

1. Hemolytic: Congenital spherocytosis, and elliptocy- Laboratory Work up in Hemolytic Jaundice

tosis. • Hb, reticulocyte count, total WBC
• Red cell enzyme deficiency (G6PD) • Direct Coombs test
• Hemoglobinopathies • Urine microscopy
• Autoimmune hemolytic anemia, viral infections • Red cell morphology
2. Septicemia • Peripheral blood smear for malarial parasite
3. Wilson's disease • Blood culture
4. Incompatible blood transfusion • Hb electrophoresis
5. Gilbert's syndrome • Osmotic fragility of RBC
6. Crigler-Najjar syndrome type I and type II.

Conjugated TABLE 13.15.1: The familial nonhemolytic

hyperbilirubinemias
Acute Hepato Cellular Disease
Types Diagnostic points
Viral, bacterial or parasitic metabolic abnormalities,
Unconjugated hyperbilirubinemia
drugs, toxins, nutritional. Primary Clinical picture is of compensated
hyperbilirubinemia hemolysis.
Chronic Hepatocellular Injury Gilbert's syndrome Serum bilirubin increases with
fasting and falls with phenobarbi-
Autoimmune (infective, vascular) (Table 13.15.1 and
tone. Mild deficiency of conjugating
Flow chart 13.15.1). enzyme in liver.
Crigler-Najjar syndrome
Cirrhosis Type 1 Die young with kernicterus.
No conjugating enzyme in liver.
• Post necrotic biliary or genetic
No response to phenobarbitone.
• Infiltrative, e.g. Hodgkin's lymphoma Type 2 Less severe deficiency of
• Intrahepatic cholestasis conjugating enzyme in liver.
• Biliary hypoplasia syndrome Response to phenobarbitone.
• Benign recurrent cholangitis
Conjugated hyperbilirubinemia
Dubin-Johnson Blackish-brown melanin—like
Diseases of Extrahepatic Biliary Tree
syndrome pigment on liver biopsy. No
• Choledochal cyst concentration of cholecystographic
media.
• Choledocholithiasis
Secondary rise in BSP test
• Roundworm obstruction characteristic.
• Sludges Rotor syndrome Normal liver biopsy. Normal
• Bile duct stricture cholescystography. No uptake in
• Familial conjugated hyperbilirubinemia BSP test.
654 IAP Textbook of Pediatrics

Flow Chart 13.15.1: Diagnostic approach to neonatal jaundice

• Heinz body test 2. Fevery J, Blanckaert N, Mclntyre N et al: Hyperbili-

• Test for red cell enzymes, e.g. G6PD, pyruvate kinase etc.
BIBLIOGRAPHY
1. Behrman RE, Kliegman RM,Balistreri WF et al: Metabolic
diseases of the liver. In: Nelson Test book of Pediatrics,
15th Edn., Philadelphia, WB Saunders 1996;1138–41.
rubinemia: In: Oxford Textbook of Clinical Hepatology,
1st Edn, Ed. Rodes J Oxford, Oxford University Press
1991;985–91.
3. Sherlock S, Dooley J: Disease of the liver and biliary
system, 9th Edn., London, Blackwell Scientific Publica-
tions 1993;199–213.
 Diseases of Gastrointestinal System and Liver 655

13.16 Viral Hepatitis

Malathi Sathiyasekaran, Ramaswamy Ganesh

INTRODUCTION days but may persist even for 12 weeks in older children.
During the recovery phase, the constitutional symptoms
Viral hepatitis is a systemic viral infection marked by
disappear, appetite improves and size of the liver
diffuse hepatic cell necrosis and inflammation, which
decreases .The biochemical abnormalities may persist for
leads to a characteristic constellation of clinical,
1-2 months after the acute infection.
biochemical, and pathological changes. Several viruses
can cause hepatitis but the term “viral hepatitis” is
Chronic Viral Hepatitis
usually associated with disease due to hepatotropic
viruses. The major hepatotropic viruses are Hepatitis A, The two viruses which cause chronic hepatitis are
B, C, D, E and G. and the viral “hepatitis alphabet” is hepatitis B (HBV) and hepatitis C (HCV). In India chronic
gradually expanding. Over the years, the newer hepatitis B is more common than chronic hepatitis C since
hepatotropic viruses namely TT and SEN virus have been perinatal transmission plays a very significant role in
associated with transfusion hepatitis though they are less HBV infection.
common. Viruses such as Epstein-Barr, Herpes simplex,
Coxsackie B, Cytomegalovirus (CMV) and some exotic HEPATITIS A
viruses like Marburg and Ebola can also cause hepatitis
Epidemiology
and should be considered in the differential diagnosis.
The two common presentations of viral hepatitis are Hepatitis A virus (HAV) is a 27 nm spherical, non-
acute and chronic hepatitis, occasionally the initial enveloped entero virus of Picorna viridea family
manifestation may be as an acute liver failure. The term (Fig. 13.16.1) HAV infection is endemic in India and in
acute hepatitis is used when the illness is acute in onset most developing countries. The exact incidence of the
and usually lasts less than 4 weeks. The term chronic disease is not known and it is difficult to estimate because
hepatitis implies continuing hepatic inflammation for of the high proportion of asymptomatic cases. According
more than 6 months which can either resolve or progress to WHO about 10-50 persons per 1, 00,000 are infected
to cirrhosis. annually and in India, 50-75 percent of acute sporadic
hepatitis in children is due to HAV. The majority of
Acute Viral Hepatitis (AVH)
In India, the common viruses causing sporadic hepatitis
are hepatitis A (HAV), hepatitis E (HEV) and hepatitis B
(HBV) whereas the epidemics are mainly due to HEV.
In younger children, the classical clinical symptoms may
be absent or may consist of only nausea, vomiting and
diarrhea. In older children the three stages of AVH
namely the prodrome, icteric stage and convalescence
may be more distinct. The clinical presentation is more
or less same whatever may be the viral etiology and hence
it may be difficult to differentiate them clinically. The
prodrome usually lasts for 2-7 days and is characterized
by nausea, vomiting, high colored urine, fever and right
hypochondrial pain. During the icteric stage, the child
has jaundice, pale stools and tender hepatomegaly. The
prodromal symptoms decrease and disappear with the
onset of icterus. The icteric stage usually lasts for 7-14 Figure 13.16.1: Hepatitis A virus
656 IAP Textbook of Pediatrics
children acquire natural immunity by the age of 10 years
without developing symptoms of the illness. Recent
studies have shown a changing epidemiology with a
lower prevalence of anti HAV IgG in the higher
socioeconomic group exposing the susceptible older
children and adolescents to the infection at a later age.
Transmission
HAV is highly contagious and transmission is through
faeco-oral route either due to consumption of contami-
nated food or water. The virus is inactivated by boiling
for 5 minutes, autoclaving or UV radiation. Parenteral
transmission has been reported. Transmission occurs
during the preicteric stage of the disease. Antenatal HAV
infection does not result in increased complications or
clinical disease in the fetus or newborn. The virus can be
isolated from the liver, bile, stools and blood during the
late incubation period and pre icteric phase of the illness.
Natural infection confers life long immunity. There is
no evidence for chronic carrier state.
Pathogenesis
The ingested virus multiplies in the small bowel and
migrates via the portal vein to the liver. Although HAV
has a cytopathic effect in tissue culture, the hepatocyte
injury is secondary to a host immune response. HAV
infection causes periportal inflammation, pericentral
cholestasis without significant cellular inflammation.
Clinical Manifestations
The incubation period is 2 to 7 weeks and fecal shedding
occurs for 2-3 weeks before and 1 week after the onset of
jaundice. The characteristic features include an age
dependent expression of clinical illness, low rate of
fulminant disease and absence of chronicity. In children
less than 6 years of age, majority have an anicteric
hepatitis and only 10% develop typical illness with
icterus. In older children, 40-60% will present with
icterus whereas 70-80% of adults will manifest as icteric
hepatitis. In those presenting with jaundice the illness is
heralded by a mild prodrome and recovery occurs within
a period of 5 to 7 days. Older children can have atypical
manifestations such as ascites, pleural effusion, firm
hepatomegaly and disturbing prolonged cholestasis.
Extra hepatic manifestations are uncommon and include
evanescent skin rash, transient arthralgia, pancreatitis,
vasculitis, thrombocytopenia, triggering of autoimmune
hepatitis in susceptible children , red cell aplasia,
myocarditis, nephritis, cryoglobulinemia and Guillian
Barre syndrome due to circulating immune complexes.
The incidence of fulminant hepatitis or acute liver failure
occurs in less than 1% of acute infection. The case fatality
ranges from 0.15 to 3 per 1000. Co-infection with HEV or
HBV may increase the morbidity. HAV infection in
individuals with chronic liver disease of any age group
is associated with increased mortality.
Diagnosis
Acute HAV infection is confirmed by the presence of IgM
antibodies to HAV which is detected at the onset of
symptoms and remains positive for 4-6 months. Anti
HAV IgG indicates past infection and can be detected
within 8 weeks of onset of symptoms and continues to
remain positive indefinitely (Fig. 13.16.2). Polymerase
chain reaction (PCR) for detection of viral particles in
stool or blood is not done routinely and reserved only
for research purposes. The total serum bilirubin is
increased with the direct component showing variable
rise depending on the phase of illness. Serum trans-
aminases are more than 20 times upper limit of normal,
these levels only indicate liver injury and do not correlate
with the degree of liver cell dysfunction. Prothrombin
time is an important predictor of severity of infection
and reflects severe hepatic synthetic defect and extensive
hepatocellular necrosis. A fall in serum albumin is
uncommon in uncomplicated HAV infection. Serum
Figure 13.16.2: Sequence of HAV serological
marker appearance
 Diseases of Gastrointestinal System and Liver 657

alkaline phosphatase may be normal or mildly elevated. Prognosis

Lymphopenia and neutropenia may occur during the
The prognosis of HAV infection in those who recover is
course of illness.
excellent with no long term sequelae. Acute liver failure
is still associated with a high mortality and liver
Prevention
transplantation is life saving.
HAV infection is a disease of the developing countries
and therefore general measures to improve hygiene is HEPATITIS B
very essential to decrease the over all prevalence. Clean
Hepatitis B (Fig. 13.16.3) virus stands unique in the group
and potable drinking water supply, hand washing and
of hepatitis virus with a potential to cause chronic
hygienic preparation of food are important steps in
hepatitis, cirrhosis and hepatocellular carcinoma. It is a
preventing the spread of Hepatitis A virus.
complex hepadna virus which produces surplus protein
coat namely the surface antigen (HBsAg), earlier termed
Immunization
as Australia antigen as it was first isolated from an
Active Immunization Australian aborginee. The intact HBV is the “Dane
particle” or virion, which is double shelled and 42 nm in
Effective and safe vaccine for HAV is available in India
size. Serologically HBV is recognized by its three antigens
though at present it is not indicated for universal
namely surface (HBsAg), core (HBcAg), and nucleo
immunization. The vaccine is recommended on a one to capsid (HBeAg) antigens and their corresponding
one “named child” basis for children especially from
antibodies namely antiHBs, antiHBc and antiHBe
higher socio economic group, adolescents and adults who
(Fig. 13.16.3). HBV DNA can be detected quantitatively
are leaving homes for education or employment without and is a sensitive marker of active replication. HBV has
past history of viral hepatitis or are antibody negative,
been classified into A to H genotypes. A genotype is
all children and adults with underlying chronic liver
pandemic, B and C are prevalent in Asia, D is seen in
disease and family contacts, all immunocompromised southern Europe, E in Africa, F in USA, UK and France
individuals, household contacts of acute HAV infection
and H in Central America.
(within 10 days), children attending day care centers and
creches, travellers from abroad (eg NRI’s) visiting India Epidemiology
or other endemic areas.
The inactive hepatitis A vaccine is administered The incubation period ranges from 60-180 days.
intramuscularly as a prime boost schedule on an elected Transmission of HBV is by the parenteral route and
date (0) followed by a booster dose after 6 months. A occurs by exposure to infected blood, blood products and
live attenuated human diploid cell vaccine for subcu- body fluids. The risk factors include frequent needle
taneous use is also available. Recently a novel inactivated pricks, intravenous drug abuse, transfusion with
vaccine using virosome technology has been introduced.
IAP recommends two doses of HAV vaccine anytime
after 18 months of age.

Passive Immunization
HAV specific immunoglobulin is not available in India
and there are very few indications for passive immuni-
zation. The dose is 0.02 ml/kg of Immune globulin which
should be administered within two weeks after exposure
to HAV. It is indicated for newborns of HAV infected
mothers and children with chronic liver disease who are
exposed to HAV. The protection is immediate, effective
but temporary. Immunoglobulin prophylaxis is not
indicated for healthy household contacts. Figure 13.16.3: Hepatitis B virus
658 IAP Textbook of Pediatrics
improperly screened blood, acupuncture or tattoos,
sexual contact, institutional care and intimate contact
with carriers and perinatal exposure to an HBsAg
positive mother. HBV is present in high concentration
in blood, serum and body fluids such as vaginal
secretions, semen, saliva, nasopharyngeal secretions,
tears and sweat. HBsAg is inconsistently recovered in
breast milk of infected mothers and feeding of infants
under cover of active immunization is permitted. The
main source of infection is the chronic hepatitis B virus
infected individual. Depending on the prevalence of
HBsAg the world is divided into three endemic zones
namely low<2%, intermediate 2-8%, high >8% and India
lies in the intermediate zone.
Pathogenesis
HBV is predominantly a noncytopathogenic virus that
causes injury by immune mediated process and the
severity of injury reflects the degree of immune response.
Hepatocyte lysis occurs as a result of polyclonal and
multispecific immune response. The elimination of virus
infected hepatocyte is dependent on the recognition by
cytotoxic ‘T’ lymphocytes of viral determinants in
association with HLA protein present on infected cell.
Clinical Manifestations
In India children with HBV infection presenting as
sporadic acute hepatitis occurs in 10-15 %. Most cases of
acute HBV infection in children are asymptomatic as
evidenced by the high positivity of serum markers in
persons without history of acute hepatitis. In those who
are symptomatic the prodrome of anorexia, nausea,
vomiting with or without fever may be quite marked
compared to HAV infection. Jaundice may last for 1 to 2
months and is accompanied by hepatosplenomegaly and
intense fatigue. Immune mediated extra hepatic
manifestations such as maculopapular or urticarial rash,
migratory arthritis or nephritis may be a presenting
feature. Papular acrodermatitis of childhood or Gianotti-
Crosti syndrome may be a manifestation of HBV
infection.
Natural History
The risk of chronicity is inversely proportional to the age
of acquisition of the illness. A neonate born to a mother
who is HBsAg and HBeAg positive has about 90 percent
chance of acquiring the infection. This decreases to 30%
if the age of acquisition is 1 to 5 years and is 5 to 10 percent
if acquired after the age of 5 years. Children with chronic
hepatitis may progress to cirrhosis and/or hepatocellular
carcinoma (HCC).
There are four stages in the natural history of HBV
infection.
1. Replicative phase-Immune tolerance: This represents the
period of immune tolerance where the virus is
actively multiplying but there is no hepatic infla-
mmation. In perinatal transmission this phase lasts
for many years and is associated with a low annual
HBeAg clearance of < 2% in children less than 3 years
and 4-5% in children more than 3 years, whereas in
horizontal transmission this stage is relatively short
and the annual HBeAg clearance is much more being
5-15%. Though treatment appears justifiable in the
immuno tolerant phase, no effective therapy is
available.
2. Replicative phase—immune clearance: In this phase the
immune system of the host responds by hepatic
inflammation and direct cell lysis. If the immune
response is ineffective, this phase may persist for
many years. Maximum liver damage occurs in this
phase. The child may present with jaundice and
elevated transaminases and serologically is HbeAg
positive with high HBV DNA. A viral load level of
more than 105 DNA copies per ml is taken as the cut
off for considering therapy. It is important that
children in this phase of the illness are treated
appropriately because the long term prognosis
depends upon the duration of this stage. The results
of therapy depend upon the degree of underlying
liver damage when seroconversion occurs. The
treatment strategies aim to reduce the duration of this
phase of the disease.
3. Integrative phase-non replicative: When the immune
response of the host is successful, active viral
replication decreases. HBV DNA becomes undetec-
table and antibodies against HBeAg (HBe Ab) become
positive. The seroconversion to anti HBe is an
important event in the natural history of chronic
hepatitis B. The infection has cleared for all practical
purposes, even though the HBsAg remains positive
and integration would have occurred. This event is
characterized by a brief and self limiting rise in
transaminases followed by biochemical and histolo-
gical remission. These children are infective to others
but at a much lower rate than HBeAg positive
 Diseases of Gastrointestinal System and Liver
individuals. They may go on to develop cirrhosis and
hepatocellular carcinoma. There is no indication to
treat these patients unless they have elevated liver
enzymes or an ‘active disease’ on liver biopsy. These
findings would then suggest that the wild virus has
undergone mutation to a precore mutant. The
response of precore mutant infection to treatment is
not satisfactory.
4. Integrative phase viral clearance: In this phase there is
complete cessation of viral replication and the HBsAg
becomes negative. The person is completely cured of
the disease. Patients with acute Hepatitis B will
achieve this phase, but those with chronic infection
may not always reach this phase.
Interpretation of Serological Markers (Fig. 13.16.4)
HBsAg: This surface antigen appears 6 weeks after
infection and disappears by 3 to 6 months. The
persistence of this antigen for more than 6 months
indicates chronicity. HBsAg is only a marker of exposure
to the virus and is therefore positive both in acute and
chronic infection.
Figure 13.16.4: Sequence of HBV serological marker appearance
659
Anti HBs: This is a protective antibody and appears soon
after the disappearance of HBsAg and persists lifelong
though the titres may decrease. Anti HBs is also detected
following an effective immunization but unlike following
natural infection anti HBc will not be present. The
protective titre is more than 10 mIU/ml.
HBeAg: This antigen is detected soon after the appearance
of HBsAg and is a marker of infectivity and active viral
replication. It usually disappears by 6 weeks; persistence
of this antigen for more than 6 weeks indicates
progression to chronicity. It is detected in chronic
hepatitis due to wild virus infection but not in pre core
mutant infection. An infant born to a mother who is
HBsAg and HBeAg positive has more chance (about
80%) of acquiring the infection than an infant born to a
mother who is positive only for surface antigen.
Anti HBe: This is not a protective antibody. It appears
after the disappearance of HBeAg. The seroconversion
of HbeAg to antiHbe positivity during therapy for
chronic HBV infection indicates a good response to
treatment.
660 IAP Textbook of Pediatrics
HBcAg (core antigen) is detected only in the hepatocyte
and not in serum. The ground glass hepatocytes seen on
histopathology indicate the presence of core antigen.
AntiHBc: This is also not a protective antibody but is a
useful marker in sero diagnosis. Anti-HBc IgM indicates
recent infection and anti HBc IgG indicates past infection.
HBV DNA: The presence of HBV DNA indicates active
viral replication and can be assessed qualitatively or
quantitatively. Quantitative measurement of the viral
load is necessary before commencing therapy in chronic
hepatitis. The fall in viral load is monitored during
therapy.
Diagnosis
Acute hepatitis B is diagnosed by the presence of HBsAg
and antiHBcIgM whereas in chronic hepatitis B the
serological markers can be detected according to the stage
of the disease. The presence of HBsAg more than
6 months indicates chronic infection; if HBV DNA is
present with or without HBeAg it indicates active
multiplication.The interpretation of the various viral
markers is shown in Table 13.16.1 and Figure 13.16.4.
Prevention
General measures: Since HBV is spread parenterally proper
screening of blood and blood products is necessary prior
to transfusion. Disposable needles should be used and
unnecessary needle pricks including tattooing avoided.
Common religious practices in India namely hair tonsure,
ear and nose boring should be performed with due
precaution only after immunization.
TABLE 13.16.1: Interpretation of serologic markers with SGPT in hepatitis B infection
HBsAg HBeAg antiHBe antiHBc antiHBS HBV DNA
+ + - IgM - High
+ +/- - IgG - High
IgG + -
+ -
+ - + IgG - Low/not
detected
+ + - IgG - High
UL—Upper limit
Immunization
Active immunization with hepatitis B vaccine is
recommended for all children. The current IAP
recommendation is to administer the recombinant
genetically engineered subunit HBV vaccine intra-
muscularly in 3 doses of 10 mg for children less than 12
years and 20 mg for those more than 12 years. The three
schedules endorsed by IAP are 0, 1 and 6 months or birth,
6 and 14 weeks or combination with triple antigen at 6,10
and 14 weeks. The genetically engineered recombinant
DNA vaccine is safe and immunogenic. It is preferable
to administer Hepatitis B Immunoglobulin (HBIG) within
6 hours of birth and hepatitis B vaccine to babies born to
HBsAg positive mothers using two separate syringes and
sites for injection. HBIG has also been recommended for
those with history of acute exposure to HBsAg infected
material (eg: needle stick injury).
HEPATITIS C
Hepatitis C virus (HCV) is an important cause of post
transfusion hepatitis and is a single stranded RNA virus
and is the only member of the genus Hepacivirus in the
family Flaviviridae. It is an enveloped, linear, single
stranded RNA flavivirus (Fig. 13.16.5) with 6 genotypes
and several subtypes based on genomic differences. The
various subtypes permit the virus to escape the host
immune surveillance.
Epidemiology
HCV is transmitted more often by blood and blood
products compared to body secretions. It is therefore
SGPT Significance
↑ Acute hepatitis
> 2 times Chronic hepatitis-immune clearance
UL of normal
Recovery
Vaccination immunity
Normal Chronic hepatitis Inactive
carrier
Normal Immune tolerance
 Diseases of Gastrointestinal System and Liver
Figure 13.16.5: Hepatitis C virus
not as infective as HBV but results in more morbidity.
HCV is less common in children compared to adults with
a prevalence of 0.2% in children younger than 11 years
of age and 0.4% in children more than 11 years of age.
The risk factors for HCV transmission in children include
repeated blood transfusions, illegal drug usage and
unsafe sex. Perinatal transmission of HCV is much less
than which occurs in HBV infection and depends on the
maternal HCV viral load and HIV positivity status.
Pathogenesis
Chronic HCV infection is not a consequence of direct
cytopathic effect but rather an intermediate immune
response that is sufficient to induce hepatic cell
destruction and fibrosis but not sufficient enough to clear
the virus. Cell mediated immune responses and
elaborations by T cells of anti viral cytokines contribute
to containment of infection and pathogenesis of liver
injury. Certain characteristic features are identified on
histopathology such as periportal lymphoid aggregates,
steatosis and piling up of biliary epithelial cells with out
interruption of basement membrane in the liver. The
natural history of the disease depends upon several viral
and host factors. Genotype I do not respond to antiviral
therapy as well as non I genotypes and needs longer
duration of treatment
Clinical Manifestations
The incubation period of HCV infection is 7 to 9 weeks.
Acute HCV infection is insidious in onset and takes a
661
milder course in children. Acute liver failure occurs in <
1%.The symptoms of malaise, fatigue and jaundice are
mild; the transaminases are elevated for a longer period.
Spontaneous remission occurs in 40 to 60% of individuals
following acute HCV infection, 40-50 percent may
progress to chronicity and later to cirrhosis and
hepatocellular carcinoma. Sporadic hepatitis in children
due to type C hepatitis is rare. Children who require
repeated blood transfusion, e.g. Thalassemia major are
at a higher risk for type C infection.
Diagnosis
Detection of antibodies to HCV and HCV RNA helps in
the diagnosis of HCV infection. Enzyme immunoassays
for detection of antibodies are sensitive in high risk
populations but not in the low risk group. Recombinant
Immuno Blot Assay (RIBA) has a higher sensitivity in
low risk patient groups. Anti HCV antibody is not a
protective antibody and hence does not confer immunity
and is usually present with the virus. Detection of HCV
RNA is more sensitive and a viral load >105 copies/ml
of HCV RNA is taken as a cut off for initiating therapy.
Prevention
Screening of donor blood is essential in prevention of
HCV infection. Vaccines for HCV are on the pipeline but
are not yet available for regular use. Vaccine develop-
ment has been impeded by the various HCV genotypes
and presence of quasispecies.
HEPATITIS D
Hepatitis D virus (HDV) or “Delta agent” is a unique
hybrid virus which requires HBsAg to replicate and was
first isolated from the chronic carriers of HBV. It is an
enveloped incomplete RNA virus 35-38 nm in size,
containing a small circular single stranded RNA, with
an outer coat formed by HBsAg.
Pathogenesis
Hepatocyte injury resulting from infection with HDV
may be caused by direct virus cytotoxicity, in contrast to
immune mediated injury associated with HBV. Repli-
cation is limited to the liver and the pathologic changes
in HDV infection are limited to this organ.
Clinical Manifestations
The clinical features depend on the status of the
underlying HBV infection. Acute HDV infection can
662 IAP Textbook of Pediatrics
occur either as a co-infection with acute HBV infection
or as a superinfection in an asymptomatic or sympto-
matic chronic HBsAg positive child.
Co–infection follows simultaneous exposure to an
innoculum containing both HBV and HDV. The
incubation period is same as that for HBV infection. A
biphasic illness occurs which is uncommon in other forms
of hepatitis. The incidence of acute liver failure is as high
as 10 percent.
Superinfection can occur in an asymptomatic HbsAg
positive child or in those with HBV related chronic liver
disease. It results in deterioration of the pre existing
condition with the appearance or deepening of jaundice
and worsening of ascites. Acute liver failure is as high as
20 percent.
Diagnosis
Coinfection with HBV is diagnosed by the presence of
HBsAg, anti-HBc IgM and low titres of anti-HDV IgM
whereas in superinfection, HBsAg is present with high
titres of anti-HDV IgM but without anti-HBc IgM.
Prevention
HDV can be prevented by taking all steps to prevent HBV
infection.
HEPATITIS E
Hepatitis E virus (HEV) is an important cause of both
sporadic and epidemic forms of hepatitis. It is a 27-32
nm RNA virus of calici group and is spread by faeco-
oral route. Several strains have been identified based on
the nucleotide sequence. HEV has been the causative
organism in the major epidemics of hepatitis in India.
The 1978 epidemic in Kashmir was studied extensively
which gave several new insights to this virus.
Clinical Manifestations
The incubation period of HEV is between 3 to 9 weeks.
The illness is similar to type A hepatitis and chronicity
does not occur. During epidemics, children usually have
a subclinical infection and intrafamilial spread is
uncommon. Pregnant women are more symptomatic
than non pregnant women especially during the 2 nd
and 3 rd trimester. Pregnancy is complicated with a high
maternal mortality of 5-30%, still births, fetal wastage
and preterm labor may be as high 60%. Acute liver failure
due to HEV is also seen more during pregnancy.
Diagnosis
The presence of anti-HEV IgM indicates recent infection.
Prevention
Vaccine against HEV is on the pipeline but is not available
for regular use at present.
HEPATITIS F
It is well documented that even after a detailed
serological study, 10 percent of children will not have
markers to the known viruses A to E. These could be
HBV variants with mutation, or a budding RNA virus.
French workers have identified an enteric virus in this
non A –E group and call it the hepatitis French Virus
(HFV).
HEPATITIS G
Hepatitis G (HGV) virus is a single stranded RNA flavi
virus which shares limited identity with HCV. It is
distributed widely among the population and spreads
by parenteral route.
Clinical Manifestations
HGV has been linked to post-transfusion hepatitis,
chronic hepatitis and cirrhosis but it is unlikely that HGV
by itself can cause disease. Some workers feel that the
virus is still searching for a disease and is an innocent
bystander.
SEN and TT Virus: These viruses derive their identity from
the patients from whom they were isolated.
SEN virus is a single stranded, circular, non enveloped
DNA circo virus associated with transfusion associated
hepatitis. However its definite role in acute or chronic
hepatitis is still debated.
TT virus is also a single stranded DNA circovirus trans-
mitted parenterally. It has also been associated with
transfusion associated hepatitis. The prevalence rates of
this virus in hemodialysis patients and blood donors are
reported as high as 50%. Isolation of this virus as the
aetiological agent in acute, chronic or fulminant hepatitis
has been inconsistent.
 Diseases of Gastrointestinal System and Liver
NON HEPATOTROPHIC VIRUSES
Several nonhepatotrophic viruses can cause hepatitis and
though they are less common in older children, they form
an important group in neonates and young infants.
Children with this form of hepatitis usually present with
features of the underlying illness such as the exanthem
in measles and varicella in addition to hepatomegaly and
elevated serum transaminases. The diagnosis is usually
made clinically and if necessary confirmed serologically.
Some of the important non hepatotrophic viruses causing
hepatitis are:
Measles virus: Measles presenting with anicteric hepatitis
is an atypical manifestation of the illness and usually
results in spontaneous recovery. Measles virus can
trigger autoimmune hepatitis type 1 within 3 months of
the infection in susceptible individuals.
Parvovirus B19: Human parvovirus B19 can present with
hepatic dysfunction, elevated transaminases and acute
liver failure with or without aplastic anemia.
Herpes Simplex 1 and 2(HSV): HSV hepatitis is usually
rare beyond the neonatal period unless the child is
immunocompromised. It may present as part of a
generalized herpetic disease in infants. In older children
it is rare and the mucocutaneous lesions may be absent.
The diagnosis is made by the presence of IgM antibodies
and the isolation of virus from the vesicles or other tissue.
Liver biopsy shows the characteristic inclusion bodies.
Dengue virus: Dengue fever presents with fever, hepato-
megaly, rash, pleural effusion and features of capillary
leak. There is a moderate elevation of transaminases espe-
cially AST more than ALT. In the presence of Dengue
shock syndrome, the transaminases may be very high in
several thousands due to ischemic or hypoxic hepatitis.
This elevation of transaminases unlike in viral hepatitis
is associated with a significant rise in LDH which drops
sharply once the child is resuscitated. The diagnosis is
confirmed by the high hematocrit, low platelet and the
presence of IgM dengue antibodies.
Cytomegalovirus (CMV): Cytomegalovirus hepatitis
usually occurs in neonates presenting as prolonged
cholestasis of newborn and later may progress to
cirrhosis. In older children it may occur in recipients of
renal or liver transplant. The disease resembles EBV
related mononucleosis without pharyngitis and posterior
663
cervical lymphadenopathy. The diagnosis is made by
isolation of the virus from urine or saliva using PCR. A
four-fold rise in the antibody titre is also helpful in diag-
nosis. Liver biopsy demonstrates the characteristic
nuclear and cytoplasmic inclusion bodies.
Epstein Barr virus (EBV): Infectious mononucleosis caused
by EBV usually presents as prolonged fever with sore
throat, evanescent rash and lymphadenopathy. At times
these features subside and the child presents as acute
hepatitis with hepatosplenomegaly and elevated
transaminases. The diagnosis is confirmed by the
detection of IgM antibody to the viral capsid antigen.
Human herpes virus 6 (HHV 6): Liver dysfunction in
association with HHV 6 virus infection may present as
infectious mononucleosis like syndrome, hepatitis or
acute liver failure.
Varicella zoster: VZ virus causing liver disease is unusual
except in immunosuppressed children with HIV
infection or post transplant recipients.
Human Immunodeficiency Virus: Infants with HIV hepatitis
may manifest with cholestasis and later present with
chronic hepatitis. Liver involvement in HIV infected
individuals is indicative of a poor prognosis.
Other viruses: Echo virus, coxsackie and adeno virus may
present in neonates and infants with acute liver failure.
Differential Diagnosis
The differential diagnosis of acute viral hepatitis includes
all the causes of “viral marker negative hepatitis” apart
from congenital hyperbilirubinemia and some surgical
causes. It is important that this group is recognized since
specific therapy is available unlike in the viral marker
positive hepatitis where only supportive therapy is
recommended. In India the following conditions should
be considered.
1. Bacterial hepatitis: typhoid, tuberculosis, Brucella.
2. Protozoal: Malaria.
3. Spirochaetal: Leptospirosis
4. Drug induced or toxic hepatitis
5. Metabolic: Wilson’s , Glycogen Storage disease
6. Biliary disease: Cholangitis, gallstone disease
7. Congenital hyperbilirubinemia: Gilbert’s syndrome,
Dubin Johnson.
664 IAP Textbook of Pediatrics
Typhoid fever: Typhoid hepatitis can mimic AVH and
the differentiating features of toxemia, high fever and
hepatosplenomegaly if present may help in diagnosis.
Some children may also have minimal ascites and pleural
effusion similar to liver disease. The transaminases are
moderately elevated (3-20 times the upper limit of
normal) with an ALT/LDH ratio less than 4 whereas in
AVH it is >4. The diagnosis is confirmed by a positive
blood culture for Salmonella typhi.
Bacterial sepsis: Bacterial sepsis should be considered in
children presenting with fever, jaundice, hepato-
splenomegaly and mild elevation of transaminases. Liver
involvement is secondary to parenchymal or biliary
invasion as a part of a systemic manifestation of sepsis.
The prolonged prothrombin time and the high mortality
is due to DIC and sepsis respectively rather than liver
failure.
Tuberculosis: Tuberculous hepatitis should be considered
in those children presenting with fever of unknown
origin, hepatomegaly, mild to moderate elevation of
transaminases and high alkaline phosphatase. Liver
biopsy shows the characteristic caseating granuloma.
Brucellosis: Brucellosis can occur in children who consume
unpasteurised milk and presents with fever, lymph-
adenopathy and elevated transaminases. The diagnosis
is confirmed by a high initial titre of 1:160 or a rising
titre done 2 weeks apart.
Leptospirosis: The clinical presentation may range from
inapparent infection, to features of acute hepatitis or fatal
disease. Jaundice, hepatosplenomegaly, fever, myalgia,
congested conjunctiva, bleeding manifestations, minimal
ascites and pleural effusion are some of the features.
Renal manifestations such as hematuria, albuminuria,
azotaemia, oliguria or anuria are findings in some
children. Apart from rise in serum bilirubin and
transaminases the CRP and CPK are elevated which may
help to differentiate it from viral hepatitis. A single high
antibody titre by Microscopic Agglutination Test (MAT)
or a rising titre 2 weeks apart helps in diagnosis.
Malaria: Malarial hepatitis or malarial hepatopathy (since
inflammatory cells are not a characteristic feature on
histology) is diagnosed when there is a 3 fold rise in
ALT with or without rise in conjugated hyperbilirubi-
nemia, in the absence of clinical and serological evidence
of viral and drug induced hepatitis and with a clinical
response to antimalarials. It is usually seen with
P.falciparum but may occur in P. vivax infection. The exact
pathogenesis is unknown but could be due to impaired
bilirubin transport caused by blockage of reticulo
endithelial cells, microvilli damage or cyto -adherence
of parasites to the vascular endothelium leading to
stagnant anoxemia.
Drug induced liver disease (DILD): The common drugs
causing hepatitis are anticonvulsants, anti tuberculous
drugs, antimetabolites, NSAIDS, paracetamol, herbals
and indigeneous medications. It may be very difficult to
differentiate DILD from viral hepatitis. The child presents
with elevated transaminases with or without jaundice,
rash and hepatomegaly. The absence of prodrome and
the history of drug intake is a clue to diagnosis. The
challenge or onset of symptoms occurs within 5-90 days
of introducing the drug. On dechallenge, 50% drop in
transaminases occurs within 8 days of stopping the drug.
Autoimmune hepatitis (AIH): Autoimmune hepatitis
should be considered during the evaluation of acute
hepatitis. It is a progressive inflammatory liver disease
of unknown etiology presenting with elevated trans-
aminases, hypergammaglobulinaemia., interface
hepatitis, non organ and liver specific antibodies and
good response to immunosuppressive treatment..
Children may present with type I or type II hepatitis. In
type I hepatitis, antinuclear antibody (ANA) and anti
smooth muscle antibody (ASMA) are present whereas
in the later LKM1 antibody is detected.
Obstructive jaundice: Obstructive jaundice due to
choledocholithiasis or biliary ascariasis can rarely mimic
acute hepatitis. Abdominal pain and features of
cholangitis are an important clue to diagnosis. The direct
bilirubin, alkaline phosphatase and ALT are elevated.
Ultrasound helps in identifying the site and cause of
obstruction.
Glycogen storage disease (GSD): In type I and III GSD , the
elevated transaminases may suggest anicteric hepatitis
but the presence of massive hepatomegaly and other
features such as short stature, doll like facies, voracious
appetite and early morning seizures will give a clue to a
diagnosis of storage disorder. Jaundice is not a presen-
tation. Fasting hypoglycemia, elevated lactate and uric
acid levels are more suggestive of type I whereas elevated
CPK and moderate elevation of transaminases especially
 Diseases of Gastrointestinal System and Liver
AST are suggestive of type III. The liver biopsy shows
swollen hepatocytes with glycogen (PAS positive and
diastase sensitive) and steatosis in type I and PAS positive
cells without steatosis in type III.
Wilson’s disease (WD): Wilson’s disease should be
suspected in any child more than 3 years who presents
with jaundice, elevated transaminases and a firm liver.
Early appearance of free fluid, hemolysis, family history
and a set back in school performance are pointers to
suspect WD. The diagnosis is made by the presence of
KF ring, decreased serum ceruloplasmin and elevated
24 hour copper and confirmed by liver biopsy, dry copper
estimation and mutational studies.
Complications
AVH in children is usually a self limiting illness.
However atypical presentations can occur. The spectrum
of this illness includes:
1. Anicteric hepatitis
2. Classical hepatitis
3. Subacute hepatic failure
4. Chronic hepatitis (B, D, C)
5. Acute liver failure
6. Prolonged hyperbilirubinemia
7. Prolonged cholestasis
8. Relapse.
In addition, certain extrahepatic manifestations are
seen such as aplastic anemia, glomerulonephritis,
Guillain-Barre syndrome, myocarditis, pancreatitis,
urticaria, polyarthritis and papular acrodermatitis. All
the hepatotropic viruses can cause acute liver failure or
subacute hepatic failure. The morbidity and mortality is
higher in co infections but this is controversial.Chronic
hepatitis occurs as a complication only with hepatitis B,
C or D viruses and not with hepatitis A or E.
Investigations
The characteristic biochemical feature of hepatitis is the
detection of elevated transaminases more than twice the
upper limit of normal. In viral hepatitis, ALT is higher
than AST indicating cytoplasmic rather than mitochon-
drial injury. These are elevated during the acute phase
of the illness and fall during recovery. The other
investigations in AVH include complete blood counts,
urine for bile salts and pigments and liver tests such as
bilirubin, AST, ALT and alkaline phosphatase. Prothrom-
665
bin time is a useful test for assessing prognosis. Blood
glucose, blood urea, serum creatinine, total protein,
serum albumin, A/G ratio are included if hospitalized.
Investigations to confirm etiology are done as mentioned
in those with atypical manifestations. HBsAg is an
important screening test. Lepto IgM ELISA, blood Widal
and work up for Wilson’s disease are included in the
panel of investigations. Ultrasound examination is done
to exclude liver abscess or gallstones. Liver biopsy is not
done in children with acute hepatitis but is essential in
those with suspected acute on chronic liver disease or
chronic hepatitis.
Management of Acute Viral Hepatitis
Most of the children with AVH will recover sponta-
neously and require only supportive treatment. During
the period of acute illness, the child should take adequate
calories in the form of a nutritious diet, avoid undue
physical exercise, hepatotoxic drugs and constipation.
The role of herbal hepatotrophic drugs in management
of acute viral hepatitis remains controversial. It is of
utmost importance to avoid unnecessary medications to
children with acute hepatitis, unless the drug is essential
and its mechanism of action is well understood. Water
soluble vitamins may be prescribed during acute
hepatitis. All children with acute hepatitis do not require
hospitalization unless there is persistent vomiting, fever,
fluid retention, altered sensorium or gastrointestinal
bleed. Ascites may be a presentation in some children
with AVH and can be treated with a short course of
spirinolactone. In the presence of spontaneous bacterial
peritonitis, antibiotics such as 3rd generation cephalos-
porins may be required. Fever if present during AVH
should be managed with tepid sponging and if necessary
paracetamol is administered at half the recommended
dose. NSAIDS should be strictly avoided. If the child is
on anticonvulsants such as sodium valproate or
phenytoin it can be changed to phenobarbitone and if
on antitubercular therapy with rifampicin, isoniazid and
pyrazinamide, they should be stopped and ethambutol
continued with streptomycin or fluoroquinolones. Older
children and adolescents may present with significant
and prolonged cholestasis or hyperbilirubinemia.
Cholestasis can be treated with ursodeoxycholic acid 20
mg/kg/day. Very rarely steroids may be required for
the management of severe cholestasis in type A hepatitis.
666 IAP Textbook of Pediatrics
Specific Therapy
1. Hepatitis A: Since the majority (>95% )of children
with acute hepatitis A recover spontaneously without
any sequlae, no specific antiviral therapy is
recommended
2. Hepatitis E: Isolated Hepatitis E infection in children
is usually mild and does not require any specific
treatment.
3. Hepatitis B: In acute hepatitis B no antiviral therapy
is advised. These children should be followed up for
6 months to monitor spontaneous clearance of
HBsAg.
4. Hepatitis C: Children and adolescents with acute
hepatitis C acquired either by post transfusion or
following IV drug abuse should be monitored closely
for 12 weeks to establish spontaneous sero -conver-
sion. Those who have persistent viremia (i.e) HCV
RNA positive for 12 weeks after the infection are the
candidates for treatment with Interferon (IFN). Since
the genotype plays a major role in the prognosis and
therapeutic response it should be tested before
therapy.
The current recommendation in adults is to initiate
treatment with IFN alpha or PEG IFN as early as
possible in asymptomatic patients infected with HCV
genotype 1, while treatment may be delayed in icteric
individuals with significant symptoms. Treatment
can also be safely delayed in patients with genotype
2 and 3 disease because these individuals clear acute
hepatitis C more often than those with genotype 1
and treatment success in chronic HCV is much better.
A shorter duration of therapy (12 weeks) compared
to that required for the treatment of chronic hepatitis
has been suggested.
5. Hepatitis D: Treatment is only supportive and liver
transplant may be required.
Treatment for Hepatitis due to Other
Non Hepatotropic Viruses
The treatment for hepatitis due to other viruses is also
usually supportive, Some specific antiviral agents such
as acyclovir for herpes simplex, ganciclovir for CMV and
HAART for HIV are available and may be used
judiciously.
PREVENTION
The most important aspect of therapy in hepatitis is the
prevention of the disease. The common viruses such as
HAV, HBV, HCV, HDV and HEV can be prevented by
improving personal, food and environmental hygiene,
avoiding unnecessary needle pricks; using disposable
syringes and screened blood for transfusion and active
immunization against HAV and HBV.
BIBLIOGRAPHY
1. Dienstag JL, Isselbacher KJ. Acute viral hepatitis. In
Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser
SL, Jameson JL eds. Harrison’s principles of Internal
Medicine. (16 th Edn). USA; McGraw Hill, 2005;2:
1822-38.
2. Evans JS. Acute and chronic hepatitis. In Wyllie R, Hyams
JS (eds). Pediatric Gastrointestinal disease-Pathophysio-
logy, Diagnosis, Management (2nd Edn): Philadelphia:
WB Saunders, 1999;600-23.
3. Novak DA, Suchy FJ, Balistreri WF. Disorders of the liver
and biliary system. In McMillanJA, Feigin RD, DeAngelis
C, Jones DM (Eds). Oski’s Pediatrics—Principles and
Practice (4 th edn). Philadelphia: Lippincott: Williams
and Wilkins, 2006;2013-39.
4. Viral hepatitis. In Sherlock S, Dooley J (Eds). Diseases of
the liver and biliary system. 11th edn. UK Blackwell
Science 2007;267-319.
5. Yazigi N, Balistreri WF. Viral hepatitis. In Kliegman RM,
Behrman RE, Jenson HB, Stanton BF (Eds). Nelson text
book of Pediatrics (18th edn). Philadelphia: WB Saunders
2007;2:1680-90.
 Diseases of Gastrointestinal System and Liver 667

13.17 Chronic Hepatitis in Children

BR Thapa

Chronic hepatitis (CH) in children is defined as
continuing inflammation of liver parenchyma for
6 months or longer, leading to chronic liver injury that
resolves with or without treatment or progresses to
cirrhosis. It warrants a liver biopsy to establish the
pathological diagnosis. There are many diseases, which
primarily affect the liver and lead to CH.
Histopathological Classification,
Grading and Scoring
Pathologically, chronic hepatitis has been classified into
chronic persistent hepatitis (CPH), chronic active
hepatitis (CAH), and chronic lobular hepatitis (CLH)
based on the extent of liver parenchymal injury. The
distinctive features of the three types are given below in
Table 13.17.1. The original classification suggested by
DeGroote et al has been replaced by scoring the grades
of necroinflammation and stages of fibrosis. But in the
text, this has been retained as it is still mentioned in the
literature to explain the histopathology of liver with CH.
Very recently the histological classification has
undergone tremendous changes based upon
i. Etiology
ii. The grade of necroinflammation and
iii. The stage of fibrosis/cirrhosis.
There is always some evidence of etiology demons-
trated on immunohistochemistry, special staining and
specific pathological features of underlying disease. The
necroinflammation is graded depending upon the extent
of necrosis and inflammation in portal tracts and in the
lobules. Similarly staging is done based upon the extent
of fibrosis occurred following injury. There are several
scoring systems (Ishak et al, Scheuer PJ, Knodell et al,
Batts and Ludwig, METAVIR scoring) to define the
severity and extent of necroinflammation and fibrosis.
Knodell’s histology activity index (HAI) is widely used
to define CH. The more simplied scoring system of
grading and staging of liver histology is given in Table
13.17.2.
Etiology of CH
Common causes of chronic hepatitis in children are:
Infections: HBV, HCV, HDV, CMV, rubella, HIV,
congenital syphilis, TTV, HGV.
Autoimmune: Three types:
1. Smooth muscle antibodies (SMA), antinuclear
antibody (ANA) positive
2. Liver kidney microsomal antibody (LKMA) positive
and
3. Soluble liver antigen and liver pancreas (SLA/LP)
positive
Metabolic: Wilson’s disease, α-1-antitrypsin deficiency,
galactosemia, fructosemia, tyrosinemia, etc.
Drugs: INH, ethyldopa, methotrexate, oxyphenacetin,
ketoconazole, etc.
Non-alcoholic steatohepatitis (NASH)
Cryptogenic hepatitis: Chronic hepatitis unclassified.
Chronic HBV Infection
Ten percent of patients with acute HBV hepatitis progress
to CH. Ninety percent of the infants with perinatally

TABLE 13.17.1: Characteristics of chronic hepatitis (DeGroote et al)

Chronic persistent hepatitis Chronic lobular hepatitis Chronic active hepatitis

It is characterized by portal triaditis It resembles acute viral hepatitis Its hallmark is piecemeal necrosis
histologically

Expanded portal tracts with Predominantly, intra-acinar inflam- Erosion of limiting plates
mononuclear infiltration mation and necrosis

Liver architecture and limiting Rosette formation in zone 1, bridging

plate-intact necrosis is also seen
668 IAP Textbook of Pediatrics

TABLE 13.17.2: Grading and staging of chronic hepatitis on histology

Grade Portal Periportal Lobular Stage Degree of Fibrosis Hepatic Architecture

0 None or minimal
1 Portal inflammation
2 Mild limiting plate
(lymphocyte piecemeal)
necrosis
3 Moderate limiting plate
(lymphocyte piecemeal)
necrosis
4 Severe limiting plate
(lymphocytic piecemeal)
necrosis
None 1 None or too mild Portal tracts not appreciably
to affect size of portal enlarged, no septa
tract
Inflammation 2 Mostly periportal Enlarged portal tracts,
but no necrosis periportal fibrosis, or portal-to-
portal septa without
architectural distortion
Severe focal cell 3 Septal Prominent septal fibrosis with
damage architectural distortion or
definite cirrhosis
Severe focal cell 4 Cirrhosis Probable or definite cirrhosis
damage
Bridging
necrosis

acquired HBV infection develop immune tolerance and

suffer from asymptomatic chronic hepatitis B (CHB)
infection. They show rise in transaminases, HBe and
DNA positivity and liver histology shows active
necroinflammation. Serology shows HbsAg positivity.
Presence of HBe and HBV DNA, serve as markers of
active viral replication. In presence of superinfection with
delta virus, HbsAg + anti HDV are positive. Liver biopsy
shows HbsAg containing hepatocytes having ground
glass appearance and may show core antigen (HbcAg)
in infected hepatocytes by immunohistochemistry (Figs
13.17.1A and B). Progression is slow but usually relentless
especially in HbeAg positive or combined hepatitis B and
D infection eventually leading to cirrhosis. Hepato- Figure 13.17.1A: Ground glass hepatocyte (HBsAg+)
cellular carcinoma (HCC) is a long-term complication.

Chronic HCV Infection

HCV infection runs a milder course. It invariably leads to
chronic liver disease (CLD). Cirrhosis is likely to develop
later. Serology for anti-HCV antibodies and HCV RNA is
positive. Histological features of chronic hepatitis C are
intense chronic portal inflammation with lymphoid aggre-
gate and sometimes follicles with germinal centers, fat
accumulation and bile duct injury (Figs 13.17.2A and B).

Autoimmune Hepatitis (AIH)

Autoimmune hepatitis (AIH) is associated with other
autoimmune diseases like thyroiditis, pernicious anemia Figure 13.17.1B: HBc antigen on immunostaining
 Diseases of Gastrointestinal System and Liver 669

Figure 13.17.3: AIH interface hepatitis

Figure 13.17.2A: Chronic hepatitis C liver showing lymphoid
follicle, bile duct destruction in the portal tract and fatty change
in lobule
there is underlying chronic liver disease. The histological
changes are mild to severe chronic hepatitis with or
without cirrhosis. Orcein staining shows increased
copper associated protein (Fig. 13.17.4). Rhodamine and
rubanic acid staining confirms increased copper deposits.
The diagnosis depends upon positive KF rings; low
serum ceruloplasmin and liver copper more than 250 mg
of dry weight.

α-1-Antitrypsin Deficiency (AAT)

The disease may manifest as cholestasis during infancy.
In older children it may manifest as chronic liver disease.
Histopathology of liver biopsy shows PAS positive
Figure 13.17.2B: HCV hepatitis lymphoid aggregate diastase resistant granules, which are diagnostic of AAT.

Galactosemia
and Coomb’s positive hemolytic anemias. It is associated
with hypergammaglobulinemia (IgG) and positive This autosomal recessive disorder manifests during
antinuclear antibodies (ANA), smooth muscle antibodies neonatal period after exposure to milk. The clinical
(SMA) or liver/kidney microsomal antibodies (LKM) or picture is characterized by neonatal hepatitis, cataract in
SLA/LP. Exacerbations and remissions are common and eyes, failure to thrive, vomiting and sepsis. The histology
eventually lead to cirrhosis and its complications.
Histopathological features of autoimmune hepatitis are
severe inflammation, collapse of multiple acini,
numerous plasma cell infiltrate in the portal tract and
interface hepatitis (Fig. 13.17.3). The interface hepatitis
is akin to piece meal necrosis described in chronic active
hepatitis. Hepatocellular injury is in form of ballooning
of hepatocytes, regeneration of hepatocyte leading rosette
formation and confluent zone 3 hepatocellular necrosis.
The fibrosis sets in fast and leads to cirrhosis.

Wilson’s Disease
The disease occurs in 3 to 50 years age group. The hepatic
manifestation is quite varied. In majority of the situations Figure 13.17.4: Wilson’s disease orcein staining positive
670 IAP Textbook of Pediatrics
of liver is characterized by portal triaditis, periportal
cholangiolar proliferation pseudoacinar transformation
and fatty change. Cirrhosis develops very fast.
Non-alcoholic Steatohepatitis (NASH)
NASH is well-recognized entity in children occurring
with increasing incidence of obesity and diabetics in
them. There may be enzyme rise and hepatomegaly.
Histopathology of liver is characterized by fatty
infiltration (microvesicular or macrovesicular or mixed),
ballooning of hepatocytes, mallory hyaline, neutrophil
infiltrate (satellitosis) and pericellar fibrosis (Fig. 13.17.5).
These changes are pronounced in zone 3 of the lobule
and are progressive and develop into cirrhosis.
Clinical Presentation
Clinical presentation is chronic hepatitis is variable.
Acute hepatic illness with waxing and vaning course for
more than 6 months suggests chronic inflammation
occurring in the liver parenchyma. There may or may
not be overt features of chronic liver disease and portal
hypertension. In children asymptomatic hepatomegaly
picked up on routine examination may reveal chronic
hepatitis on liver biopsy. Suspect CH, if there is history
of hepatotoxic drugs, family history of liver disease,
relapse of acute hepatitis, hepatitis persisting for more
than 3-6 months and previous history of hepatitis B or C
infection. Look for non-hepatic manifestations of AIH
and Wilson’s disease.
Clinically child shows jaundice, firm hepatomegaly,
splenomegaly, ascites and features of chronic liver
Figure 13.17.5: NASH Masson staining pericellular
fibrosis + fat
Figure 13.17.6: Course of chronic hepatitis
disease. There may be non-hepatic manifestations
depending upon the underlying etiology of liver disease
like AIH, Wilson’s disease, galactosemia, etc. The overall
course of chronic hepatitis is given in (Fig. 13.17.6).
Investigations
1. Liver function tests: Serum bilirubin–direct/indirect,
liver enzymes (ALT, AST); alkaline phosphatase; total
proteins and A/G ratio, and prothrombin time to
assess liver damage.
2. Ultrasound examination of abdomen is done to see
for the echotexture of liver, ascites and the collaterals
due to portal hypertension.
3. Upper gastrointestinal endoscopy is done to see for
esophageal varices in case of portal hypertension.
4. Every effort should be made to have an etiological
diagnosis. The investigations depend upon the age
of occurrence of the chronic hepatitis. Approach to
etiological diagnosis is given in (Fig. 13.17.7).
• Viral markers: HBsAg, HBeAg, HBV DNA, co-
infection anti HDV antibodies, anti HCV anti-
bodies and HCV RNA
• AIH markers: SMA, ANA, LKMA, SLA
• Wilson’s disease: KF ring, serum ceruloplasmin,
pre and post d-penicillamine urinary copper levels
and copper in the liver tissue.
• Serum α-1 Antitrypsin levels
• During infancy: Intrauterine infection TORCH
work up, GALT levels, reducing substance in
urine, urinary succinyl acetone, etc.
5. Liver biopsy: The percutaneous liver biopsy is done
to study the morphological changes in the liver
 Diseases of Gastrointestinal System and Liver
Figure 13.17.7: Approach to the etiological diagnosis
parenchyma. The changes seen in the histopathology
and immunohistochemistry also give clue to the
diagnosis of the underlying disease as discussed
under specific conditions.
Differential Diagnosis
At times it is very difficult to differentiate cirrhosis from
CH. The liver biopsy is confirmatory. Based on the clinical
approach and investigations, various diseases leading to
CH can be differentiated from each other. But high index
of suspicion in a clinical setting can guide to reach to
definite diagnosis of CH.
Management
Management can be divided into 2:
Complications
Bleeding: Endoscopic sclerotherapy (EST) or endoscopic
variceal ligation (EVL) is the preferred mode to control
bleeding from esophageal varices. Bleeding due to
coagulopathy requires fresh blood transfusion and
vitamin K.
Ascites: Peritoneal fluid should be analyzed to rule out
infection. Spontaneous bacterial peritonitis (SBP) should
be treated with appropriate antimicrobial agents like,
cefotaxime or ciprofloxacin. Intake, of salt should be
restricted and diuretics help in controlling the ascites.
671
Encephalopathy: Intake of proteins should be restricted.
Animal proteins should be avoided. Balance calories and
protein should be given to maintain normal growth in a
child.
Treatment of specific diseases: There is no specific treatment
of CH but certain potentially treatable conditions are:
Chronic hepatitis B (CHB): Interferon (5 million units/m2
body surface area given subcutaneously on alternate days
for 6 months) is effective to treat chronic hepatitis B in
30 to 50 percent of cases whereas the results with
pegylated interferon therapy are encouraging (75%). But
strict criteria should be followed. For CHB the criteria
are disease for more than 6 months, raised liver enzymes,
positive HBe and HBV DNA and liver histology showing
core antigen positivity. Lamivudine is another promising
drug to treat CHB; possibly in combination with
interferon will be more effective. The treatment with
interferon is very costly.
Hepatitis C
Hepatitis C infection in majority leads to chronic liver
disease. This takes time to develop chronic hepatitis and
cirrhosis due to HCV. The enzyme rise is quite variable,
so histopathology of liver is mandatory to define the
necroinflammatory and fibrosis scoring based upon
which therapy with interferon (3-5 million units/m2 body
surface area given subcutaneously on alternate days for
12 months) is instituted. The results with pegylated
interferon with ribavarin are encouraging and the
response rate varies from 30 to 60 percent. The
indications for interferon therapy in children are acute
HCV infection with raised transaminases for more than
12 weeks and HCV infection with normal enzymes but
liver histology showing significant necroinflammatory
changes.
Autoimmune hepatitis: Steroids are very helpful but in
certain situations when growth retardation is problem,
azathioprine can be added. Prednisolone in dose of 2 mg/
kg/day is given, till clinical and biochemical improve-
ment occurs. This is followed by maintenance dose till
the histological reversal is seen. The relapse of the disease
is very common, therefore the maintenance dose is given
for a prolonged period.
Wilson’s disease: Avoid copper containing food items like
chocolate, nuts, mushrooms, shellfish, liver, etc. D-
672 IAP Textbook of Pediatrics
penicillamine (10-20 mg/kg/day), a copper chelator is
very effective. Zinc can be given to prevent copper
absorption from gastrointestinal tract. Other alternate
drugs to treat Wilson’s disease are trientine and
tetrathiomolybdate. The treatment is required for life-
long. Family screening should be done so that treatment
can be started at the earliest to the affected individual.
Galactosemia: Withdrawal of milk (Galactose) from diet
can stop the ongoing liver damage.
Fructosemia: This requires withdrawal of fructose from
diet to stop further progression of disease.
Congenital Syphilis: This is treated with penicillin.
NASH
Treatment lies in reduction of weight and appropriate
treatment of diabetes to have good control of blood sugar
levels. Prevention is very important and is not to put on
extra weight.
Outcome
As shown before CPH, CLH and mild CAH can revert
back to normal whereas severe CAH invariably
progresses to cirrhosis. Certain situations like Wilson’s
disease and AIH changes reverse back to normal with
specific therapy. Withdrawal of offending factors can
ameliorate the clinical picture in some of the metabolic
disorders.
13.18 Chronic Liver Disorders in Children
Chronic Liver Disease (CLD) includes a wide spectrum
of disorders with ongoing inflammation of liver tissue,
potentially progressing to cirrhosis or end stage liver
disease.
It may be six months in adults but in pediatrics it
maybe 3-6 months or more when one can include the
disease as chronic liver disease.
CLD at times may present as acute on chronic liver
disease, acute or fulminant viral hepatitis (HA V, HEV)
BIBLIOGRAPHY
1. Batts KP, Ludwig J. Chronic hepatitis: An update on
terminology and reporting. Am J Sug Pathol 1995;19:
1409-17.
2. Bedossa P, Poynard T and The French METAVIR
Cooperative Study Group. An algorithm for grading
activity in chronic hepatitis C. Hepatology 1996,24:
289-93.
3. DeGroote J, Desmet VJ, Gedigk P, et al. A classification
of chronic hepatitis. Lancet 1968;2:626-28.
4. Desmet VJ, Gerber M, Hoofnagle JH, et al. Classification
of chronic hepatitis: diagnosis, grading and staging.
Hepatology 1994;19:1513–20.
5. Gurkan F, Koeak N, Ozen H, Yuu A. Comparison of
standard and high dosage recombinant interferon L-2b
for treatment chronic hepatitis B in children. Pediatr
Infect Dis J 2000;19:52-56.
6. Ishak K, Baptista A, Bianchi L, et al. Histological grading
and staging of chronic hepatitis. J Hepatol 1995;22:
696–99.
7. Jonas M M. Hepatitis C in children. Hepatol Review 2004,
1.23-31.
8. Knodell RG, Ishak KG, Black WG, et al. Formulation and
application of a numerical scoring system chronic active
hepatitis. Hepatology 1981;1:431-35.
9. Maggiore G, Bernard O, Harchonel M et al. Treatment
hepatitis in childhood. J Pediatr 1984;106:529–30.
10. Mowat AP (Ed). Chronic hepatitis. In: Liver Disorders
in child 3rd edn. Butterworths and Co. Publishers
London, Oxford 1994;317–29.
11. Scheuer PJ. Classification of chronic viral hepatitis: need
for reassessment. J Hepatol 1991;13:372-74.
12. Thapa BR, Joshi K, Singh V, Dilawari JB. Clinicopatho-
logical profile of chronic hepatitis in children. Indian J
Gastroenterol 1993;120:A74.
13. Wilinson SP, Portmann B, Cochrane AMG et al. Clinical
course of chronic lobular hepatitis. Q J Med 1978;47–21.
VS Sankaranarayanan, S Srinivas
on top of silent Wilson’s disease and eventually obscure
the nature of the original insult unless one has a high
degree of suspicion.
Histologically chronic hepatitis, cirrhosis or hepatic
fibrosis are included under this category which maybe
active or inactive depending on the presence of
biochemical or histological evidence of hepatocellular
necrosis, inflammation and fibrosis with varying degree
of regenerating nodules in advancing disease.
 Diseases of Gastrointestinal System and Liver 673

Incidence NEONATAL CHOLESTASIS SYNDROME

CLD accounts upto 5% of pediatric ward admissions with
a mortality upto 20% in our set up. The changing pattern
of CLD during the last 25 years is given in the Table
13.18.1. Yacha et al had reported that CLD constitutes
36% of hepatobiliary diseases in their institution.
Causes of CLD
1. Biliary: Neonatal cholestasis syndrome (Extrahepatic
biliary atresia, choledocral cyst, ductal paucity (with
or without Watson Alagille syndrome), Progressive
familial intrahepatic cholestasis (PFIC), etc.)
2. Hepatic: Neonatal hepatitis, Hepatitis B, Hepatitis C,
TORCH, Autoimmune hepatitis, drugs and toxins.
3. Genetic/Metabolic: α 1 Antitrypsin deficiency,
Wilson’s disease, Glycogen storage disease III, IV,
Galactosemia, Tyrosinemia, Urea cycle disorders,
Neonatal hemochromatosis, Nieman Picks-type C,
Gaucher’s disease, Peroxisomal (Zelweiger
Syndrome) mitochondrial disorders or respiratory
chain defects, Cystic fibrosis and rarely Indian
Childhood cirrhosis.
4. Fibrocystic disorders: Caroli’s and congenital hepatic
fibrosis (both do not cause cirrhosis)
5. Vascular: Non cirrhotic portal fibrosis
Chronic Budd Chiari syndrome
Veno occlusive disease
6. Cardiac: Constrictive pericarditis
Chronic congestive cardiac failure
7. Nutritional: Hypervitaminosis A
Total Parenteral Nutrition
8. Cryptogenic or idiopathic.
(PROLONGED CHOLESTASIS OF INFANCY)
Diagnostic Criteria
Prolonged elevation of serum conjugated bilirubin more
than 1.5 mg% or more than 20% of total bilirubin beyond
the first 14 days of life, often presenting as jaundice, high
coloured urine with yellowish staining of diaper, varying
degree of acholic stools and hepatomegaly or hepato-
splenomegaly.
The presentation can be even little later upto even
3 months of life.
Two major categories of presentation namely
neonatal hepatitis due to injury to liver cells and biliary
atresia due to complete obliteration of the biliary tree
due to cholangitis and progressive sclerosis and
narrowing of biliary tree with complete obstruction are
encountered frequently.
Basic clinical differences between EHBA and
Neonatal hepatitis are important in the management of
NCS (Table 13.18.1) to facilitate prompt surgical
consultation of extrahepatic biliary atresia infants before
4-6 wks of age.
The topic on neonatal cholestasis syndrome will be
discussed separately in the following chapter 13.20.
Chronic Heptitis is defined as continuing inflamma-
tion of the liver cells for a short period of more than 3-6
months, which may resolve spontaneously or with
treatment or progress to cirrhosis
Refer 13.17 chapters on chronic hepatits in children
for more details
Cirrhosis of the liver is a chronic liver disease almost
irreversible due to varieties of chronic liver disorders

TABLE 13.18.1: Basic clinical differences between NH and extra hepatic biliary atresia

Features Neonatal hepatitis EHBA

Age of onset Anytime in neonatal period End of 1st week

Gestation Preterm or SFD Term baby
General Appearance May look sick Well looking
Stool Incompletely acholic Completely acholic (pale stool)
Hepatosplenomegaly Early Late
Liver Mild to mod, soft Mod to large
Multisystem Often present Firm to hard
involvement (Cataract, microcephaly, feeding Rare
difficulty, septicemia, blue berry Polysplenia may be present
naevus, seizures etc)
674 IAP Textbook of Pediatrics
characterized by nodular, firm and shrunken liver with
evidence of portal hypertension, ascites and encephalo-
pathy classically.
Refer chapter 13.19 on cirrhosis of the liver.
Metabolic Liver Diseases (MLD)
Incidence
Eight to forty-three percent in most of the centers with
GE services and includes Wilson’s disease, GSD,
Tyrosinemia, α 1 Antitrypsin deficiency, galactosemia,
neonatal hemochromatosis, inborn errors of bile acid
metabolism, fatty oxidation defects, and mitochondrial
and peroxisomal disorders and cystic fibrosis
Most of the above diseases are likely to progress to
cirrhosis.
Fibrocystic Diseases of the Liver
They are inhertited heterogenous disorders that include
congenital hepatic fibrosis (CHF) and Caroli’s syndrome.
The child usually presents with hepatosplenomegaly and
portal hypertension. Enlarged left lobe of the liver may
suggest CHF and liver biopsy is confirmatory showing
periportal fibrosis containing proliferating bile duct like
structures due to ductal plate malformation.
Non Cirrhotic Portal Fibrosis (NCPF)
The etiology is obscure and the syndrome is characterized
by periportal fibrosis and portal vein sclerosis due to
portal pyemia and occlusion of III and IV degree
intrahepatic branches of portal vein. Often seen in older
children and girls with splenomegaly and well tolerated
recurrent variceal bleeds due to NCPF in 2-10% of
patients of CLD. The diagnostic triad includes patent
splenoporto venal axis, absence of cirrhosis and presence
of portal venopathy involving third and fourth degree
intrahepatic portal venules.
Clinical Features of CLD
Often child with CLD may be asymptomatic in compen-
sated liver disease and is also anicteric. Indication of
chronic liver disease in these children may be an
incidental finding of firm hepatosplenomegaly, isolated
firm splenomegaly, with increased transaminases or
increased alkaline phosphatase. Decompensated liver
disease often presents with liver synthetic functiom
failure, occurrence of complication and poor response to
medication. The features of CLD at presentation include
Muscle wasting
Growth failure
Edema
Ascites and jaundice
Firm liver
Hard or nodular liver
Enlarged left lobe
Firm splenomegaly
Complications of CLD
Cirrhosis, Portal hypertension and ascites, variceal bleed,
Coagulopathy, hepatorenal and hepatopulmonary
syndromes. Hypersplenism, recurrent infections due to
impaired immunity and later hepatocellular carcinoma
especially in chronic Hepatitis B and Tyrosinaemia-type
II.
Growth retardation, hepatic encephalopathy and
death are inevitable in the end stage of liver disease
Laboratory Investigations in CLD
Baseline investigations include:
1. Complete urine examination (including albumin,
sugar, bile salt, bile pigment, and urobilonogen) CBC
and reti count to identify hypersplenism or hemolysis.
2. Prothrombin time and activated partial thrombo-
plastin time are sensitive indices of liver function. An
increased PT not responding to Vit K indicates poor
synthetic capacity of the liver and decompensated
hepatocellular disease.
3. Biochemical: Refer chapter 13.19 on cirrhosis of Liver
-Laboratory work up.
4. Liver Biopsy is the gold standard for diagnosis of any
chronic liver disease for confirmation of chronic
hepatitis, cirrhosis and hepatic fibrosis. The grading
of liver injury and staging of liver disease will help
in the prognosis and follow up of the patient. Certain
liver diseases like GSD, CHF and ductopenia have
typical histological findings.
The liver tissue can also be processed for estimation
of copper, special staining and enzyme analysis.
5. Specific investigations for etiology of liver disease
should be done as suggested in Chapter 13.19.
 Diseases of Gastrointestinal System and Liver
Biochemical Features of CLD
1. Persistent elevation of serum transaminases and
alkaline phosphatase (Eg: biliary disorders)
2. Reversal of albumin globulin ratio (serum albumin <
3.5G/100ml and serum globulin above 3G/100ml
3. Prolonged prothrombin time (despite vitamin K
injection)
Note: above laboratory support in correlation with clinical
findings of CLD like firm hepatosplenomegaly, prolon-
ged jaundice ± pruritus, ascites, abdominal wall veins
and coagulopathy especially with a sib +ve history/death
due to chronic liver disease and consanguineous parents.
The gold standard test for confirmation of CLD is only
liver biopsy which will show significant fibrosis,
regenerating nodules and lobular disarray of liver cells.
Management of CLD
1. Aim of management is to reduce or prevent pro-
gression of the disease. Eg: Wilson’s disease, auto
immune disease, hepatitis B and C and tyrosinemia.
2. To anticipate, prevent and treat complications
3. Supportive therapy includes nutrition and vitamins
and salt restriction, antibiotics, diuretics and growth
monitoring.
To select candidates for liver transplantation
Liver transplantation is an accepted modality of manage-
ment of chronic liver disease currently and has changed
the lifestyle of these children with CLD. The commonest
13.19 Cirrhosis of Liver
Cirrhosis of the liver is relatively a common form and
the end stage of chronic liver disease and is due to a
variety of etiologies (Table 13.19.1). Clinically established
cirrhosis is characterized by a shrunken (short liver span),
firm to hard nodular liver with evidence of portal
hypertension and varying degree of liver cell failure.
675
indications for liver transplantations are biliary atresia,
ductal paucity, α 1 Antitrypsin deficiency, tyrosinemia
type I, GSD type III and IV, PFIC, Wilson’s disease and
primary biliary cirrhosis and fulminant hepatic failure.
KEY MESSAGES
Chronic Liver Disease in children is likely to progress to
cirrhosis and needs a complete work up for diagnosis,
confirmation of etiology and grading and staging of the
disease histologically. These children should be referred
to tertiary care centers where there is facility for pediatric
GE workup and follow up management
BIBLIOGRAPHY
1. Ashish Bavdekar. Metabolic liver diseases, lAP speciality
series on paediatric gastroenterology 2008;(16):217-27.
2. Bavdekar AR. Wilson’s disease—A diagnostic dilemma.
Indian J Gastroenterology 2003;22-23.
3. Malathi Satyasekharan—Approach to a child with CLD,
Indian J of Pract Pediatrics. Hepatology 2002;4(4):
362-69.
4. Sheila Bhave. Chronic liver disorders in children, lAP
speciality series on paed gastroenterology 2008;(14):
188-96.
5. Surendar Kumar A Yacha. Neonatal cholestasisfAP
speciality series pn ped.gastroenterology 2008;(13):
178-87.
6. Sutapa ganguly. Portal hypertension. IAP speciality
series on paediatric gastroenterology 2008;(15):196-216.
7. VS Sankaranarayanan, S srinivas. Chronic hepatitis in
children and cirrhosis of liver in children. Partha’s
fundamentals ofpediatrics 2007;(11):354-61.
VS Sankaranarayanan, S Srinivas
Pathologically, hepatic cirrhosis is characterized by
fibrosis, nodules created by regeneration of hepatocytes
and disruption of parenchymal lobular architecture of
the entire liver.1,8 Fibrosis is generally reversible.
Causes of Cirrhosis
Causes of cirrhosis in children are listed in Table 13.19.1.
676 IAP Textbook of Pediatrics

TABLE 13.19.1: Etiology of cirrhosis in children

Young infants Children < 4 years of age Children > 4 years of age

Extra hepatic biliary atresia Extension of problems of Chronic hepatitis

Severe form of neonatal neonatal cholestasis Wilson’s disease and other
hepatitis beyond infancy and more metabolic diseases
Bile acid abnormalities than 2 yrs of age Glycogen storage disease
(PFIC, inborn error of bile Tyrosinemia Cystic fibrosis
acid metabolism) Glycogen storage disease Hemochromatosis
Tyrosinemia Alpha 1 antitrypsin Autoimmune chronic hepatitis
Galactosemia deficiency Cryptogenic
Congenital hemochromatosis Histiocytosis
Post TPN Nieman pick disease
Drug induced (anti cancer,
anti epileptic, anti TB etc)
Veno occlusive disease

Pathogenesis of Cirrhosis • Past history of neonatal cholestatic syndrome or

Chronic and persistent liver cell injury leads to cell death
(necrosis) replaced by scar formation (fibrosis) and
nodular formation (regeneration).Intracellular liver
enzymes and electrolytes are released from the injured
hepatocytes.
This results in changes in extracellular matrix -
increased collagen (especially type 3 and 4). This
produces perisinusoidal broad septa formation. Vascular
changes take place at sinusoidal level due to deposition
of Lamin causing arteriolar and venous intrahepatic
shunts. Ischemia, decreased synthetic liver function,
increased pressure effects result ultimately and the
viscious cycle of necrosis, fibrosis and nodular formation
continue ending in irreversibility even if the cause is
removed.
Clinical Features
Clinical clues for cirrhosis in history:
• History of consanguinity/sib history of death due to
chronic liver disease - metabolic cause
• Family history of neuro psychiatric disease - Wilson’s
disease
• Risk factors of hepatitis B/Hepatitis C like blood
transfusion, needle injury, tattooing, dental extraction
etc
• History of ingestion of hepatotoxic drugs—INH,
methotrexate, methyl dopa, sodium valproate,
ketoconazole, nitrofurantoin, prolonged TPN, etc.
prolonged jaundice atleast two years ago.
• History of seizures with abdominal distension -
Nieman pick’s disease, Gaucher’s
• History of frequent feeds with dizzy spells on fasting-
Glycogen storage disease.
Cirrhosis should be suspected whenever there is
persistent jaundice, ascites, GI bleed, peripheral oedema,
family history of chronic liver disease or past history of
jaundice due to HBV, HCV, HDV or hepatotoxic drugs
with firm and nodular liver with abnormal tortuous
abdominal wall midline veins with palmar erythema,
clubbing and fatiguability.
General Clinical Examination in Cirrhosis
Examination will reveal features of hepatocellular failure
and features of decompensated liver disease.
Abdominal examination may reveal ascites, abnormal
and tortuous veins, nodular liver, splenomegaly and
opening of hernial orifices and peripheral and scrotal
oedema and other complications of cirrhosis.
Complications of Advanced and
Decompensated Cirrhosis
Ascites, encephalopathy, GI bleeds, hepatorenal
syndrome, hepatopulmonary syndrome (cyanosis)
spontaneous bacterial peritonitis and hepatocellular
carcinoma. (HBV, HCV and HDV cirrhosis).
 Diseases of Gastrointestinal System and Liver
Diagnosis
Labarotary Investigations
Hematology—Basic: Haemoglobin, total and differential
count, platelet count and peripheral smear.
Liver function tests: serum bilirubin and (conjugated +
unconjugated fraction), SGOT and PT.
Serum albumin and globulin ratio, Serum alkaline
phosphatase, GGTP and cholesterol.
Prothrombin time and activated partial thrombo-
plastin time.
If ascites is present serum sodium, potassium.
Bicarbonate, chloride, urea and creatinine levels may
help.
Serology for hepatitis B (HBsAg, HbeAg, HBV DNA),
HCV (HCV elisa and HCV RNA), CMIV, EB virus, HIV
and TORCH group.
Screening for metabolic liver disease.
Biochemical Features of Cirrhosis Liver
1. Persistent elevation of serum transaminases and
serum alkaline phosphatases
2. Reversal of albumin: globulin ratio S.albumin (< 3.5
g/100 ml)
3. Prolonged prothrombin time (despite Vitamin K
injection).
Ultrasonogram
For splenoporto venal axis, echo texture of liver, portal
vein collaterals and minimal ascites, hepatoma, and
choledoccal cyst, extrahepatic biliary atresia, gallstones
can be easily identified by USG abdomen. Colour doppler
USG abdomen will provide more details about the portal
hypertension.
TABLE: 13.19.2 Child’s prognostic grading of portal hypertension (Modified Pughs)
Prognosis Compensated (A)
Jaundice (bilirubin) Mild or nil < 2 mg/dl
Ascites — Mild and treatable
Albumin >3.5 g/dl
Encephalopathy — Past history
Prothrombin time N or × 1 ↑
677
Liver Biopsy
Liver biopsy is the gold standard and confirmatory for
chronic hepatitis and cirrhosis liver.
Presence of periportal fibrosis and necrosis, nodular
regeneration with loss of hepatic lobular architexture are
the confirmatory findings for cirrhosis
Helps in diagnosis, disease activity, classification,
follow up and identifying Differential diagnosis
1. Extrahepatic portal hypertension (absent liver cell
failure abdominal wall veins)
2. Chronic hepatitis (absence of nodular liver, abdo-
minal wall veins and portal hypertension)
Course and Prognosis
It is variable, depending on Child’s grading system
(Table 13.19.2).
Interpretation: Any two of the below will guide physician
Childs A: Patient with good liver dysfunction
Childs C: Patient with poor liver function and surgical/
invasive procedures will carry increased mortality in 90%
in non bleeding cirrhotics.
Management
1. Early detection and management of complications
due to decompensated cirrhosis.
2. There is no specific treatment per se that will arrest
or reverse the cirrhotic changes. Treatment of portal
hypertension, ascites and hepatic encephalopathy has
been discussed separately.
3. Treatment of specific cause if any, like Wilson’s
disease, drug induced hepatitis and hepatitis B and
C.
4. Patients with compensated cirrhosis can lead a
normal life and no specific diet is helpful.
Guarded (B) Decompensated (c)
Moderate 2-3 mg/dl Intense > 3 mg/dl
Severe/refractory
3-3.5 g/dl < 3 g/dl
++
X2↑ X many ↑
678 IAP Textbook of Pediatrics

5. Hepatic herbal supportives, antioxidants, liver cell
membrane protectives and maintenance of adequate
calories, fluid and electrolytes, vitamin especially fat
soluble vitamins are routinely recommended with
variable outcome.
6. Liver transplantation is the future hope in EHBA,
tyrosinemia, glycogen storage disease, acetyl
transferease deficiency and severe bile acid metabolic
defects (PFIC)
Encephalopathy
Encephalopathy is characterized by irritability, inco-
herent speech, mental confusion and violence (Grade l)
Drowsiness and somnolence, flapping tremor, fetor
hepaticus (Grade II), Exaggerated reflexes with upgoing
plantar reflex, stupor (Grade III) and Coma (Grade IV).
Metabolic complications like hypoglycemia, dyselec-
trolytemia, renal failure, Coagulopathy with bleeds,
hyperammonemia, convulsions etc may supervene in Gr
III and IV encephalopathy. Early detection of hepatic
encephalopathy can be by demonstrating constructional
apraxia (inability to draw or copy a star)
Predisposing Causes
GI bleed with excess protein in the bowel, rapid
abdominal paracentesis, intercurrent infection (Gram
negative septicemia) use of hepatotoxic drugs (morphine)
major surgical procedures and electrolyte imbalance
(diurectics)
Management Guidelines
Goal of therapy is to identify the complications of hepatic
encephalopathy and decompensated cirrhosis and
prevent by avoiding predisposing factors mentioned
above.

Disease Defect Clinical Diagnosis Treatment Prevention

Extrahepatic Atresia of EHB Persistent pale stools U/S screening Kasai-Hepatico

biliary atresia passage in neonate absent gallbladder porto
intrahepatic Firm big liver Liverbiopsy jejunostomy
biliary atresia Well fed neonate Bile duct within 6 wks of
Early cirrhosis proliferation, bile life and follow
stasis and plugs and up
dense fibrosis with Liver
cirrhosis transplantation
Hepatobiliary scan-
no isotope excretion
in intestine, even
after 24 hrs
(mebrefenin)
Preoperative
cholangiogram
chromosome Jaundice urine porphins carotene
mutations CLD in teenage normal Cholestyramine
frequent Red cell free UDCS for itch
Autosomal Protoporphyrin Livertransplant
dominant increase --
Kidney
transplant
Neonatal Viral, metabolic Small for date Tests for etiologic Supportive care Prevention of
Hepatitis drugs, TPN, Sick and septic baby agents antenatal
endocrine, etc or Occasional yellow Liver biopsy, infection
idiopathic stools Giant cells+++ and
(common) Multiorgan necrosis
involvement
Hepatosplenomegaly

Contd...
 Diseases of Gastrointestinal System and Liver 679

Disease Defect Clinical Diagnosis Treatment Prevention

Post hepatic HBV, HCV or Pat h/o 2 yrs ago HBsAg, Symptomatic HBV
cirrhosis HDV s/s of CLD HBeAg, antiHBcIGM and supportive immunization
s/s of DNA polymerase, treatment of
decompensated CLD R.T.PCR-HBV, anti- variceal bleed.
macronodular HCV ABD,PCR, PoSE, ascites
cirrhosis anti HDV IGM coagulopathy
ABD. Liver biopsy
U/S endoscopy and
biochemical
(A;G,PT,PTT)
Wilson’s Copper binding Hepatosplenomegaly CT scan/MRI brain Chelators D Genetic
disease membrane viral hepatitis,FHF for deposition of penicillamine counseling
spanning protein Chronic hepatitis, copper in basal (750 mg/m2)+
with P type features of cirrhosis ganglia,cortical pyridoxine
ATPase motifs neuro-psychiatric atrophy etc after Trientine
at chromosome (choreoathetoid ophthalmic opinion Triethylene
13 at 14 q 21 movements, for KFR, Tetramine
mutation C to A dyslexia, dysarthria, S.Ceruloplasmin HCL,
transversion ataxia)renal:tubular reduced mostly test ammonium
Frame shift dysfunction rickets is a screening test Tetra
autosomal 24 hrs urinary Cu thiomolybdate,
recessive excretion is> zinc, liver
100 μg/day transplant diet:
especially after decrease the
penicillamine intake of shell
Liver copper being fish,chocolate,
gold standard is nuts
usually above 250
μg/g dry weight
Inborn error of Synthesis of Neonatal cholestasis Serum bile acids Oral bile acides Genetic
bile acids primary bile cirrhosis (CDCA and CA (UDCA) counseling
acids decrease Intense pruritus decrease) urine,bile Liver transplant
acids increase
enzyme estimation
by spectrometry and
gaschromatography
Erythropoietic Ferrochelatase Photosensitivity<6 Micro-hypoanemia Local:UV and Genetic
Protoporphyria decrease Yrs Bone marrow:ring sunscreens counseling
Gene locus:18 Pain abdomen sideroplastic iron Oral beta prenatal diagnosis
and MTP

ICC (Indian Not clear Insidious onset/AVH Liver biopsy D. penicillamine Remove copper
child hood possibly onset H/o creeping fibrosis Zinc from diet
cirrhosis) inherited copper utensils Mallory hyaline Steroids?
tendency+ 3 stage CLD- rcein+ for liver
copper triggered Early (1-1½ yr) copper, no fatty
Intermediate(1-1½ yr) change
Late (6/12 year)6
months. Malignant
(6/12) hepatitis
6 mths to 4 yrs
Age: 6/12-4 years

Contd...
680 IAP Textbook of Pediatrics

Contd...
Disease Defect Clinical Diagnosis Treatment Prevention

Alpha 1 Abnormal A-1 Neonatal cholestasis Serum AIAT Liver transplant

antitrypsin AT in Chronic hepatitis decreases Gene therapy
deficiency endoplasmic Cirrhosis + PCR for nucleotides Aerosol AAT
reticulum and Emphysema in A-1AD at for COPD
intracellular ‘Z’ mutation site MTP after PND
hepatic Prenatal
inclusions >
liver damage
Gene locus: 12-
Kb on
chromosome 14
‘Z’ AIAT and Z-
AIAT deficiency
common
Tyrosinemia Fumaryl Neonatal cholestatis Alpha fetoprotein Diet low Prenatal screening
(Type 1) acetoacetate CLD-Ch hepatitis increases. LFT may tyrosine and MTP
decreases Cirrhosis be normal methionine and
Autosomal HCC Confirmation by red PA Nacety
recessive Renal: renal rickets cell, lymphocyte, cystine
Genelocus at and tubular cultured fibroblast Enzyme
chromosome dysfunction or liver analysis for therapy
15 qu 23-25 Failure to thrive, fumaryl acetoacetate Anti oxidants
diarrhea and vomit, hydrolase (FAH) Liver transplant
anemia, bleeds and Urine +
neurological succinylacetone is Kidney
increased PCR transplant
Prenatal screening
Cystic fibrosis Mutations in Meconium ileus, Sweat chloride Treat of CLD Genetic counseling
CFTR gen locus neonatal cholestasis, (> 60 mEQ/L) (Cholestasis, prenatal diagnosis
at chromosome 7 cirrhosis, rectal Fecal chymotrypsin pH, cirrhosis) and MTP
at position prolapse COPD → (< 60 MS/GM) Nutrition
7q31→abnormal corpulmonale Neonatal screening copper (low fat,
secretions (IRT) (serum MCT vits)
(mucoviscidosis) trypsinogen on filter Pancreatic
in resp, pancreatic, paper) CF genotyping enzymes
hepatobiliary and Prenatal > CV Somatic gene therapy
GI tract sampling >
amniocentesis
Glycogen Autosomal Common types Fasting blood Frequent feed
storage recessive Massive liver, glucose decrease with glucose
disease (except type VI) Hypoglycemic spells Glucagon test (no Raw, uncooked
enzyme defect in Chubby cheeks response rise of corn starch—
the metabolic Age of onset 1-2 yrs blood glucose) 1.5 to 2 gms/kg
pathways in Mutation: N liver biopsy-large 5 to 6 times a
glycogen liver cells day useful.
breakdown vacuolations Liver transplant for
Usually type IV liver enzymes and end stage liver
(branching enzyme) estimation disease
or type I (G-6-
phosphatase) or
type III
(debranching)
→ insufficient
glucose production
by liver
 Diseases of Gastrointestinal System and Liver
Specific treatment includes:
To identify any site of bleeding by endoscopy and treat
appropriately (variceal bleed, gastric or duodenal
erosions etc).
Maintenance of fluid and electrolyte balance. Sodium
restriction may be required despite hyponatremia which
may be dilutional.
Potassium replacement for hypokalemia Diuretics
(spironolactone/loop diuretics) for edema and parenteral
IV glucose for hypoglucemia.
Infection: Culture studies of ascitic fluid and if
positive to treat infection as indicated.
Lactulose produces two liquid stools (15-30 ml twice
of thrice daily). It produces osmotic diarrhoea, prevents
absorption of ammonia from colon and prevents
proliferation of ammonia producing organisms.
Selective intestinal decontamination by adminis-
tration of non absorbable antibiotics (norfloxacin,
neomycin).
Sedation (short acting benzodiazepines Oxazepam,
medozolam) preferred.
Coagulation defects to be corrected with fresh frozen
plasma or clotting factors and vit K (single dose).
Parenteral vitamins (Fat soluble and water soluble
especially B vitamins).
Orthoptic liver transplantation in selected tertiary
care liver transplant units-cost prohibitive.
Variceal bleed to be treated by somatostatin, octreo-
tide, vasopressin or glypressin or endoscopic band
ligation or sclero/glue therapy and Sengstaken tube.
Specific causes of cirrhosis and management of treatable
causes like Wilson’s disease, autoimmune hepatitis, drug
induced, hepatitis B and C etc recommended.
PORTAL HYPERTENSION
Clinical criteria includes variceal upper G I bleed,
splenomegaly, tortuous veins on anterior abdominal wall
away from umbilicus especially in intrahepatic type and
ascites getting localized in all end stage of cirrhosis in
the presence of portal hypertension. Cirrhotic portal
hypertension will have history suggestive of chronic liver
disease and clinical features of underlying cause for
portal hypertension. Nodular and shrunken liver,
681
abdominal veins and features of decompensation with
extrahepatic manifestations of chronic liver disease will
differentiate patients of extrahepatic portal hypertension
where the above features are absent until late stage.
However laboratory work up including ultrasound/
Doppler abdomen will help to identify the pathology in
the SPV axis. Pressure criteria: portal venous pressure>
10 mm of Hg (normal < 10 mm of Hg), Hepatic venous
pressure gradient: if more than 12 mm it is a useful
predictor of impending variceal bleed.
Abdominal ultrasound will give details about the
patency, size and collaterals of SPV axis and presence of
ascites. Echotexture of the liver and right sided plural
effusions and evidence of SOL in liver can be picked out
easily.
Oesophago gastro duodenoscopy not only helps to
identify the oesophageal and fundic varices and porto
hypertensive gastropathy but also facilitates endo-
therapy.
Identification of the cause of portal hypertension is
almost laboratory etiologic work of cirrhosis liver and
chronic hepatitis. Evaluation of hyper coagulable state-
causing thrombosis of splenoportovenous axis includes
complete coagulation profile, protein S and C, antiphos-
pholipid antibody, antithrombin and fibrinogen
estimation in selected patients, as specific therapy for this
is possible.
Liver biopsy will be the gold standard for confir-
mation of cirrhosis, noncirrhotic portal fibrosis,
congenital hepatic fibrosis, chronic biliary diseases
including biliary atresia, PFIC etc. Diagnosis of portal
hypertension should also include screening for hyper-
splenism, posttransfusion complications and work up for
minimal chronic hepatic encephalopathy like psycho-
metry analysis.
Management of portal hypertension should include
emergency resuscitation of upper GI bleed [control of
bleeding with somatostatin and analogues or vasopressin
and glypressin, emergency endoscopy therapy and long
term prevention of variceal bleeds with propranalol (1
mg/kg/day) and isosorbide mononitrate]. Proper
counseling of close relatives for long term follow up and
the natural course of the illness is mandatory. Indication
for surgical management includes:
682 IAP Textbook of Pediatrics
1. Recurrent rebleeds even after 4 to 6 endotherapy
sessions
2. Hypersplenism
3. Outstation patients (from remote places) where
medical treatment is not available
4. If patient is not fit for surgery or not willing for
surgery, TIPS (transjugular intrahepatic porto
systemic shunt) can be attempted.
Ascites: see chapter on ascites
BIBLIOGRAPHY
1. Ashish Bavdekar. Metabolic liver diseases, lAP speciality
series on paediatric gastroenterology 2008;(16):217-27.
2. Bavdekar AR. Wilson’s disease—A diagnostic dilemma.
Indian J Gastroenterology 2003;22-23.
3. Hardy S, Kleinman ER. Cirrhosis and chronic liver
failure. Text book of liver disease in chidren2nd edition.
Eds Suchy FJ, Sokol RJ. Balistreri WF Lippincott Williams
and Wilkins: Phildelphia, 2001;89-127.
13.20 Neonatal Cholestasis Syndrome
INTRODUCTION
Neonatal cholestasis is a pathological condition in which
bile flow is affected. Neonatal cholestasis syndrome
(NCS) comprises of a heterogeneous group of hepato-
biliary disorders responsible for cholestasis during
neonatal life. The cholestasis due to some disorders can
extend beyond neonatal period hence it is also referred
to as ‘cholestasis of infancy’. Most of the disorders have
linkage with insults during antenatal, natal and postnatal
periods. Main causes of NCS are infections, metabolic
disorders and extrahepatic biliary obstruction.
Epidemiology
The present scenario about the spectrum of illnesses is
changing fast, the premature babies are now being looked
after in neonatal specialized care units, the causes of
4. Kelly DA. Useful investigations in the assessment of liver
disease. Textbook of diseases of the liver and biliary
system in children. Deidre A Kelly 1999;3-8.
5. Malathi Satyasekharan—Approach to a child with CLD,
Indian J of Pract. Pediatrics, Hepatology 2002;4(4):
362-69.
6. Sheila Bhave. Chronic liver disorders in children, lAP
speciality series on paed gastroenterology 2008;(14):
188-96.
7. Surendar Kumar A Yacha. Neonatal cholestasisiAP
speciality series pn ped.gastroenterology 2008;(13):
178-87.
8. Sutapa ganguly Portal hypertension. lAP speciality series
on paediatric gastroenterology 2008(15);196-216.
9. VS Sankaranarayanan, S srinivas. Chronic hepatitis in
children and cirrhosis of liver in children. Partha’s
fundamentals of pediatrics 2007;(11):354-61.
10. Thapa BR, Bansal D .Management of upper gastro-
intestinal bleeding in children- portal hypertension-acute
variceal bleeding. Indian J of Practical pediatrics-
Hepatology 2002;4(4):403-10.
BR Thapa
cholestasis due to sepsis, total parenteral nutrition (TPN)
and drugs are emerging as a large group.
Approach to Jaundice
Jaundice is a very common symptom encountered during
neonatal life. Approach to jaundice during neonatal
period and infancy is given (Fig. 13.20.1). This is also
called hyperbilirubinemia when defined by raised serum
bilirubin > 2 mg/dl. Based upon the composition of
serum bilirubin, this is divided into unconjugated and
conjugated hyperbilirubinemia. Unconjugated hyper-
bilirubinemia is very common during first few weeks of
life and the unconjugated bilirubin constitutes 80 percent
of total serum bilirubin level. This is characterized by
icterus, normal colored urine and yellow normal colored
stools. Most of the times it is attributed to physiological
jaundice or breast milk jaundice.
 Diseases of Gastrointestinal System and Liver
Figure 13.20.1: Approach to jaundice during infancy and
classification of cholestasis
Definition
Conjugated hyperbilirubinemia is defined when the
conjugated fraction of bilirubin is more than 20 percent
of the total serum bilirubin or when conjugated bilirubin
is more than 1.5 mg/dl in neonatal period and persists
beyond first 14 days of life then it is labeled as neonatal
cholestasis.This is associated with retention of bile salts
in the blood. Cholestasis is also defined as pathological
stage of reduced bile formation or flow and clinical
criteria are passage of high colored urine that stains the
diaper yellow and pale/white/acholic or intermittent
pale and yellow or yellow stools (Fig. 13.20.2). Cholestasis
is characterized by itching that may not be recognized
during early life but irritability is a common feature. After
6-months of life itching is quite apparent. These clinical
pointers are very important to differentiate between
cholestasis and unconjugated hyperbilirubinemia.
Histopathological definition of cholestasis is the
appearance of bile within the liver parenchyma
responsible for secondary cell injury.
683
Figure 13.20.2: Normal yellow stool (1) and pale/alcoholic
stool in case of EHBA or severe cholestasis (2)
Classification
Neonatal cholestasis is divided into two groups, intra-
hepatic cholestasis and extrahepatic cholestasis based
upon the nature and site of pathological lesions.
Intrahepatic cholestasis covers two important groups
hepatocellular cholestasis: neonatal hepatitis and paucity
of intrahepatic bile ducts (PIBD). Cholestasis can also be
classified into neonatal hepatitis and obstructive
cholangiopathy or obstructive cholestasis. Obstruction
could be at level of extrahepatic biliary tree and/or
intrahepatic biliary tree.
Predisposing Factors
Newborn infants are prone to develop cholestasis
because of immaturity of excretory function, inborn
errors of metabolism manifesting in early life and
inherent susceptibility to various viral, septic and toxic
insults. The immature liver cells are associated with
peculiar kind of pathological response to different kind
of noxious agents during neonatal life and infancy.
The ineffective enterohepatic circulation of bile
further compromises the excretory function. There is
gradual maturation of hepatocytes in respect to handling
of bilirubin, excretion of bile, synthetic functions and
enzyme system during infancy. The maturation of these
functions may be equivalent to adulthood by age of 4 to
6 months. Some biochemical markers of cholestasis like
684 IAP Textbook of Pediatrics
alkaline phosphatase and glutamyl transpeptidase are
raised during early life. Serum unconjugated bilirubin,
and bile acids concentration are normally in higher
concentration in blood again suggesting that there are
clearance problems in neonatal liver. Due to these reasons
the neonatal hepatobiliary system is affected by various
infective, metabolic and obstructive causes faster as
compared to older children and adults.
Etiology
Various causes of cholestasis are given in Table 13.20.1.
Neonatal hepatitis is more common than EHBA. The
etiology of neonatal hepatitis is idiopathic if known
causes are ruled out.
Pathophysiology
The effects of cholestasis are devastating secondarily due
to retention of bile and results into widespread problems
with the advancing life, of the cholestatic infants and
children. Figure 13.20.3 gives the consequences of
prolonged cholestasis.
Figure 13.20.3: Consequence of prolonged cholestasis
Approach to NCS
In NCS it is mandatory to differentiate between neonatal
hepatitis and EHBA. Neonatal hepatitis warrants medical
treatment whereas obstructive cholestasis largely EHBA
needs only surgical treatment and is effective, if done
within 60 days of life.
If the baby is passing pale or acholic or white stools
from very beginning or after few weeks of life one should
act very fast to make the diagnosis of EHBA. In EHBA
fibrosis sets in as early as 4 weeks of life.
EHBA babies are usually term born and have good
weight. Twenty percent of these babies may have
associated congenital malformations. Liver function tests
at times may not help to differentiate. Liver enzymes like
ALT and AST are nearly normal in EHBA but are always
raised in NH. Gamma GT may be raised in EHBA. In
EHBA prolonged PT usually responds to vitamin K
administration.
The approach to cholestasis to differentiate between
obstructive cholestasis and hepatocellular cholestasis is
given in Figure 13.20.4 whereas approach in late
presentation of EHBA is given in (Fig. 13.20.5).
 Diseases of Gastrointestinal System and Liver 685

TABLE 13.20.1 Causes of cholestasis in infancy

A. Extrahepatic
Correctable
Biliary atresia CBD ligation
Noncorrectable CBD stricture
Bile duct stenosis Biliary hypoplasia
Spontaneous perforation of bile duct Pancreatico-ductal anomaly
Common bile duct (CBD) stone Choledochal cyst
Primary sclerosing cholangitis (PSC) Mass (neoplasia)

B. Intrahepatic
I Idiopathic neonatal hepatitis
II Intrahepatic cholestasis: persistent
a. Nonsyndromic PIBD
b. Syndromic PIBD
c. Others
Arteriohepatic dysplasia (Alagille syndrome)
Progressive familial intrahepatic cholestasis (PFIC I, II, III and IV)
Byler disease
Trihydroxycoprostanic acidemia
Zellweger syndrome (cerebrohepatorenal syndrome)

III. Intrahepatic cholestasis: recurrent

a. Familial benign recurrent cholestasis
b. Hereditary cholestasis with lymphedema
c. Alpha 1 antitrypsin deficiency
d. Miscellaneous
Cystic fibrosis
Idiopathic hypopituitarism
Hypothyroidism
Multiple acyl-CoA dehydrogenase deficiency
IV. Hepatitis
a. Infections Others:
Bacterial infections Malaria
Hepatitis B virus Toxoplasmosis
Herpes virus Syphilis
Coxsackie virus Listeriosis
Cytomegalovirus
ECHO virus
Rubella virus
HIV
Varicella virus
b. Metabolic disorders
A. Disorders of amino acid metabolism
Tyrosinemia
Hypermethioninemia
B. Disorders of lipid metabolism
Cholestasis associated with parenteral nutrition
Niemann-Pick disease type C.
Infantile Gaucher disease
C. Disorders of carbohydrate metabolism
Galactosemia
Fructosemia
Glycogen storage disease, III and IV

Contd...
686 IAP Textbook of Pediatrics

TABLE 13.20.1 Contd...

V. Genetic chromosomal disorders
• Trisomy F
• Down syndrome
• Donohue’s syndrome (leprechaunism)
VI. Miscellaneous
• Histiocytosis X
• Congenital hepatic fibrosis
• Shock
• Caroli’s disease
• Intestinal obstruction
• Neonatal iron storage disease/hemochromatosis
• Hemangioendothelioma

Figure 13.20.4: Algorithmic approach to differentiate EHBA from NH (<60 days)

 Diseases of Gastrointestinal System and Liver 687

Figure 13.20.5: Approach to late presentation of EHBA (>60 days of life)

Ultrasound (UDCA) 20 mg/kg/day for 5 days. However, EHBA is

ruled out when dye is seen in duodenum (Figs 13.20.6A
Ultrasound is a non-invasive modality to see the status
and B). The sensitivity is very high to pick up severe
of liver parenchyma, dilated intrahepatic or extrahepatic
cholestasis whereas specificity to pick up EHBA is very
biliary tree and presence of gallbladder. Conditions like
low 60 to 70 percent. In some centers this investigation
choledochal cyst, bile plug syndrome, common bile duct
is not done routinely since there is wastage of 6 to 7 days
(CBD) stone and Caroli’s disease can be picked up with
period.
great accuracy. Absence of gallbladder is correlated with
EHBA with low sensitivity and specificity (60–70%). But Liver Biopsy
there is significant overlap. Even in severe cholestasis
It is important to do liver biopsy. But for interpretation
gallbladder may not be defined because of less pro-
there is need of an expert pathologist who is familiar with
duction of bile and it may be hypoplastic. Ultrasono-
developing neonatal liver and then reaction to various
graphic triangular cord (TC) sign is a cone shaped fibrotic
toxic factors like infections, metabolic and obstructive
mass in front of bifurcation of portal vein. This is very
insults. In best hands histopathology can differentiate
specific for EHBA in expert hands.
NH and EHBA up to the tune of 95 percent. But in
5 percent cases there can be overlap.
Scintigraphy (HIDA Scan)
EHBA is characterized by presence of proliferation
In severe cholestasis due to NH there may not be of interlobular ducts, plugged with bile casts and portal
excretion of dye even after adequate priming with tracts show fibrosis. The liver parenchyma may be
phenobarbitone 5 mg/kg/day or ursodeoxycholic acid normal, or may show intrahepatocytic or canalicular
688 IAP Textbook of Pediatrics

Figures 13.20.7A and B: (A) Classical histopathology of

EHBA, (B) EHBA with secondary cirrhosis
Figures 13.20.6A and B: (A) Showing dye into the duodenum
EHBA rules out, (B) Dye not seen in duodenum: EHBA or severe
cholestasis

cholestasis. But in advanced cases after 2 months of life

there may be full-fledged changes of secondary biliary
cirrhosis (Figs 13.20.7A and B).
In neonatal hepatitis there is marked parenchymal
injury suggesting focal necrosis, ballooning degeneration,
giant cell transformation (Fig. 13.20.8 showing giant cell
hepatitis), inflammatory infiltrate, pseudoacinar
formation and portal tract may show mild portal triaditis.
There is no fibrosis until the disease is chronic.
Diagnosis of PIBD can be made on histology if the
ratio of presence of bile ducts to portal tracts is less than
0.4 to 0.6. But liver biopsy should contain minimum Figure 13.20.8: Showing giant cell neonatal hepatitis
5 portal tracts to make the diagnosis of PIBD in a biopsy
specimen. after 10 to 14 days should be done. The other modalities
If the results of biopsy are equivocal (5%) and age is used are MRCP and ERCP but all depends upon the
less than 6 weeks, BRIDA scan and or repeat liver biopsy expertise available.
 Diseases of Gastrointestinal System and Liver
Magnetic Resonance
Cholangiopancreatography (MRCP)
This is a new noninvasive modality but experts are
required for interpretation of neonatal bile ducts.
Endoscopic Retrograde
Cholangiopancreatography (ERCP)
Problem with ERCP is technical failure and non-
availability of small diameter ERCP scopes in most of
the centers.
Laparoscopy
Laparoscopic visualization of hepatobiliary tree has not
been popularized in children.
Duodenal Intubation
Aspiration of duodenal fluid over 24 hours to see for bile
is popular procedure in Japan. This can be done during
scintigraphy to define the radioactivity in stomach and
duodenal fluid.
Intraoperative Cholangiography (IOC) or
Peroperative Cholangiography (POC)
This is the gold standard to confirm the diagnosis of
EHBA, when above given investigations do not suggest
EHBA. In presence of gallbladder IOC showing dye in
duodenum and after clamping the CBD showing dye in
intrahepatic radicles rules out EHBA. On the other hand
if dye is not going to duodenum or there is no extra
hepatic biliary tree also confirms EHBA. There is
advantage of taking wedge biopsy of liver. Kasai’s
portoenterostomy can be done simultaneously in EHBA.
Approach to Neonatal Hepatitis
Neonatal hepatitis is the most important cause of NCS
(60-70%). It is important to record detail history regarding
antenatal, natal and postnatal events, family history,
exposure to various drugs, maturity of the baby, neonatal
sepsis, intrauterine infections, various metabolic and
genetic disorders. Thorough clinical examination is
warranted. The clue to the etiological diagnosis should
come from good clinical evaluation of the case. Infections
in our set up are very important cause of neonatal
hepatitis. If there is direct clue to some metabolic or
genetic disorders the investigations should be done
689
accordingly. If the infections have been ruled out
reasonably, the next choice is to do metabolic work up.
High index of suspicion of these disorders should be
based upon certain clinical pointers like family history
of previous sib death due to similar disorder, repeated
hypoglycemia, seizures, vomiting, failure to thrive, and
cataract. Preliminary metabolic work up includes urine
for reducing substances like galactose or fructose, serum
alpha-1 antitrypsin level, thyroid function tests, serum
amino acids, urine amino acids screening, eye exami-
nation, urinary succinyl acetone, and serum ferritin.
Based upon the suspected diagnosis the specific enzyme
estimation/genetic work up should be done.
Inspite of elaborate workup in 30 to 40 percent cases
of neonatal hepatitis the etiology can not be defined. This
group is labelled as idiopathic neonatal hepatitis or giant
cell hepatitis. Liver histology shows marked giant cell
reaction. Liver biopsy also gives clue towards metabolic
disorders at times.
Treatment
Neonatal Hepatitis
Infections constitute a major cause of neonatal hepatitis
in developing countries. Bacterial infections must be
treated very effectively. Urinary tract infection remains
hidden infection in neonatal period that should be
diagnosed and treated energetically. Viral infections
perse do not require any specific therapy in this age group
but protozoal infections like malaria and toxoplasmosis
and congenital syphilis should be treated effectively.
Treatment of various metabolic disorders should be
started at the earliest. The offending agent should be
withdrawn promptly for example in case of galactosemia,
milk should be stopped immediately to avoid effect on
the developing brain. In case of fructosemia, fructose
containing food items must be withdrawn immediately.
Treatment of various endocrinologic and metabolic
disorders should be done accordingly. Genetic coun-
seling and need of the antenatal diagnosis should be
stressed in the affected families.
Obstructive Cholestasis: EHBA
The necro-inflammation of the biliary tree leads to
fibrosis also called obliterative cholangiopathy. Exact
etiology is not clear so far. EHBA is a big challenge
worldover but it is more alarming problem in developing
690 IAP Textbook of Pediatrics
countries. This constitutes 30 percent of the NCS seen at
our center. The late presentation of the disease is
responsible for development of cirrhosis. This is a stage
when it becomes untreatable and death is inevitable
within 2 years of life. Bile flow can be established in 80–
90 percent cases after Kasai’s portoenterostomy if done
within 60 days of life. With the advancing age the bile
flow decreases. If the surgery is done within 2-3 months
the bile flow can be established in 40–45 percent cases
whereas of surgery done after 3 months of age, the bile
flow can be established in 10–20 percent of cases only. In
85 percent of EHBA patients, the extrahepatic biliary tree
is fibrosed and needs portoenterostomy and are called
noncorrectable EHBA. Fifteen percent of EHBA may
have part of CBD or hepatic duct patent and these require
choledochoduodenostomy and hence called as correc-
table EHBA.
This shows that diagnosis of EHBA should be done
early and surgery should be performed within 60 days
of life. Best time is 4 to 6 weeks of life.
Inspite of advancement in surgical skills the outcome
is not encouraging. Even after portoenterostomy one-
third cases deteriorate in perioperative period and first
year of surgery and may require liver transplantation,
one-third develop complications of liver disease during
first decade of life and require liver transplantation,
whereas one-third survive beyond 10 years of life
abnormal liver functions.
One year survival reported is varying from 30–71
percent. The highest survival rate is reported by Japanese
workers. One year survival in our country is 25–30
percent. This shows that surgery is not fool-proof
treatment and needs liver transplantation. Good
prognostic factors for EHBA surgery are surgery done
under 60 days of life, minimal or no fibrosis on histology,
good bile flow after surgery and absence of cholangitis
in immediate postoperative period or first year of life
and availability of surgical expertise. In our set up late
presentation of the cases and cholangitis are the main
deterimental reasons for fatal outcome of these cases.
Choledochal cyst during infancy is also very
important cause of cholestasis (6%) and needs surgical
treatment.
Liver Transplantation
Liver transplantation has revolutionized the outcome of
EHBA world over. The indications are failed Kasai’s
procedure, progressive liver disease inspite of successful
Kasai’s procedure and late presentation of EHBA
(unoperated). Ten years survival is 85 to 90 percent in
various centers.
PAUCITY OF INTRAHEPATIC BILE DUCT (PIBD)
The hypoplasia of bile ducts can occur in intrauterine
infections and in alpha 1 antitrypsin deficiency and is
selflimiting. The PIBD may occur in sporadic or in
syndrome form. There is paucity of bile ducts (<0.6) in
relation with portal vein and hepatic artery in the portal
tracts. The disease is progressive and leads to cirrhosis
during infancy and early childhood. This is considered
to be analogous to disappearing bile duct syndrome in
adults.
Alagille Syndrome (Arteriohepatic Dysplasia)
This is the commonest syndromic cause of PIBD and is
characterized by broad forehead, deep set widely spaced
eyes, long straight nose and mandible hypoplasia, ocular
abnormalities posterior embryostoxon, palmostenosis,
tetralogy of Fallot, butterfly vertebrae and tubulo-
interstitial nephropathy. Chronic cholestasis leads to lot
of complications like xanthomas, vit E. deficiency,
pruritus, growth retardation and defective spermato-
genesis. This is linked with human jagged 1 gene (JAGI).
Progressive Familial Intrahepatic
Cholestasis (PFIC)
There are various types of PFIC.
PFIC 1 Type
In Amish families after Jacob Byler this is called Byler
disease. There is defect in the structure of bile canaliculi
membrane so excretion of bile is affected. The disease is
characterized by failure to thrive, marked pruritus,
rickets, steatorrhea and low gamma glutamyl trans-
peptidase (GGT) levels. The serum cholesterol is normal
but bile acids are raised. The disease is progressive and
develops in cirrhosis and hepatocellular dysfunction
during first decade of life. Liver transplantation is the
only definite treatment. PFIC 1 gene is mapped on
chromosome 18q12.
PFIC 2 Type
The presentation is similar to Byler disease but occurs in
non-Amish families also called Byler syndrome. The
 Diseases of Gastrointestinal System and Liver
manifestations and outcome are similar to PFIC1 type
but GGT is high. There are transporter defects (bile salt
export pump, BSEP) and gene is mapped on chromosome
2q24.
PFIC 3 Type
There is high GGT and is absence of multidrug resis-
tance 3 p glycoprotein with deficient translocation of
phosphotidyl choline across the canalicular membrane.
The disease is having milder course as compared to PFIC
1 and 2 types. Ultimately the disease progresses to
cirrhosis.
PFIC 4 Type
This is still under consideration when the cases of PFIC
cannot be classified.
There are certain syndromes like Aagenaes synd-
rome, Zellweger (cerebrohepato renal) syndrome and
inborn errors of bile acid metabolism (deficiency of
reductase, steroid dehydrogenase, isomerase hydroxy-
lase). These are also responsible for intrahepatic
cholestasis and there is accumulation of abnormal bile
acids.
All there conditions are progressive despite of
treatment with UDCA and other supportive measures
and invariably require liver transplantation.
Metabolic Liver Disease
During neonatal period and infancy various important
metabolic disorders are pertaining to carbohydrates
(galactosemia, fructosemia, glycogen storage disease type
I, III and IV), proteins (tyrosinemia, urea cycle defects,
amino acid disorders, etc.) and fats (Niemann-Pick
disease type C, infantile Gaucher’s disease). These have
distinct clinical presentation and need enzyme estimation
for confirmation of the diagnosis.
Medical Treatment
Chronic cholestasis is responsible for various life
threatening consequences which need prolonged
therapy.
Pruritus: Pruritus is a most distressing symptom. It leads
to miserable life in term of lack of sleep, emotional
problems and children become mentally reckoned.
Various treatment modalities like cholestyramine,
phenobarbitone 5 mg/kg/day, rifampicin (10 mg/kg/
691
day), terfenadine, UDCA (20–40 mg/kg) and photo-
therapy have been tried with variable results. UDCA
seems to be promising as it is one of choleretic drug. Some
times untreatable and unremitted pruritus becomes sole
indication for liver transplantation.
Malnutrition: Malnutrition is very common and is due to
obvious reasons mentioned in Fig. 13.20.1. Breastfeeding
should be encouraged in these babies. If anorexia is a
prominent feature nasogastric feeding is indicated. The
diet should have 200 calories/kg and protein 1–2 g/kg
body weight. The diet should be constituted by MCT (2–
3% calories from PUFA), carbohydrates (glucose
polymers), minerals, trace elements and vitamins. MCT
rich available diets are coconut oil, simyl MCT,
Progestimil and Portagen. All vitamins should be given
in double the daily requirement.
Vitamin A: Vitamin A should be given 2500 to 5000 IU/
day. Monitor the vitamin A level. If blood level is less
than 30 mg/dl increase the oral dose by 10 folds or give
50,000 IU IM.
Vitamin D: Daily 400 to 1200 IU of vitamin D is
recommended. This can be given in form of 40,000 IU
IM monthly. 25-hydroxycholecalciferol 5 to 7 mg/kg can
be given daily. Monitor serum calcium, phosphate and
alkaline phosphatase and X-ray wrist at 2 months
interval.
Vitamin E: Vitamin E deficiency is now recognized very
often since the age of the children with cholestasis is
increasing. The dose of vitamin E recommended is 15 to
200 mg daily. Serum monitoring is mandatory. If levels
are lower side then higher dose should be given. Six
monthly neurological and yearly eye examination are
required.
Vitamin K: In case of prolonged cholestasis with
steatorrhea vitamin K 5 mg IM monthly should be given.
Treatment of other complications of liver disease like
ascites, portal hypertension, variceal bleed and encepha-
lopathy should be done accordingly.
Liver Transplantation
Liver failure due to metabolic conditions in neonatal
period and infancy is difficult to manage medically. Liver
transplantation have changed the outcome in western
world.
692 IAP Textbook of Pediatrics
Prognosis and Outcome
Prognosis of NH is very good if diagnosed early and
appropriate treatment is instituted depending upon the
etiology. In idiopathic neonatal hepatitis 70-80 percent
recover whereas 10 to 20 percent may have progressive
liver disease and very small percentage of 1 to 2 percent
may develop cirrhosis. Death occurs due to sepsis,
bleeding or acute liver failure. In EHBA even after
successful portoenterostomy one-third die during 1 year
of operation, one-third die by 10 years of age whereas
one-third survive after 10 with some compromised liver
functions. With liver transplantation survival of EHBA
has improved to 90 percent in best centers.
BIBLIOGRAPHY
1. Chardot C, Carton M, Spire – Bendelae N et al. Is Kasai’s
operation still indicated in children older than 3 months
diagnosed with biliary atresia? J Pediatr 2001;138:
224–28.
2. Chhabra M, Poddar U, Thapa BR, Singh K. Spectrum of
cholestasis of infancy. Indian J Gastroenterol 1996;15:
(Suppl 1) A 73.
3. Kader HH, Balisteri WF. In: Rd Behrman, RM Kliegman,
HB Jenson, (Eds): Cholestasis from Nelson text of
13.21 Fulminant Hepatic Failure
Definition
Fulminant hepatic failure (FHF) is defined as the severe
impairment of hepatic dysfunction (INR > 1.5 +
encephalopathy or INR> 2 + encephalopathy) in the
absence of preexisting liver disease. Hepatic encephalo-
pathy is a state of disturbed neurological function
associated with liver disease. Unlike in adults where
encephalopathy is central it may be absent, late or
unrecognized especially in neonates and infants.
Based on the onset of symptoms various presentations
have been proposed. Hyper acute liver failure is defined
as coagulopathy due to acute liver dysfunction of up to
10 days duration, acute liver failure is when it is more
than 10 days but less than 30 days and subacute liver
failure from 31 days to less than 6 months.
Pediatrics. Saunders company. (17th edition) 2003;
1314–19.
4. Kotb MA, Sheba M, EL Koofy N, et al. Evaluation of
“Triangular cord sign” in the diagnosis of biliary atresia
pediatrics 2001;108:416–20.
5. Lai MW, Chang MH, Hsu SC, Cheng TS, Kao CL, Lee
CY. Differential diagnosis of extrahepatic biliary atresia
from neonatal hepatitis: a prospective study. J Pediatr
Gastroenterol Nutr 1994;18:121–217.
6. McEvoy CF, Suehy FJ. Biliary tract disease in children.
Ped Clin North Am 1996;43:75–98.
7. Paltiel HJ. Imaging of neonatal cholestasis. Semin
Ultrasound CT and MRI 1994;15:290–305.
8. Poddar U, Thapa BR, Chhabra M, Rao KLN, Mitra SK,
Singh K. Choledochal cysts in infants and children.
Indian Pediatr 1998;35:613–18.
9. Shah HA, Spivak W. Neonatal cholestasis: New
approaches to diagnostic evaluation and therapy. Ped
Clin North Am 1994;41:943–66.
10. Thapa BR: In Sachdev HPS, Choudhary P (Eds): Role of
nutrition in liver and biliary disorders in nutrition in
children. Developing country concerns (First edition).
Cambridge Press, Kashmere gate New Delhi; 1994;
376–89.
11. Whitington PI. Chronic cholestasis of infancy. Ped Clin
North Am 1996;43:1–26.
Rajiv Chandra Mathur
Etiology
Etiology varies with age of presentation (Table 13.21.1).
The most common causes in neonates and infants are
metabolic liver disease, septicemia and neonatal
hemochromatosis. In children older than one year viral
hepatitis, drugs systemic infection and unknown causes
are the most common etiologies.
Pathology
Severe liver damage to the liver has already occurred by
the time of presentation. Histologic examination at the
time of presentation typically demonstrates confluent
necrosis with cell drop out and parenchymal collapse in
either a zonal or non zonal distribution. Many activated
sinusoidal lining cells, kupffer cells, stellate cells and
 Diseases of Gastrointestinal System and Liver
TABLE 13.21.1: Etiology of Fulminant hepatic failure
Neonates and infants Older children
Septicemia Viral hepatitis A, B,B+D,E
Inborn errors of metabolism Parvo virus,
Tyrosinemia Adeno virus
Galactosemia Herpes simplex
Hemochromatosis Hepatotoxic drugs*
Hereditary fructose Circulatory failure, Ischemic
intolerance disease
Hematological malignancy
Hodgkin’s disease
Leukemic infiltrates
Reyes syndrome
Autoimmune hepatitis type 2
Wilson’s disease
Metabolic liver disease
Infections#
*Valproic acid, INH, Paracetamol, Halothane, Phenytoin, Ketoconazole
#CMV, Herpes, EBV, Leptospira, Dengue, Typhoid
endothelial cells are seen at the site of the hepatocyte
drop out. Marked cholestasis in the remaining paren-
chyma may occur and is a poor prognostic sign. There
may be sinusoidal dilatation, congestion and cirrhosis
specific to the underlying cause. In most cases of FHF a
variable degree of liver regeneration in the form of
proliferation of hepatocytes and ducts is evident.
Pathophysiology
FHF is characterized by marked splanchnic and systemic
arteriolar vasodilatation along with hyperdynamic
circulation and low arterio venous oxygen content
difference. Tissue hypoxia develops despite adequate
arterial oxygen and this contributes to the development
of multiorgan failure and is a marker of poor prognosis.
Microcirculatory plugging caused by formation of
micro thrombi as a consequence of activation and
consumption of platelets along with increased adhesion
of leukocytes to the endothelial wall. Increased activity
of cGMP results in vasodilatation.
Encephalopathy results from the accumulation of
unmetabolized ammonia, mercaptans, fatty acids and
GABA. Production of false neurotransmitters is enhanced
due to decreased aromatic and branched chain amino
acids in the blood. The cerebral metabolism is altered.
Decreased cerebral blood flow is due to impaired auto
regulation in FHF. In patients with grade III and IV
693
encephalopathy subclinical epileptiform activity is seen
and seen this exacerbates the oxygen demand.
Renal failure of various degrees occurs in FHF
patients. Hypovolemia caused by vasodilatation, micro
circulatory disturbance and acute tubular necrosis are
important contributing factors. Rapid deterioration in
nutritional status with depletion of muscle and fat stores
often occurs as a consequence of impaired gluconeo-
genesis and impaired glycogen storage. Hypoglycemia,
hypophosphatemia and hypomagnesaemia are common.
Metabolic acidosis is relatively frequent due to tissue
hypoxia, increased peripheral lactate production and
renal failure.
Reduced hepatic synthesis of clotting factors and
increased consumption of multiple clotting factors and
platelets contribute to the coagulopathy associated with
FHF. Children with FHF are susceptible to infections as
a consequence of impaired neutrophils and kupffer cell
phagocytic function and reduced complement levels.
Induced bacterial changes in the gut flora may also
contribute to this. The common infections that occur are
pneumonia, septicemia, urinary tract infection and
spontaneous bacteria peritonitis. A vicious cycle of
endotoxemia, circulatory collapse, tissue hypoxia,
increased bacteria translocation and leaky intestinal
mucosa contribute to multi organ failure.
Precipitating Factors
Stress, gastrointestinal bleeding, constipation, large
volume animal protein diet, rapid abdominal paracen-
tesis, hypoglycemia, sepsis, CNS depressant drugs and
hypoxia are common precipitating factors.
Clinical Manifestations
FHF affects previously healthy children with no
recognized risk factors for liver disease. Children usually
present with hepatitis and worsening of symptoms over
a period of several days or weeks. Jaundice is the
presenting symptom in most children. A prodrome of
flu like illness may precede jaundice. Fever, anorexia,
vomiting, abdominal pain and fetor hepaticus are
common. Altered consciousness, mental changes present
later. Infants initially may present with poor feeding,
irritability and disturbances in sleep rhythm.
Hemorrhagic diathesis and ascites may develop later.
Patients should be observed for signs of hepatic
encephalopathy (Table 13.21.2).
694 IAP Textbook of Pediatrics

TABLE 13.21.2: Grades of hepatic encephalopathy

Grade of Mental status Behavior Motor activity Tone and Reflexes Response to pain pupils
encephalopathy

Grade I Alert oriented Restless, Incoordination Normal Obeys Normal

irritable, tremor
confusion
Grade II Lethargic Combative, Yawning, ↑ Tone brisk Localizes Hyperactive
confused euphoric grimacing reflexes
irritated intention-tremor
Grade III Stupor Sleeps ↓ Motor activity Up plantars, Flexes Hippus
arousable all times, marked intention clonus
marked tremor
confusion
Grade IV Unarousable Unconscious Absent Sustained clonus Extends Dilated
sluggish

TABLE 13.21.3: Supportive treatment of FHF

Goal Intervention

Maintain hemodynamic Colloid, dopamine/dobutamine infusions.

stability and electrolyte balance Avoid fluid overload,
Prevention of stress ulcer H2 Blocker
Sedation Propofol
Optimize oxygen delivery Oxygen, N acetyl cysteine & prostaglandin E 1 infusions.
Coagulopathy Recombinant Factor VII a 5-10 ug/kg
FFP in active hemorrhage
Packed cell transfusion in hemodynamicaly destabilizing anemia
Plasmapheresis
Prevention and correction of 10-20 % dextrose
hypoglycemia
Prevention of hepatic Dietary protein restriction < 0.5 g/kg/day
encephalopathy (Decrease ammonia) Lactulose 1 mg/kg/6 hourly till 3 loose motions/day
L ornithine L aspartate infusion 1-2 g/day
Benzodiazepine antagonist (Flumazenil) for short reversal of
encephalopathy
Cerebral edema Monitor ICP (Subdural transucer) Keep < 20-25 mmhg
Quiet environment, 30° head elevation, pyrexia control, sedation
20% mannitol infusion
Elective ventilation
Induction hypernatremia (145-155 meq/I) by 3% Nacl
Induction of Hypothermia (Core body temperature 32-33° C)
Sub clinical or clinical seizures Phenytoin infusion, Thiopental infusion
Diet High calorie 30-50 K cal/Kg 50% non protein calories
High carbohydrate, protein restriction BCCA rich vegetable protein
Prevention and treatment of infections IV line care, infection surveillance
Prophylactic antibiotic & anti fungal
Renal failure Maintain intravascular volume, pressure
Dialysis in established failure
 Diseases of Gastrointestinal System and Liver
Complications are often encountered in association
with grade III and IV encephalopathy. They include
cerebral edema, convulsions, hypoglycemia, dyselec-
trolytemia, metabolic acidosis, hypotension, sepsis,
gastrointestinal bleeding, coagulopathy, hepatorenal
syndrome and multi organ failure.
Investigations
These include serum bilirubin, AST, ALT, blood
ammonia, prothrombin time, blood sugar, serum
electrolytes, blood gas analysis, infection screening, viral
serological markers blood grouping and other tests
specific for the suspected etiology.
Management
Management in an intensive care is mandatory for all
patients with more than grade II encephalopathy.
Treatment is supportive but specific for multiorgan
dysfunction (Table 13.21.3). Specific therapies where
treatable etiologies can be identified needs to initiated
early.
Orthotropic liver transplant using whole, split or
auxiliary liver from either cadaver or living related
donors has shown promising results and is indicated
when there is severe liver damage. Extra corporeal liver
support provides temporary liver support in FHF. MARS
(Molecular Adsorbent Recirculating System) involves
usage of albumin, resin dialysate to remove protein
bound and low molecular toxins.
13.22 Ascites
DEFINITION
Ascites is of Greek derivation (askhos) which refers to a
‘bag’ or ‘sack’. The word describes pathologic fluid
accumulation within the peritoneal cavity (Fig. 13.22.1).
BACKGROUND
Inside the abdomen there is a membrane called the
peritoneum which has two layers. One layer lines the
abdominal wall and the other layer covers the organs
695
Prognosis
The overall mortality exceeds 60%. The prognosis may
vary with the cause of hepatic failure, severity of
encephalopathy and development of complications.
BIBLIOGRAPHY
1. Bansal S, Dhawan A. Acute liver failure. Indian Journal
of Pediatr 2006;73(10):931-34.
2. Bhaduri BR,Mieli-Vergani G. Fulminant hepatic failure
pediatric aspects. Semin Liver Dis 1996;16(4):349-55.
3. Chuansumrit A,Chantarojansin P ,Isarangkura S etal.
Recombinant activated factor VII in children with acute
bleeding resulting from liver failure and DIC. Blood
Caogul Fibrinolysis.2000;11(Supp 1): 5101-5105.
4. Cochran JB, Losek ill. Pediatr Emerg Care 2007;23(2):
129-35.
5. Dhawan A,Cheeseman P, Mieli-Vergani G.Approaches
to liver failure in children.Pediatr transplant. 2004;8:
84-588.
6. Kortsalioudaki C, Taylor RM, Cheeseman P, Bansal S,
Mieli- V ergani G, Dhawan A. Safety and efficacy of N-
acetylcysteine in children with non-acetaminophen-
induced acute liver failure. Liver Transpl. 2008
Jan;14(1):25-30.
7. Mathur RC. Management of difficult problems in
Fulminant hepatic failure. Indian J Pediatr 1995;4:
361-366.
8. Mathur RC, Chandra N, Mathur YC. Viral etiology and
outcome of Fulminant hepatic failure.J Fed Child Health.
1997;33:I:S 52.
9. Poddar U, Thapa B, Prasad A et al. Natural history and
manifestations in FHF. Arch Dis Child. 2002;87:54-56.
Balvir S Tomar, Anurag Tomar
inside the abdominal cavity. The peritoneum produces
a fluid that acts as a lubricant and allows the abdominal
organs to glide smoothly over one another. Sometimes
an excess of this fluid can build up between the two layers
and this is called ascites.
The accumulation of fluid in the abdominal cavity
can be associated with portal hypertension. This means
there is an increased blood pressure in the veins draining
the liver. The higher pressure can be caused by liver
damage. It can also be caused by impaired drainage in
696 IAP Textbook of Pediatrics
Figure 13.22.1: Child with ascites
the lymph system. This system takes excess fluid and
particles away from the liver. Low levels of albumin and
other proteins in the blood also contribute to ascites. The
force that holds plasma water within the blood vessels is
reduced. Plasma water is lost into the abdominal cavity.
Albumin in the ascitic fluid pulls yet more fluid across
into this cavity. Blood flow to the kidneys might be
reduced. This leads to increased secretion of aldosterone.
This causes the kidneys to retain salt and water. Urinary
output is decreased, and fluid is retained. In some cases,
kidney disease contributes to impaired elimination of salt
and water. Fluid may leak from capillaries, the pancreas,
or the lymph system. Capillary fluid leakage can be
caused by inflammation or infection.
PATHOPHYSIOLOGY
The accumulation of ascitic fluid represents a state of
total-body sodium and water excess, but the event that
initiates the unbalance is unclear. Three theories of ascites
formation have been proposed.
A. Under filling theory: This suggests that the primary
abnormality is inappropriate sequestration of fluid
within the splanchnic vascular bed due to portal
hypertension and a consequent decrease in effective
circulating blood volume. This activates the plasma
renin, aldosterone, and sympathetic nervous system,
resulting in renal sodium and water retention.
B. Overflow theory: This suggests that the primary
abnormality is inappropriate renal retention of
sodium and water in the absence of volume depletion.
This theory was developed in accordance with the
observation that patients with cirrhosis have
intravascular hypervolemia rather than hypovolemia.
C. Peripheral arterial vasodilatation hypothesis: This
includes components of both of the other theories. It
suggests that portal hypertension leads to vaso-
dilatation, which causes decreased effective arterial
blood volume. As the natural history of the disease
progresses, neurohumoral excitation increases, more
renal sodium is retained, and plasma volume
expands. This leads to overflow of fluid into the
peritoneal cavity. According to the vasodilatation
theory, the under filling theory is proposed to be
operative early and the overflow theory is proposed
to be operative late in the natural history of cirrhosis
(Fig. 13.22.3).
Although the sequence of events that occurs between
the development of portal hypertension and renal
sodium retention is not entirely clear, portal hypertension
apparently leads to an increase in nitric oxide levels.
Nitric oxide mediates splanchnic and peripheral
vasodilatation. Patients with ascites have greater hepatic
artery nitric oxide synthase activity compared to patients
without ascites.
Regardless of the initiating event, a number of factors
contribute to the accumulation of fluid in the abdominal
cavity. Elevated levels of epinephrine and nor epine-
phrine are well-documented factors. Hypoalbuminemia
and reduced plasma oncotic pressure favor the extra-
vasation of fluid from the plasma to the peritoneal fluid,
and, thus, ascites is infrequent in patients with cirrhosis
unless both portal hypertension and hypoalbuminemia
are present. If the liver is damaged, it may produce less
blood protein. This may upset the body’s fluid balance
which causes fluid to build up in the body tissues,
including the abdomen.
Cancer cells can block the lymphatic system. The
lymphatic system is a network of fine channels, which
runs throughout the body. One of its functions is to drain
off excess fluid, which is eventually got rid of in the urine.
If some of these channels are blocked, the system cannot
drain efficiently and fluid can build up. The patho-
physiologic mechanisms of ascites is shown in Table
13.22.1.
 Diseases of Gastrointestinal System and Liver 697

Figure 13.22.2: Pathophysiology of ascites

TABLE 13.22.1: Pathogenic mechanisms in ascites formation ETIOLOGY

A. Increased hydrostatic pressure NEONATAL ASCITES/CONGENITAL ASCITES

Cirrhosis (Fig. 13.22.3)
Hepatic vein occlusion (Budd-Chiari syndrome) Ascites in the newborn (Fig. 13.22.4) can be grouped as:
Inferior vena cava obstruction I. Associated with hydrops
Constrictive pericarditis II. Isolated ascites
Congestive heart failure
III. Ascites due to peritonitis
B. Decreased colloid osmotic pressure
End-stage liver disease with poor protein synthesis
Nephrotic syndrome with protein loss Associated with Hydrops
Malnutrition
Protein-losing enteropathy 1. Cardiovascular (20% cases) (failure or poor output)
C. Increased permeability of peritoneal capillaries a. Rhythm disturbances: Heart block, auricular
Tuberculous peritonitis
Bacterial peritonitis
tachycardia
Malignant disease of the peritoneum b. Cardiac malformation: Hypoplastic left heart,
D. Leakage of fluid into the peritoneal cavity Ebstein’s disease
Bile ascites 2. Hematological disorders (10% cases) (Chronic in
Pancreatic ascites (secondary to a leaking pseudocyst)
utero anemia): Isoimmune hemolytic disease,
Chylous ascites
Urine ascites homozygous alpha thalassemia
E. Miscellaneous causes 3. Chromosomal (10% cases): Turner syndrome,
Myxedema trisomy 13, 18 and 21
Ovarian disease (Meigs’ syndrome)
4. Infection (8% cases): TORCH group, syphilis
Chronic hemodialysis
5. Renal (5% cases): Nephrosis, posterior urethral valve
698 IAP Textbook of Pediatrics

Figure 13.22.3: Ascites formation in cirrhosis Figure 13.22.4: Ascites in neonate

6. Pulmonary (5% cases): Diaphragmatic hernia.

7. Gastrointestinal (5% cases): Atresia
8. Maternal conditions (5% cases): Toxemia, diabetes
9. Placenta or cord (rare): Cord compression, choran-
gioma
10. Miscellaneous (10% cases): Wilms’ tumors, neuro-
blastoma
11. Storage disease: Mucopolysaccharidosis VIII
12. Skeletal abnormalities: Osteogenesis imperfecta,
achondrogenesis
13. Cirrhosis: α-1 antitrypsin deficiency
14. Liver failure: Neonatal hemochromatosis
15. Unknown (20% cases).
Isolated Ascites
1. Chylous: Congenital anomaly of lymphatic channels
2. Biliary: Spontaneous perforation of biliary tree
3. Pancreatic duct anomaly.
Figure 13.22.5: Ascites with portal hypertension showing
dilated veins
Peritonitis
1. Chemical: Bile, meconium
2. Bacterial. 2. Intrahepatic disorders
a. Biliary tract disease: EHBA, cystic fibrosis,
ETIOLOGY IN CHILDREN
choledochal cyst, sclerosing cholangitis, intra-
Associated with Portal Hypertension (Fig. 13.22.5) hepatic cholestasis syndromes
1. Extrahepatic disorders b. Hepatocellular disease: Autoimmune hepatitis,
Venous obstruction: Splenic vein thrombosis, portal hepatitis B,C, Wilson’s disease, antitrypsin
vein thrombosis/cavernous transformation, Budd- deficiency
Chiari syndrome, inferior vena cava obstruction c. Toxins: Ethanol, methotrexate, 6-mercaptopurine
Miscellaneous: CHF, AV fistulae d. Miscellaneous: Histiocytosis X, schistosomiasis.
 Diseases of Gastrointestinal System and Liver 699

OTHER CAUSES • Other rare conditions

– Familial Mediterranean fever
Tuberculosis, heart failure, nephrotic syndrome,
– Vasculitis
pancreatitis, chlamydial infection and rheumatoid
– Granulomatous peritonitis
arthritis.
– Eosinophilic peritonitis
ETIOLOGY OF ACUTE ASCITES
PRESENTATION
i. Venous obstruction: Budd-Chiari syndrome, portal
vein thrombosis, inferior vena cava obstruction, History
splenic vein thrombosis, venoocclusive disease of Most cases of ascites are due to liver disease or due to
liver some precipitating factors deteriorating liver functions,
ii. Peritonitis: Spontaneous perforation of bile duct e.g. drugs (NSAIDs). History of abdominal distention,
iii. Fulminant hepatic failure increasing weight, respiratory embarrassment, asso-
ciated pedal edema.
ETIOLOGY OF ASCITES IN REFERENCE TO
NORMAL AND/OR DISEASED PERITONEUM Risk Factors for Liver Diseases

Normal Peritoneum • Chronic viral hepatitis or jaundice

• Intravenous drug use
• Portal hypertension (serum-ascites albumin gradient
• Sexual promiscuity
[SAAG] > 1.1 g/dl)
• Transfusions: Hepatitis C has been linked to
– Hepatic congestion, congestive heart failure,
transfusions
constrictive pericarditis, tricuspid insufficiency,
• Tattoos
Budd-Chiari syndrome
• Habitation or origination from an area endemic for
• Liver disease, cirrhosis, alcoholic hepatitis, fulminant
hepatitis.
hepatic failure, massive hepatic metastasis
Patients with a history of cancer, especially gastro-
• Hypoalbuminemia (SAAG < 1.1 g/dl)
intestinal cancer, are at risk for malignant ascites.
– Nephrotic syndrome
Malignancy-related ascites is frequently painful, whereas
– Protein-losing enteropathy
cirrhotic ascites is usually painless.
– Severe malnutrition with anasarca
• Miscellaneous conditions (SAAG < 1.1 g/dl)
EXAMINATION
– Chylous ascites
– Pancreatic ascites Ascites needs to be differentiated from abdominal
– Bile ascites distension due to other causes like gross obesity, gaseous
– Nephrogenic ascites distention, bowel obstruction, abdominal cysts or masses.
– Ovarian disease The clinical manifestations of ascites can vary from an
asymptomatic patient to patients complaining of
Diseased Peritoneum (SAAG < 1.1 g/dl) increased abdominal girth, early satiety, and respiratory
distress depending on the amount of fluid accumulated
• Infections
in the abdominal cavity. Flank dullness which is present
– Bacterial peritonitis
in about 90% of patients, is the most sensitive physical
– Tuberculous peritonitis
sign.
– Fungal peritonitis
– HIV-associated peritonitis Per abdomen: Increasing weight and abdominal girth (if
• Malignant conditions previous values are available), shifting dullness (Puddle
– Peritoneal carcinomatosis sign), fluid thrill, peritoneal tap (Table 13.22.2). Elicitation
– Primary mesothelioma of increased flank dullness to percussion with patient
– Pseudomyxoma peritonei supine and shifting dullness (> 1500 ml free fluid). The
– Hepatocellular carcinoma physical examination should focus on the signs of portal
700 IAP Textbook of Pediatrics

Lymph nodes: For enlargement. A pathologic left-sided

TABLE 13.22.2: Grading of ascites
supraclavicular node (Virchows node) suggests the
Grade Severity Signs presence of upper abdominal malignancy.
The puddle sign indicates that as little as 120 ml of
I Mild Puddle sign (+) fluid is present. When peritoneal fluid exceeds 500 ml,
Detected by ultrasound abdomen ascites may be demonstrated by the presence of shifting
II Moderate Shifting dullness (+) dullness or bulging flanks. A fluid-wave sign is notoriously
No fluid thrill inaccurate.
III Tense Fluid thrill (+)
Respiratory difficulty (+)
INVESTIGATIONS
• Confirming the presence of ascites
TABLE 13.22.3: Staging of ascites
• Finding the cause for the ascites
• Assessing any complication due to the ascites
Stage Signs
BLOOD TESTS
1+ Detectable only after careful examination
2+ Easily detectable but of relatively small volume • Complete blood counts
3+ Obvious ascites but not tense ascites • Complete urine examination
4+ Tense ascites
• Liver Function Tests including plasma proteins
• Clotting screen, especially if invasive investigations
are considered

hypertension and chronic liver disease. Liver is examined
to see if it is enlarged or tender. The liver may be difficult
to palpate if a large amount of ascites is present
(Table 13.22.3).
MONITORING
Simple assessment of the progress of ascites may be made
by serial measurements of the abdominal girth. The tape
measure must be placed in the same position each time.
Serial measurement of weight also indicates fluid gain
or loss. This tends to be much faster than gain or loss of
fat or lean body mass.
Neck: Check for jugular venous distention.
Heart: Check for tricuspid murmur or signs of heart
disease.
Lungs: Examine for signs of fluid (heart failure).
Skin: May show cutaneous spider angiomas, palmar
erythema, Dupuytren’s contracture, or large veins on the
abdomen.
Asterixis may be present, ascitis may be part of
generalized oedema. Patients with cardiac disease or
nephrotic syndrome may have anasarca.
White cell count: Normal ascitic fluid contains fewer than
500 leukocytes/ml and fewer than 250 polymorpho-
nuclear leukocytes/ml. Any inflammatory condition can
cause an elevated white blood cell count. White cell count
when greater than 350/microliter is suggestive of
infection. A neutrophil count of more than 250 cells/ml
is highly suggestive of bacterial peritonitis. In tuberculous
peritonitis and peritoneal carcinomatosis, a predo-
minance of lymphocytes usually occurs. If most cells are
polymorphonuclear, bacterial infection should be
suspected. When mononuclear cells predominated,
tuberculosis or fungal infection is likely. This is the single
most useful test. Only recent trauma gives false results.
To correct this, one PMN is subtracted from absolute
ascitic fluid PMN count for every 250 RBC. In old trauma,
PMN will have lysed so no correction is needed.
Red cell count: When greater than 50,000/microliter
denotes hemorrhagic ascites, which usually is due to
malignancy, tuberculosis or trauma.
IMAGING STUDIES
• Chest and Plain Abdominal Films
Elevation of the diaphragm, with or without
sympathetic pleural effusions (hepatic hydrothorax),
is visible in the presence of massive ascites. More than
 Diseases of Gastrointestinal System and Liver
500 ml of fluid is usually required for ascites to be
diagnosed based on findings from abdominal films.
Many nonspecific signs indicate ascites, such as
diffuse abdominal haziness, bulging of the flanks,
indistinct psoas margins, poor definition of the intra-
abdominal organs, erect position density increase,
separation of small bowel loops, and centralization
of floating gas containing small bowel.
The direct signs are more reliable and specific. In 80
percent of patients with ascites, the lateral liver edge
is medially displaced from the thoracoabdominal wall
(Hellmer sign). Obliteration of the hepatic angle is
visible in 80 percent of healthy patients. In the pelvis,
fluid accumulates in the rectovesical pouch and then
spills into the paravesical fossa. The fluid produces
symmetric densities on both sides of the bladder,
which is termed a “dog’s ear” or “Mickey Mouse”
appearance. Medial displacement of the cecum and
ascending colon and lateral displacement of the
properitoneal fat line are present in more than
90 percent of patients with significant ascites.
• Ultrasound
Abdominal ultrasound can be used to detect ascites
in morbidly obese, to indicate appropriate site for
paracentesis, in patients with multiple abdominal
surgical scars and with serum alphafetoprotein, to
detect hepatic malignancy. It can detect as little as
100 mL of fluid in the peritoneal cavity. Uncompli-
cated ascites appears as a homogenous, freely mobile,
anechoic collection in the peritoneal cavity that
demonstrates deep acoustic enhancement. Free
ascites does not displace organs but typically situates
itself between them, contouring to organ margins and
demonstrating acute angles at the point at which the
fluid borders the organ.
The smallest amounts of fluid first tend to collect
in the Morison pouch and around the liver as a
sonolucent band. With massive ascites, the small
bowel loops have a characteristic polycyclic,
“lollipop,” or arcuate appearance because they are
arrayed on either side of the vertically floating
mesentery.
Certain sonographic findings suggest that the
ascites may be infected, inflammatory, or malignant.
Findings include coarse internal echoes (blood), fine
internal echoes (chyle), multiple septa (tuberculous
peritonitis, pseudomyxoma peritonei), loculation or
atypical fluid distribution, matting or clumping of
701
bowel loops, and thickening of interfaces between
fluid and adjacent structures. In malignant ascites,
the bowel loops do not float freely but may be tethered
along the posterior abdominal wall plastered to the
liver or other organs or they may be surrounded by
loculated fluid collections.
• Upper gastrointestinal endoscopy: To confirm
esophageal/fundal varices
• CT and MRI: Ascites is demonstrated well on CT scan
images. Small amounts of ascitic fluid localize in the
right perihepatic space, the posterior subhepatic space
(Morison pouch), and the Douglas pouch. A number
of CT features suggest neoplasia. Hepatic, adrenal,
splenic, or lymph node lesions associated with masses
arising from the gut, ovary, or pancreas are suggestive
of malignant ascites. Patients with malignant ascites
tend to have proportional fluid collections in the
greater and lesser sacs, whereas, in patients with
benign ascites, the fluid is observed primarily in the
greater sac and not in the lesser omental bursae.
INVASIVE PROCEDURES
• Ascitic tap (Abdominal paracentesis)
ABDOMINAL PARACENTESIS
Abdominal paracentesis is the most rapid and perhaps
the most cost-effective method of diagnosing the cause
of ascites formation. Therapeutic paracentesis may be
performed for refractory or tense ascites.
Position
For large volume ascites: Supine with head slightly
elevated.
For low volume ascites: Lateral decubitus position.
For small volume ascites: Face down position or hand knee
position (Fig. 13.22.6).
Figure 13.22.6: Minimal ascites is tapped in knee chest position
702 IAP Textbook of Pediatrics
SITE
1. Midline site: Below the umbilicus, this is avascular
area.
2. When midline site is inappropriate (presence of scar),
then a site two-finger breadth medial to the anterior
superior iliac spine is chosen.
3. Ultrasonic guidance is needed only in, specific
indications.
Technique
Needle is inserted, using a Z tract to prevent leakage of
fluid. This is achieved by retracting (with one glove hand)
the skin approximately 2 cm caudal in relation to the
deep abdominal wall and then slowly inserting the
paracentesis needle. The skin is not released until the
needle has penetrated the peritoneum or fluid flows.
When the needle is finally removed at the end to
procedure, the skin resumes its original position and seals
the needle pathway (Fig. 13.22.7).
Ascitic Fluid Analysis
• Routine Tests Optional tests
• Total protein Gram’s stain and culture
• Albumin AFB smear and culture
• Cell count Cytology
• Amylase
• Lactate dehydrogenase (LDH)
• Glucose
Lab studies: Peritoneal fluid should be sent for cell count,
albumin level, culture, total protein, Gram stain, and
cytology for new-onset ascites of unknown origin.
Figure 13.22.7: Site of ascitic tap
Gross appearance: Most ascitic fluid is transparent and
tinged yellow. This may be attributed to either a
traumatic tap or malignancy. Bloody fluid from a
traumatic tap is heterogeneously bloody, and the fluid will
clot. Nontraumatic bloody fluid is homogeneously red and
does not clot because it has already clotted and lysed.
Neutrophil counts of more than 50,000 cells/ml have a
purulent cloudy consistency and indicate infection. It
may be red because of presence of red cells more than
10,000/cumm, milky if it is lipid laden, dark-brown because
of bilirubin, black/tea color in pancreatic ascites, cloudy
because of absolute neutrophilic count over 5,000/cumm.
Gross Appearance of Ascites
Color Association
Translucent or yellow Normal/sterile
Brown Hyperbilirubinemia (most
common)
Gallbladder or biliary
perforation
Cloudy or tubid Infection
Pink or blood tinged Mild trauma at the site
Grossly bloody Malignancy
Abdominal trauma
Milky (“chylous”) Cirrhosis
Thoracic duct injury
Lymphoma
Total protein: In the past, ascitic fluid has been classified
as an exudate if the protein level is greater than or equal
to 2.5 g/dl. However, the accuracy is only approximately
56 percent for detecting exudative causes. The total
protein level may provide additional clues when used
with the SAAG. An elevated SAAG and a high protein
level are observed in most cases of ascites due to hepatic
congestion. Those patients with malignant ascites have
a low SAAG and a high protein level.
Gram stain: Gram stain is only 10 percent sensitive for
helping visualize bacteria in early-detected spontaneous
bacterial peritonitis. Approximately 10,000 bacteria/ml
are required for detection by Gram stain; the median
concentration of bacteria in spontaneous bacterial
peritonitis is 1 organism/ml.
Cytology: Cytology smear results are reported to be 58 to
75 percent sensitive for helping detect malignant ascites.
 Diseases of Gastrointestinal System and Liver 703

Positive in peritoneal carcinomatosis. Sensitivity TABLE 13.22.4: Types of ascites according to the level of
increased by centrifuging large volume. the serum-ascites albumin gradient (SAAG)

pH when less than 7 suggests bacterial infection. High gradient (> or = 1.1 g/dl) Low gradient (< 1.1 g/dl)
Cirrhosis Tuberculous peritonitis
Classification of ascitic fluid infection Hepatitis Nephrotic syndrome
Type PMN count Bacterial culture Fulminant hepatic failure Pancreatic ascitis
(cells/mm3) result Cardiac ascites Bowel obstruction/infarction
Portal vein thrombosis Biliary ascites
Spontaneous > 250 Positive Veno-occlusive disease Postoperative lymphatic leak
bacterial peritonitis (one organism) Myxedema Serositis in connective
Culture-negative > 250 Negative tissue diseases
neutrocytic Massive liver metastases Nephrotic syndrome
bacterascites
Monomicrobial < 250 Positive
nonneutrocytic (one organism) LDH: LDH estimation is often helpful in distinguishing
bacterascites spontaneous bacterial peritonitis from gut perforation.
Polymicrobial < 250 Positive Lactate dehydrogenase > 225 mU/L, glucose < 50 mg/
bacterascites (polymicrobial) dL, total protein > 1 g/dL and multiple organisms on
Secondary > 250 Positive gram stain suggest secondary bacterial peritonitis
bacterial peritonitis (polymicrobial) (ruptured viscus or loculated abscess).
PMN, polymorphonuclear Triglycerides: A high level of triglycerides confirms
neutrophil leukocyte chylous ascites.
Amylase: In pancreatitis or gut perforation it is markedly
Serum Ascitis Albumin Gradient (SAAG): The SAAG is the
elevated, usually greater than 2000 IU.
best single test for classifying ascites into portal
hypertensive (SAAG > 1.1 g/dl) and non-portal Bilirubin: An elevated bilirubin level suggest biliary or
hypertensive (SAAG < 1.1 g/dl) causes. Calculated by gut perforation.
subtracting the albumin concentration of the ascitic fluid Complications of paracentesis: Include infection, electrolyte
from the albumin concentration of a serum specimen imbalances, bleeding, and bowel perforation. Bowel
obtained on the same day. perforation should be considered in any patient with
Serum ascites albumin gradient (SAAG) = serum recent paracentesis who develops a new onset of fever
albumin - ascitic fluid albumin and/or abdominal pain. All patients with long-standing
It correlates directly with portal pressure. The ascites are at risk of developing umbilical hernias. Large-
accuracy of the SAAG results is approximately 97 percent volume paracentesis often results in large intravascular
in classifying ascits. High albumin gradient and low fluid shifts. This can be avoided by administering
albumin gradient should replace the ‘term transudate albumin replacement, if more than 5 liters is removed.
and exudate’, in the classification of ascites as accuracy
is not good in the latter. The test is accurate despite ascitic Indications for Admitting Patients of Chronic Liver
fluid infection, diuresis, therapeutic paracentesis, Disease with Ascites
albumin infusion and etiology of liver disease 1. For investigations of the cause of liver disease
(Table 13.22.4). 2. Child not responsive to appropriate OPD basis
therapy
Culture: The common bacterial infection of ascitic fluid 3. For intensive education of the patient in preparing
are monomicrobial with a very low bacterial concen- a diet limited to 88 mmol of sodium per day
tration. The sensitivity with bedside inoculation of blood 4. For careful monitoring of serum and urine electro-
culture bottles with ascites results in 92 percent detection lytes and serum concentration of urea nitrogen and
of bacterial growth in neutrocytic ascites. creatinine
704 IAP Textbook of Pediatrics
5. Grade III ascites with respiratory difficulty / distress
6. Ascites with suspected spontaneous bacterial
peritonitis
7. If a child develops diuretic induced complications
Electrolyte imbalances
Hyponatremia: Serum sodium < 125 mEq/L
Hypokalemia: Serum potassium < 3.0 mEq/L
Hyperkalemia: Serum potassium > 6.0 mEq/L
8. Hepatorenal syndrome
• Increase in baseline serum creatinine by > 100%
or an absolute value of 1.5 mg/dl (even if the
patient is responding to diuretics)
• Urinary Na+ < 10 mEq/L
• Creatinine clearance < 0.75 mg/kg/min
9. Hepatic encephalopathy
10. Refractory ascites.
MANAGEMENT
Principles of Treatment
1. Initial evaluation
2. Identify and treat the undelrying cause
3. Diagnostic ascitic fluid tap
4. Ascitic fluid analysis
5. Treatment of diuretic-sensitive ascites
6. Indications to stop diuretics
7. Treatment of refractory ascites
8. Spontaneous bacterial peritonitis
Non-drug Management
Bed rest: Upright position increases renin-aldosterone
activity, increased retention of sodium or water. Bed rest
reduces this activity.
Medical care: The goals of pharmacotherapy are to reduce
morbidity and to prevent complications.
Diet: sodium restriction (20-30 mEq/d) and diuretic
therapy constitute the standard medial management for
ascites and are effective in approximately 95 percent of
patients. Sodium restriction up to 5 mg per day in child
1-4 years, not greater than 20 mEq per day in child 4-11
years, not greater than 30 mEq per day in child 12-14
years.
Fluid restriction: It is the sodium restriction not the fluid
restriction, that results in weight loss. Fluid restriction is
only indicated when there is persistent hyponatremia,
serum sodium < 120 mEq/liter (reduced renal free water
clearance). Renal sodium retention is the phenomenon
primarily responsible for fluid retention and ascites
formation. It occurs months before impairment of renal
free water clearance.
Measurements of twenty-four hour urinary sodium
excretion (with measurement of creatinine to assess
completeness of collection). A major goal of treatment is
to increase urinary sodium excretion to > 78 mmol/day.
DRUGS
Diuretics
Spironolactone (Aldactone)
For management of edema resulting from excessive
aldosterone excretion. Competes with aldosterone for
receptor sites in distal renal tubules, increasing water
excretion while retaining potassium and hydrogen ions.
The peak effect of aldactone is approximately 3 days.
Dose: 2 to 3 mg/kg/day PO in divided doses q6-24h.
Contraindications: Documented hypersensitivity; anuria;
renal failure; hyperkalemia.
Precautions: Caution in renal and hepatic impairment;
may cause gynecomastia and impotence in men.
Furosemide (Lasix)
Increases excretion of water by interfering with chloride-
binding cotransport system, which, in turn, inhibits
sodium and chloride reabsorption in ascending loop of
Henle and distal renal tubule. Dose must be individua-
lized to patient.
Dose: 1 to 2 mg/kg/dose PO; not to exceed 6 mg/kg/
dose; do not administer >q6h 1 mg/kg IV/IM slowly
under close supervision; not to exceed 6 mg/kg. When
treating infants, titrate in increments of 1 mg/kg/dose
until a satisfactory effect is achieved.
Contraindications: Documented hypersensitivity; hepatic
coma; anuria; state of severe electrolyte depletion.
Precautions: Perform frequent serum electrolyte, carbon
dioxide, glucose, creatinine, uric acid, calcium, and BUN
determinations during first few months of therapy and
periodically thereafter.
Torasemide is three times more potent and longer acting
than furosemide.
 Diseases of Gastrointestinal System and Liver
Amiloride (Midamor)
A pyrazine-carbonyl-guanidine unrelated chemically to
other known antikaliuretic or diuretic agents. Potassium-
conserving (antikaliuretic) drug which, compared with
thiazide diuretics, possesses weak natriuretic, diuretic,
and antihypertensive activity.
Dose: Not established fully in pediatric practice.
Contraindications: Documented hypersensitivity; elevated
serum potassium levels (>5.5 mEq/L); impaired renal
function, acute or chronic renal insufficiency, and
evidence of diabetic nephropathy. Monitor electrolytes
closely if evidence of renal functional impairment is
present, BUN >30 mg/100 ml, or serum creatinine level
>1.5 mg/100 ml.
Precautions: Potassium retention associated with use of
an antikaliuretic agent accentuated in presence of renal
impairment and may result in rapid development of
hyperkalemia. Monitor serum potassium level. Mild
hyperkalemia usually not associated with abnormal ECG
findings.
Metolazone (Mykrox, Zaroxolyn)
Helps treat edema in congestive heart failure. Increases
excretion of sodium, water, potassium, and hydrogen
ions by inhibiting reabsorption of sodium in distal
tubules. May be more effective in those with impaired
renal function.
Dose: 5 to 20 mg/dose PO q24h.
Contraindications: Documented hypersensitivity; hepatic
coma or anuria.
Precautions: Caution in hepatic or renal disease, diabetes
mellitus, gout, or lupus erythematosus.
Mannitol (Osmitrol)
Inhibits tubular reabsorption of electrolytes by increasing
osmotic pressure of glomerular filtrate. Increases urinary
output.
Dose: mannitol (20%) 2 ml/kg every 6 hours for 2 days
or 0.5-3.0 g/kg/dose 8th hourly.
Contraindications: Documented hypersensitivity, anuria,
severe pulmonary congestion, progressive renal damage,
severe dehydration, active intracranial bleeding, and
progressive heart failure.
705
Precautions: Carefully evaluate cardiovascular status
before rapid administration because a sudden increase
in extracellular fluid may lead to fulminating CHF. Avoid
pseudoagglutination. When blood is given simulta-
neously, add at least 20 mEq of sodium chloride to each
liter of mannitol solution. Do not give electrolyte-free
mannitol solutions with blood.
Which Diuretics in Pediatrics and When to
Increase Dose
Diuretics should be initiated in patients who do not
respond to sodium restriction. A useful regimen is to start
with spironolactone. The addition of loop diuretics may
be necessary in some cases to increase the natriuretic
effect. If no response occurs after 4 to 5 days, the dosage
may be increased stepwise.
Duration of Diuretics Therapy
To treat: Diuretic therapy is continued till ascites.
To prevent: In certain conditions like cirrhosis effective
doses of diuretics have to continued for months to years,
to prevent reaccumulation of fluid.
Indications to Stop Diuretics
• Encephalopathy
• Serum sodium < 120 mmol/L despite fluid restriction.
• Serum creatinine > 2.0 mg/dl.
• Clinically significant complications of diuretics.
• Hyperkalemia and metabolic acidosis (spirono-
lactone).
Diuretic-Resistant Ascites
For ascites resistant to medical therapy treatment options
include:
• Therapeutic paracentesis
• LeVeen or Denver (peritoneovenous) shunt
• Liver transplantation
• Extracorporeal ultrafiltration of ascitic fluid with
reinfusion
• Transjugular intrahepatic portosystemic stent shunt
β -BLOCKERS (PROPRANOLOL)
Lowers portal pressure and inhibits renin secretion or
combination of these effects, results increased natriuresis.
706 IAP Textbook of Pediatrics

SURGICAL

Transjugular Interahepatic Portal-Systemic

Stent-Shunt (TIPSS)
A TIPSS is a side-to-side portal-systemic shunt placed
by an interventional radiologist (Figs 13.22.8 and 13.22.9).
TIPSS is an efficacious treatment for patients with
refractory ascites. Survival may be better than in patients
treated with serial large-volume paracentesis. TIPSS is
associated with suppression of antinatriuretic systems,
and an improvement in renal function and renal response
to diuretics. Although the main indication for TIPSS
remains variceal bleeding refractory to endoscopic
therapy, the procedure reduces the activity of the RAAS
and increases natriuresis and GFR. Shunt dysfunction
and development of encephalopathy remain the major
concerns in this patient group. Figure 13.22.9: TIPS shunt from hepatic vein to portal vein

Peritoneovenous Shunt
Peritoneovenous shunts (e.g. LeVeen [Fig. 13.22.10] or
Denver) have been shown to have poor long-term
patency. They are associated with excessive compli-
cations, including peritoneal fibrosis, and confer no
survival advantage relative to standard therapy. It should
be reserved for diuretic-resistant patients who are
candidates for neither liver transplantation nor serial
large-volume paracentesis (because of multiple surgical
scars or distance from a physician able to perform
paracentesis).

Liver Transplantation
This is the ultimate treatment modality available for
refractory ascites in end stage liver disease. By replacing

Figure 13.22.10: Peritoneovenous (Le Veen) shunt

the cirrhotic liver, portal hypertension and its underlying

Figure 13.22.8: Liver explaint showing metal mesh of a TIPS
mechanisms of ascites are corrected. Ideally trans-
plantation should be done before hepato-renal syndrome
sets in. Scarcity of facility and exorbitant costs are
currently the limiting factors in our country. A patient
with cirrhosis, the development of ascites refractory to
standard medical therapy is associated with an approxi-
mately 50 percent 6-month survival, and an approxi-
mately 25 percent 12-month survival.
 Diseases of Gastrointestinal System and Liver
Surgical Portosystemic Shunting
Portocaval shunt operation involves the anastomosis of
the portal vein and the inferior vena cava, consequently
reducing the portal pressure. The shunt also produces a
marked diuresis and natriuresis. However, despite
reported efficacy, surgical portosystemic shunts are
rarely used in the treatment of advanced cirrhotic ascites,
because of the high incidence of post-shunt encephalo-
pathy. In addition, surgical shunts may cause technical
difficulties during subsequent orthotopic liver trans-
plantation.
FOLLOW-UP
Further Inpatient Care
• Patients can actually be maintained free of ascites if
sodium intake is limited to 10 mmol/dl.
• Twenty-four hours urinary sodium measurements
are useful in patients with ascites related to portal
hypertension in order to assess the degree of sodium
avidity, monitor the response to diuretics, and assess
compliance with diet.
• For grade 3 or 4 ascites, therpaeutic paracentesis may
be necessary intermittently.
• At hospital it’s important to monitor body weight and
the intake and output of fluids. Fluid restriction is
only necessary if the serum sodium concentration
drops below 120 mmol per liter. It is also important
to determine the sodium balance which can be
approximated by monitoring intake (diet, sodium
containing medications and intravenous solutions)
and urinary excretion because, a negative sodium
balance is a predictor of weight loss.
• A reasonable goal for a patient without peripheral
edema is a negative sodium balance with a weight
loss of 0.5 kg per day.
Response to therapy is indicated by the following parameters:
1. Optimal decrease in body weight is 0.5 to 1 percent
every 24 hours as compared to the previous day’s
weight. Weight loss more than this would be harmful
and indicates rapid shift of body fluids and calls for
immediate reduction of diuretic dose.
2. Relief of abdominal distention as evidenced by
improvement of distress and decreasing abdominal
girth.
• Achieving a negative sodium balance (when the
patient is excreting more sodium than the intake)
707
indicates good diuretic response. Inadequate
sodium restriction is an important cause of
diuretic resistant ascites and can be suspected if
the patient does not lose weight and fluid despite
an appropriate natriuresis.
Further Outpatient Care
• When a patient is responding to medical treatment,
hospitalization is not necessary.
• The best method of assessing the effectiveness of
diuretic therapy is by monitoring body weight and
urinary sodium levels.
• In general, the goal of diuretic treatment should be
to achieve weight loss of 300 to 500 g/dl in patients
without edema and 800 to 1000 g/dl in patients with
edema.
• Once ascites has disappeared, diuretic treatment
should be adjusted to maintain the patient free of
ascites.
• Body weight, orthostatic symptoms, and serum
electrolytes, urea and creatinine are monitored.
COMPLICATIONS OF ASCITES
Umbilical Hernia
Some patients may develop or may show an increase in
the size of already existent umbilical hernia. Most hernias
recur after surgical repair unless the ascites is controlled.
Hydrothorax
Pleural effusion, particularly on the right side can
develop in some patients with ascites. It occurs due to
passage of fluid through small holes in the diaphragm.
These effusions may be very large.
Spontaneous Bacterial Peritonitis
Diagnosis
A diagnosis of SBP is made when an ascitic fluid bacterial
culture is positive (e.g. Escherichia coli, Klebsiella
pneumoniae, or pneumococcus) with an elevated ascitic
fluid absolute polymorphonuclear leukocyte count >250
cells/mm3, and symptoms and/or signs consistent with
infection (temperature >100 degrees F, chills, abdominal
pain, rebound tenderness, reduced bowel sounds)
without an evident intra-abdominal and surgically
treatable source of infection. A missed or delayed
diagnosis of spontaneous bacterial peritonitis (SBP) could
708 IAP Textbook of Pediatrics
potentially lead to sepsis and significant morbidity and
mortality.
Treatment
Patients with a definitive diagnosis or presumptive
diagnosis of SBP, should be treated with antibiotics.
Treatment should not be delayed in those with a
presumptive diagnosis until a positive culture is
obtained. Those with positive ascitic fluid cultures in the
absence of a neutrophil response should also be treated
with antibiotics, if symptoms and/or signs of infection
are present.
When treating empirically a broad spectrum, non-
nephrotoxic, antibiotic is administered intravenously, e.g.
cefotaxime (third-generation cephalosporin).
In well-characterized patients with SBP a 5-day course
is as efficacious as a 10-day course of intravenous
antibiotics.
Lack of antibiotic-induced clinical improvement is an
indication for repeat diagnostic paracentesis. If the ascitic
fluid PMN leukocyte count is lower and the culture
negative, a further course of antibiotic is given. If the
ascitic fluid PMN leukocyte count is higher and culture
yields a new organism, a different antibiotic is chosen.
Alternatively, if reculture yields the same organism
secondary bacterial peritonitis is suspected.
Co-treatment with intravenous albumin, 1.5 g/kg at
the time of diagnosis and 1 g/kg on day 3, reduces the
incidence of renal impairment and improves survival.
Oral ofloxacin has been reported to be as efficacious
as intravenous cefotaxime in the treatment of patients
with SBP, who are not azotemic, vomiting or in shock.
However, until more data are available, an intravenous
antibiotic regimen is preferred.
Follow-up Paracentesis
Necessary only if there are atypical features (symptoms,
clinical setting, ascitic fluid analysis, organism(s),
response to therapy) suggestive of secondary peritonitis.
Liver Transplantation
The prognosis in patients who develop SBP is so poor,
that liver transplantation should be considered in all
survivors of SBP.
Prevention
Cirrhotic patients, with low ascitic fluid total protein
levels (< 1 g/dl) or gastrointestinal hemorrhage or those
who have recovered from an episode of SBP, are at high
risk of developing SBP and are candidates for long-term
prophylactic therapy with oral antibiotics.
Oral antibiotic primary prophylaxis, with norfloxacin,
ciprofloxacin or cotrimoxazole, appears to be effective
in preventing an initial episode of SBP or a recurrence of
SBP. The emergence of infections caused by bacteria
resistant to specific antibiotics is a potential problem.
Prognosis
Depends on the underlying disorder, the degree of
reversibility of a given disease process, and the response
to treatment.
Patient Education
The most important aspect of patient education is
determining when therapy is failing and recognizing the
need to see a physician. Unfortunately, in most cases,
liver failure has a dismal prognosis. All patients must be
taught which complications are potentially fatal and the
signs and symptoms that precede them. Abdominal
distention and/or pain despite maximal diuretic therapy
are common problems, and patients must realize the
importance of seeing a physician immediately.
Monitoring of the Patient
The treatment of ascites depends on it’s cause. In the
majority of patients, cirrhosis leading to portal hyper-
tension is the major cause. A particular value of
recognizing portal hypertension as a cause of ascites is
that medical management using diuretics and salt
restriction is often effective in portal hypertensive
patients. Conversely, ascites due to peritoneal infla-
mmation or malignancy alone does not respond to salt
restriction and diuretics.
Low Albumin Gradient Ascites
These patients usually do not have portal hypertension
and do not respond to salt restriction and diuretics.
Patients with ‘Tuberculous peritonitis’ are cured by
antituberculous therapy. Pancreatic ascites may resolve
 Diseases of Gastrointestinal System and Liver
spontaneously, require endoscopic stenting or operative
intervention or need ‘somatostatin’ therapy. Lymph leak
usually resolves spontaneously or may require surgical
intervention or peritoneovenous shunting: Chlamydial
peritonitis requires tetracycline therapy. Nephrotic and
lupus ascites may require steroids. Malignant requires
surgical debulking and chemotherapy. Ascites may
respond to aggressive dialysis.
Urinary Sodium
Twenty-four hours urinary sodium measurement is a
helpful parameter. When patient has no urinary sodium
excretion despite diuretics, recommend an alternative
treatment-paracentesis.
REFRACTORY ASCITES
Definition
Defined as fluid overload that is non-responsive to
restriction of dietary sodium to 88 mmol/day and
maximal dose diuretic therapy (furosemide + spirono-
lactone), in the absence of ingestion of prostaglandin
inhibitors, such as non-steroidal anti-inflammatory
drugs. Ascites is also considered to be refractory when
there is intolerance of diuretic therapy.
Indications of failure of diuretic therapy include
minimal or no weight loss, together with inadequate
urinary sodium excretion (< 78 mmol/day).
Less than 10 percent of patients with ascites
complicating cirrhosis meet the criteria of the definition
of refractory ascites.
Management
Serial Large-Volume Paracentesis
Serial large-volume paracentesis (6-10 L) are safe and
effective in controlling refractory ascites.
Therapeutic paracentesis volume of fluid to be
tapped: Up to 100 ml/kg safely at any time. How
frequently one should tap: large volume tap is indicated
in one sitting then frequent taps.
Mechanism of Relief by Paracentesis
Taking out fluid from peritoneal cavity decreases
systemic venous congestion, increases GFR and renal
plasma flow which helps in producing diuresis.
709
Advanced cirrhosis is associated with a hyper-
dynamic circulation characterized by reduced systemic
vascular resistance secondary to splanchnic vaso-
dilatation, which leads to effective hypovolemia. Intense
activation of the renin-angiotensin-aldosterone system
(RAAS) and the sympathetic nervous system, and
nonosmotic release of vasopressin occur, with conse-
quent renal hypoperfusion. This becomes more accen-
tuated as patients progress from decompensated cirrhosis
to the hepatorenal syndrome (HRS).
In patients with no urinary sodium excretion and a
dietary intake of 88 mmol sodium daily, the required
frequency is about every two weeks. The frequency is
influenced by the degree of compliance with the low
sodium diet. The sodium content of ascitic fluid is about
130 mmol/L. Thus, a 6 L paracentesis removes 780 mmol
sodium. Patients, who ingest 88 mmol sodium per day
and excrete 10 mmol sodium in non-urinary losses and
no sodium in the urine, retain 78 mmol sodium per day.
Accordingly, a 6 L paracentesis removes the sodium
retained over a period of 10 days, and a 10 L paracentesis
removes the sodium retained over approximately 17
days.
Intravenous colloid replacement, e.g. albumin 6 to 8
g/L ascitic fluid removed is recommended immediately
following a large-volume paracentesis (>5 L), to minimize
intravascular hypovolemia, activation of vasoconstrictor
and antinatriuretic systems, and impairment of renal
function. Dextran 70 is less efficacious than albumin. If a
paracentesis is <5 L, colloid replacement appears to be
unnecessary.
Novel Treatments in Ascites
Atrial Natriuretic Peptide
Atrial natriuretic peptide (ANP) normally increases
glomerular filtration rate (GFR) and natriuresis. Patients
with advanced cirrhosis and ascites have a reduced
natriuretic response to ANP despite elevated levels.
Exogenous ANP administration, together with the
splanchnic vasoconstrictor terlipressin to counter the
hypotensive effect of ANP, increases renal blood flow,
GFR and natriuresis in patients with refractory ascites.
Other Agents
Although not tested specifically for refractory ascites, a
number of agents have been tried in humans which may
710 IAP Textbook of Pediatrics
increase diuresis in cirrhotic patients with ascites. These
include the V2 receptor antagonist, OPC-3126, Niravoline,
a k-opioid antagonist, and the adenosine-1-receptor
antagonist FK352. Future studies using these novel
agents may provide further information regarding their
efficacy in refractory ascites.
CHYLOUS ASCITES
Turbid, milky or creamy peritoneal fluid due to the
presence of thoracic or intestinal lymph having
triglyceride (fat) concentration of more than 1000 mg/
dl. If patient has nothing by mouth, then milky color will
fade and the fluid will look like transudate with
predominance of lymphocytes (85%).
Causes
Congenital anomaly of lymphatics lymphangiectasis,
obstruction of duct within its abdominal portion from
trauma, tumor, large lymph nodes, rupture of major
lymphatic channel, tuberculosis, filariasis, nephrotic
syndrome, cirrhosis, rheumatoid arthritis, other serositis.
PSEUDOCHYLOUS ASCITES
In chronic peritonitis/persistent ascites fluid have some
what similar color, from the degeneration of infla-
mmatory products (leukocytes/tumor cell), and may be
confused with chylous fluid (Table 13.22.5).
Management
a. Dietary:
i. Low fat diet - containing medium chain trigly-
cerides, because these are absorbed directly into
the portal circulation.
ii. High protein diet, and
iii. Parenteral nutrition supplementation.
b. Paracentesis
TABLE 13.22.5: Difference between true and
pseudochylous fluid
True chylous fluid Pseudochylous fluid
1. Ether test- top thick layers
becomes clear fluid Turbidity is unchanged
2. Alkali test- no change in color Becomes clear (dissolves
cellular protein)
3. Fat globules stained by Sudan Not stained
Duration of treatment may require several months
for effective medical management.
Surgical approach abdominal exploration to detect
the site of the leak.
Monitoring during Diuretic Therapy
The main concern during diuretic therapy is whether
there is too rapid fluid mobilization and diuretic induced
complications.
In OPD settings the patient needs to be assessed after
1 week of starting therapy and thereafter every 2 weeks.
At each visit compliance for low sodium diet, bed rest
and diuretic doses should be ascertained. Examination
for changes in weight, abdominal girth, pedal edema,
ascitic grading and subtle signs of spontaneous bacterial
peritonitis should be done. Weight loss of more than 1
percent per day or 4 to 6 percent per week of the previous
weight would indicate too rapid fluid mobilization and
natriuresis. This cautions us to evaluate renal functions
along with reduction in the dose of diuretics.
Evaluation of serum Na, K, blood urea and creatinine
and liver function tests would be useful in assessing
diuretic response and its attendant complications. Serial
measurement of fractional excretion of sodium is an
objective measure of the effectiveness of the diuretic
response. This requires simultaneous estimation of serum
and spot urinary sodium and creatinine concentrations.
At the earliest suspicion of spontaneous bacterial
peritonitis, an ascitic tap should be performed and
antibiotic therapy instituted. Admitted patients are
usually those who have resistant ascites or have
developed diuretic induced complications. Thus their
monitoring is more intense and repeated every 48 hours.
SUMMARY
The circulatory disturbances seen in advanced cirrhosis
lead to the development of ascites, which can become
refractory to diet and medical therapy. These abnor-
malities may progress and cause a functional renal failure
known as the hepatorenal syndrome. Management of
refractory ascites and hepatorenal syndrome is a
therapeutic challenge, and if appropriate, liver trans-
plantation remains the best treatment. New therapeutic
options have recently appeared, including the trans-
jugular intrahepatic portosystemic shunt and selective
splanchnic vasoconstrictor agents, which may improve
renal function and act as a bridge to transplantation.
 Diseases of Gastrointestinal System and Liver
BIBLIOGRAPHY
1. Albornoz L, Motta A, Alvarez D, et al. Nitric oxide
synthase activity in the splanchnic vasculature of patients
with cirrhosis: relationship with hemodynamic distur-
bances. J Hepatol 2001;35(4):452-6.
2. Arrovo V, Esptein M, Gallus G et al. Refractory ascites
in cirrhosis. Mechanism and treatment. Gastroenterology
1989;2:195.
3. Arroyo V, Gines P, Gerbes AL, Dudley FJ, Gentilini P,
Laffi G, Reynolds TB, Larsen HR, Scholmerich J.
Definition and diagnostic criteria of refractory ascites and
hepato-renal syndrome in cirrhosis. Hepatology
1996;23(1):164-76.
4. Bernadi M, Santini C, Trevisani F. Renal function
impairment induced by change of posture in patients
with cirrhosis and ascites. Gut 1985;26:629-35.
5. Cardenas A, Bataller R, Arroyo V. Mechanisms of ascites
formation. Clin Liver Dis 2000;4(2):447-65.
6. Casado M, Bosch J, Garcia-Pagan JC et al. Clinical events
after transjugular intrahepatic portosystemic shunt:
correlation with hemodynamic findings. Gastro-
enterology 1998;1114:1296-1303.
7. D’Amico G, Luca A, Morabito A, Miraglia R, D’Amico
M. Uncovered transjugular intrahepatic portosystemic
shunt for refractory ascites: a meta-analysis. Gastro-
enterology. 2005;129(4):1282-93.
8. D’Amico G, Morabito A, Pagliaro L, Marublni E. Survival
and prognostic indicators in compensated and decom-
pensated cirrhosis. Dig Dis Sci 1986;31:468-75.
9. Diseases of the peritoneum, mesentery and omentum.
In Wynngaarden JB, Smith LH, Bennet JC (Eds): Cecil
Textbook of Medicine, 20th edition. W B Saunders ny,
1996.
10. Garcia-Tsao G. Current management of the compli-
cations of cirrhosis and portal hypertension: variceal
hemorrhage, ascites, and spontaneous bacterial perito-
nitis. Gastroenterology 2001;120(3):726-48.
11. Gerbes AL. Medical treatment of ascites in cirrhosis. J
Hepatol 1993;17(suppl):S4-S9.
12. Gines P, Cardenas A, Arroyo V, Rodes J. management
of cirrhosis and ascites. N Engl J Med 2004;350:1646-54.
13. Hardikar W. Ascites and encephalopathy in chronic liver
disease. Indian J Ped 2002;69:169-73.
14. Hardy SC, Kleinman RE. In Erederick JS (Eds): Cirrhosis
and Chronic Live Failure in Liver Diseases in Children
(1st edn) Mosby 1994;229-30.
15. Heneghan MA, Harrison PM. Pathogenesis of ascites in
cirrhosis and portal hypertension. Med Sci Monit
2000;6(4):807-16.
16. Idem. Low protein concentration ascitic fluid is
predisposed to spontaneous bacterial peritonitis.
Gastroenterology 1986;91:1343-46.
17. Inturri P, Graziotto A, Rossaro L. Treatment of ascites:
old and new remedies. Dig Dis 1996;14:145-56.
711
18. Jeffery J, Murphy MJ. Ascitic fluid analysis: the role of
biochemistry and haematology. Hlsp Med 2001;
62(5):282-86.
19. Levy M. Pathophysiology of ascites formation. In: Epstein
M (Ed): The Kidney in Liver Disease, 3rd edn. Williams
and Wilkins, Baltimore 1988;209-43.
20. Lieberman FL, Denison EK, Reynolds TB. The
relation-ship of plasma volume, portal hypertension,
ascites and renal sodium retention in cirrhosis: the
overflow theory of ascites formation. Ann NY Acad Sci
1970;170:202-12.
21. Mathur P, Oberoi A, Arora NK. Management of ascites
in children with chronic liver disease. Indian J Practical
Pediatrics 2002;4(4):329-37.
22. McGillivroy BC. Neonatal ascites. Pediatr Pev 1987;9:197.
23. McVay PA, Toy PTCY. Lack of increased bleeding after
paracentesis and thoracocentesis in patients with mild
coagulation abnormalities. Transfusion 1991;31:164-71.
24. Pare P, Talbot J, Hoefs JC. Serum ascites albumin
concentration gradient: A physiologic approach to the
differential diagnosis. Gastroenterology 1983;85:240.
25. Parsons SL, Watson SA, Streele RJ. Malignant ascites. Br
J Surg 1996;83:6-14.
26. Press OW, Press NO, Kaufman SD. Evaluation and
management of chylous ascites. Ann intern Med
1982;96:358.
27. Rector WG Jr, Reynolds TB. Superiority of the serum-
ascites albumin difference over the ascites total protein
concentration in separation of “Transudative” and
Exudative” ascites. Am J Med 1984;77:83-85.
28. Reynolds TB. Ascites. Clin Liver Dis 2000;4(1):151-68.
29. Rimola AD, Garcia-Tsao G, Navasa M et al. Diagnosis,
treatment and prophylaxis of spontaneous bacterial
peritonitis: a consensus document. International Ascites
Club. J Hepatol 2000;32(1):142-53.
30. Rossle K, Ochs A, Gulberg V, et al. A comparison of
paracentesis, and transjugular intrahepatic portosystemic
shunting in patients with ascites. NEJM 2000;342:
1701-07.
31. Runyon B. Approach to the patient with ascites. In:
Yamada T, Alpers DH, Laine L, Owyang C, Powell DW,
(Eds). Textbook of Gastroenterology. 3rd ed.
Philadelphia, Pa: Lippincott Williams and Wilkins; 1999;
966-91.
32. Runyon BA, Antillon MR, Akriviadis EA et al. Bed side
inoculation of food culture bottles with ascitic fluid is
superior to delayed inoculation in detection for
spontaneous bacterial peritonitis. J Clin Microbio
1991;28:2811.
33. Runyon BA, Montano AA, Akriviadis EA et al. The
serum-ascites gradient is superior to the exudate-
transudate concept in differential diagnosis of ascites.
Ann Intern Med 1992;117:215.
712 IAP Textbook of Pediatrics
34. Runyon BA, Montano AA, Alkriviadis EA et al. The
serum ascites albumin gradient in the differential
diagnosis of ascites is superior to the exudate/transudate
concept. Ann Intern Med 1992;117:215.
35. Runyon BA. Care of patients with ascites. N Engl J Med
1994;330(5):337-41.
36. Runyon BA. Care of patients with ascites. New England
J Medicine 1994;330:337.
37. Runyon BA. Management of adult patients with ascites
caused by cirrhosis. Hepatology 1998;27:264-72.
38. Runyon BA. Paracentesis of ascitic fluid: a safe procedure.
Arch Intern Med 1986;146:2259.
39. Schiff ER, Sorrell MF, maddrey WC. Ascites and
spontaneous bacterial peritonitis. In: Schiff ER, Sorrell
MF, Maddrey WC (Eds). Schiff’s Disease of the Liver.
8th ed. Philadelphia, Pa: Lippincott Raven 1999;503-44.
40. Sherlock S, Senewiratne B, Scott A, Walker JG.
Complica-tions of diuretic therapy in hepatic cirrhosis.
Lancet 1966;1:1049-53.
41. Surgaila I, Bartie W, Walker S. Spironolactone
pharmaco-kinetics and pharmacodynamics in cirrhosis
with ascites. Gastroenterology 1992;102:168.
42. Turkel SH. Congenital ascites: Clin Perinatol 1988;9:613.
43. Valla D, Flejou JF, Labrec D. Portal hypertension and
ascites in acute hepatitis. Clinical hemodynamics and
histologic correlations. Hepatology 1978;10:482-87. http:/
/www.medstudents.com.br/medint/medint3.htm
44. Wallerstedt S, Olsson R, Simrén M, Broomé U, Wahlin S,
Lööf L. Abdominal tenderness in ascites patients
indicates spontaneous bacterial peritonitis. Eur J Intern
Med 2007;18(1):44-7.
45. Witte CL, Witte MH, Dumont AE. Lymph imbalance in
the genesis and perpetuation of the ascites syndrome in
hepatic cirrhosis. Gastroenterology 1980;78:1059-68.
46. Wong F, Blendis L. Hepatorenal failure. Clin Liver
Disease 2000;4(1):169-89.
 14.1 Renal Anatomy and Physiology: Arvind Bagga ................................................................................................................................. 714
14.2 Diagnostic Evaluation: RN Srivastava, Aditi Sinha ............................................................................................................................. 715
14.3 Imaging of the Urinary Tract: Arvind Bagga, Aditi Sinha ................................................................................................................... 719
14.4 Developmental Anomalies: M Vijayakumar ........................................................................................................................................ 722
14.5 Acute Proliferative Glomerulonephritis: BR Nammalwar, T Vasanthi, M Vijayakumar ................................................................... 724
14.6 Renal Vasculitis: BR Nammalwar, N Prahlad ...................................................................................................................................... 729
14.7 Acute Renal Failure: Arvind Bagga, Aditi Sinha .................................................................................................................................. 737
14.8 Nephrotic Syndrome: RN Srivastava, Arvind Bagga ........................................................................................................................... 743
14.9 Urinary Tract Infection, Vesicoureteric Reflux and Reflux Nephropathy: M Vijayakumar, RN Srivastava ................................... 750
14.10 Obstructive Uropathy: Kumud P Mehta .............................................................................................................................................. 754
14.11 Disorders of Micturition: Kumud P Mehta .......................................................................................................................................... 755
14.12 Chronic Kidney Disease: KD Phadke, Pankaj Hari ............................................................................................................................ 757
14.13 Hypertension: Kumud P Mehta ............................................................................................................................................................ 761
14.14 Renal Tubular Disorders: Aditi Sinha, Arvind Bagga .......................................................................................................................... 763
714 IAP Textbook of Pediatrics
14.1 Renal Anatomy and Physiology
INTRODUCTION
The kidneys are situated retroperitoneally on each side
of the vertebral column. On cut surface, the pale outer
cortex and a dark, inner medulla can be easily disting-
uished. The medulla consists of 8 to 18 conical masses,
the pyramids. The base of a pyramid is at the corti-
comedullary junction and the apex towards the renal
pelvis forming a papilla. Each papilla contains 10 to 25
small openings that represent the distal ends of the
collecting ducts.
Kidneys receive 20-25 percent of the cardiac output.
While its chief functions are glomerular filtration, tubular
reabsorption and tubular secretion, the kidneys also play
an important role in vitamin D metabolism, hemato-
poiesis and blood pressure control.
The Nephron
Each kidney contains about one million nephrons, the
functional units. A nephron consists of a glomerulus,
proximal tubule, the thin limbs, the distal tubule and the
collecting segment. The glomerulus is made up of a tuft
of capillaries and a central region of mesangium
containing cells and matrix. The capillaries arise from
an afferent arteriole and eventually join to form an
efferent arteriole. The glomerulus is surrounded by the
Bowman’s capsule lined by the parietal epithelium,
which is continuous with the visceral epithelium at the
vascular pole. The Bowman’s capsule leads into the
proximal tubule.
The early part of the distal tubule on its ascent from
the medulla comes in contact with the afferent arteriole of
the glomerulus. The smooth muscle cells of the afferent
arterioles have renin containing cytoplasmic granules. The
juxtaglomerular apparatus (JGA) is composed of the
afferent and efferent arterioles, and specialized cells of the
distal tubule, the macula densa. The JGA is involved in
systemic blood pressure regulation, electrolyte homeosta-
sis and tubuloglomerular feedback mechanisms.
Glomerular Filtration
The glomerular capillary hydrostatic pressure forces a
virtually protein free filtrate into the Bowman’s space.
Arvind Bagga
Crystalloids and low molecular weight substances such
as urea, glucose and amino acids are freely filtered. The
glomerular filter, composed of endothelial cells, the
glomerular basement membrane and the slit diaphragm
of the podocytes, restricts the filtration of protein
molecules.
The glomerular filtrate has almost the same compo-
sition as that of plasma. The normal glomerular filtration
rate (GFR) is about 100 to 125 ml/min/1.73 m2. The GFR
is determined by the degree of constriction of afferent
and efferent arterioles, and plasma colloid osmotic
pressure. Angiotensin II increases the GFR by a
preferential constriction of the efferent arteriole.
Autoregulation is the phenomenon where the GFR is
maintained despite fluctuations in systemic arterial
pressure. This is mediated through tubuloglomerular
feedback, where a marked fall in GFR results in excessive
reabsorption of Na+ and Cl- in the ascending loop of
Henle, reducing their concentrations at the macula densa,
which leads to renin release by the juxtaglomerular cells,
increased angiotensin II formation, constriction of
efferent arterioles and increase in the GFR.
Tubular Reabsorption
The proximal tubule reabsorbs about 65 percent of the
filtrate. The descending limb of Henle is the site of simple
diffusion of substances. The thick ascending limb of
Henle and the early distal tubule are almost impermeable
to both water and urea, but important for absorption of
sodium, potassium and chloride. This differential
permeability results in accumulation of sodium in the
medullary interstitium, which creates the hypertonicity
necessary for urinary concentration. The latter part of
distal tubule is involved in aldosterone controlled sodium
reabsorption and potassium secretion. The late distal
tubule and the cortical collecting duct contain specialized
cells, which actively secrete hydrogen ions against a steep
concentration gradient, necessary for maximum urinary
acidification. The small amounts of proteins that are
filtered through the glomerular barrier are normally
totally reabsorbed in the proximal tubule by pinocytosis.
Under usual circumstances, 65 percent of the
glomerular filtrate water is reabsorbed in the proximal

tubule, 15 percent in the loop of Henle, 10 percent in the
distal tubule and 9 percent in the collecting duct. Only 1
percent of glomerular filtrate water is excreted as urine.
Urinary Acidification
The role of the kidney is to stabilize plasma bicarbonate
at a level of 22 to 25 mEq/l. The filtered bicarbonate is
largely (80-85%) reabsorbed in the proximal tubule.
Maximum urinary acidification is achieved distally,
through excretion of titratable acid and ammonia.
Filtered sodium is exchanged for hydrogen ion along the
entire length of the nephron. Titratable acid is formed
by the buffering of hydrogen ions by phosphate in the
tubular fluid. Ammonia formed within the proximal
tubular cells diffuses into the lumen where it combines
with hydrogen ion to form ammonium ions. During
states of acidosis, the urine pH can be lowered to between
5.2 and 5.5.
Urinary Concentration
The tonicity of the body fluid is maintained constant
between 280 to 290 mOsm/kg. Expansion of intra-
vascular volume causes activation of stretch sensors in
the atria, leading to an increase in atrial natriuretic
peptide. Sodium and water diuresis follows. An increase
in blood osmolality, on the other hand, is sensed by
osmoreceptors leading to increased ADH secretion. ADH
increases the permeability of water in the collecting ducts
through the insertion of aquaporins (water channels) that
allow passage of water from the lumen to the hyper-
14.2 Diagnostic Evaluation
There are only a few specific manifestations of renal
diseases in infants and children, whereas other features
are subtle and do not lead to a suspicion of a renal
disorder. Renal disease should be suspected in patients
with failure to thrive, unexplained fever, obscure anemia,
dyselectrolytemia and refractory rickets. A family history
of a renal disease should always be obtained.
Diseases of Kidney and Urinary Tract 715
osmotic interstitium. In the absence of ADH, the
collecting ducts are impermeable to the passage of water
and dilute urine is passed. During maximum urinary
concentration, the urinary osmolality may rise to 1000-
1200 mOsm/kg.
Renal Function in the Newborn
Renal function in an infant is subnormal by adult
standards, especially in premature neonates, which puts
them at high risk of developing acute renal failure.
Glomerular filtration begins between 9 to 12 weeks of
gestation, initiating formation of urine and contributing
to accumulation of amniotic fluid. The GFR is low at birth
(10-20 ml/min/1.73 m2 in the first 3 days) but increases
rapidly to 75-80 ml/min/1.73 m2 by 8 weeks. The serum
creatinine level is high at birth, reflecting the maternal
value but falls to 0.4 mg/dl by the end of 2 weeks. Sodium
reabsorption is low; around 1 to 3 percent of the filtered
load is excreted. There is also limited bicarbonate
reabsorption and hydrogen ion excretion. Therefore, the
pH of urine of a newborn is inappropriately high for the
degree of acidemia.
BIBLIOGRAPHY
1. Kriz W, Elgar M. Renal anatomy. In: Johnson RJ, Feehaly
J (Eds): Comprehensive Clinical Nephrology. London:
Mosby 2000;1.1-1.10.
2. Srivastava RN, Bagga A. Renal anatomy and physiology.
In: Srivastava RN, Bagga A (Eds): Pediatric Nephrology,
4th edn. New Delhi: Jaypee Brothers 2005;1-19.
RN Srivastava, Aditi Sinha
Clinical Features of Renal Disease
Hematuria
The urine color may vary from frank red to shades of
brown, described as tea or cola-colored. A small quantity
of blood (1 mL in 1000 mL urine) is enough to make the
urine appear red; hematuria must be confirmed on urine
716 IAP Textbook of Pediatrics

microscopy. In the absence of gross hematuria, the TABLE 14.2.2 Causes of glomerular and
persistent finding of hematuria (more than 5 red cells non-glomerular hematuria
per high power field) in at least two of three urinalyses, Glomerular diseases Non-glomerular causes
performed over 2-3 weeks, warrants further evaluation.
Acute postinfectious GN Nephrolithiasis*†
Hematuria should be distinguished from other causes
of red urine, including hemoglobinuria, methemoglo- IgA nephropathy* Hypercalciuria*†
binuria, urates and ingestion of rifampicin, red dyes or Benign familial hematuria*† Viral cystitis
beet. A brown discoloration of urine may be caused by Systemic infections Urinary tract infection
myoglobinuria, porphyria and alkaptonuria. (malaria, leptospirosis,
infective endocarditis)
Blood in the initial urine suggests urethral origin
while terminal hematuria indicates bladder origin. If Membranoproliferative GN Renal vein/artery thrombosis, AV
malformations
hematuria is uniform throughout micturition, then gross
hematuria is most often due to a renal cause, e.g. Focal segmental Trauma, tumors*, exercise
glomerulosclerosis
glomerulonephritis (GN). Hematuria may be glomerular
or extraglomerular in origin; distinguishing features are Systemic lupus Bleeding or clotting abnormality
erythematosus
listed in Table 14.2.1. Important causes of hematuria in
Hemolytic uremic syndrome Hydronephrosis
the newborn include renal vein thrombosis, renal artery
thrombosis, bleeding and clotting disorders, trauma due Henoch-Schonlein purpura Renal cystic disease†
to bladder catheterization, urinary tract infection, Alport’s syndrome*† Medications: NSAIDs, anticoagu-
autosomal recessive polycystic kidney disease and lants, ritonavir, indinavir, cyclo-
phosphamide
obstructive uropathy.
Important causes of hematuria are listed in Table Goodpasture disease Tuberculosis*
14.2.2, and a protocol for evaluation in Figure 14.2.1. GN glomerulonephritis; NSAIDs non-steroidal anti-inflammatory
drugs
Edema *Causes of recurrent hematuria; †Hematuria with familial
association
Glomerulonephritis characteristically manifests with
facial puffiness and gross hematuria. Edema is turgid
and does not pit readily on pressure. In nephrotic
commonly due to posterior urethral valve. Persistent
syndrome, edema develops insidiously, starting with
dribbling of urine indicates abnormal ureteric insertion
puffiness around the eyes and then involving the feet
distal to the bladder neck. In all infants with meningo-
and legs. Edema is soft and easily pits on pressure.
myelocele, a detailed evaluation should be done to detect
bladder dysfunction. Crying during micturition and
Abnormalities of Micturition
straining suggest obstruction. Retention of urine may be
In a male infant, a poor urinary stream, especially in the due to neurogenic bladder or obstruction by stone or
presence of a full bladder, suggests obstruction, most tumor.

TABLE 14.2.1: Features distinguishing glomerular hematuria from non-glomerular hematuria

Features Glomerular hematuria Non-glomerular causes

Systemic complaints Edema, oliguria, hypertension, rash, Fever, abdominal pain, dysuria, abdominal mass
arthralgia, fever
Family history Deafness, renal disease (Alport syndrome) Renal stones, cystic kidneys
Urine color, clots Brown, tea/cola colored Bright red, clots may be present
Proteinuria 2+ or more Less than 2+
Dysmorphic red cells More than 20% Not common; less than 15%
RBC casts Common Absent
Crystals Absent Positive in few
 Diseases of Kidney and Urinary Tract 717

Figure 14.2.1: Patients with isolated hematuria should be evaluated to distinguish glomerular from extra-glomerular hematuria.
Subsequent evaluation is tailored to the likely cause. RBC red blood cells; hpf high power field; C3 complement factor 3, ASO
antistreptolysin O; ANA antinuclear antibody; anti-dsDNA anti-double stranded DNA antibody; ANCA antineutrophil cytoplasmic
antibody

Oliguria
Anuria is no passage of urine. Oliguria is passage of
insufficient volume of urine, defined as < 500 ml/day/
1.73 m2 or < 0.5 ml/kg/hour. Decreased urine output is
an important feature of renal disease. A cause such as
gastroenteritis or other conditions that lead to prerenal
type of acute renal failure may be present. Oliguria is an
important feature of moderate or severe glomerulo-
nephritis and other conditions causing serious glome-
rular injury, like hemolytic uremic syndrome.
Polyuria
Polyuria is passage of excessive amount of urine, 5-6 ml/
kg/hour or more. Impairment of urinary concentration
is a feature of obstructive uropathy and disorders
characterized by tubulointerstitial lesions, e.g. nephro-
nophthisis. In infants, these symptoms are often not
noticed. A diagnosis of nephrogenic diabetes insipidus
is rarely made until complications develop. Conditions
causing persistent hypokalemia (distal renal tubular
acidosis) also result in polyuria.
718 IAP Textbook of Pediatrics
Enuresis
In most children with nocturnal enuresis, there is no
evidence of renal disease. It is a benign and self-limiting
condition, usually remediable with patient education and
bladder training. Increased frequency or polyuria may
be due to urinary infections, bladder instability or
polyuria.
Other Features
Presence of dysuria, flank pain and cloudy urine suggest
urinary tract infections. Tenderness in the renal angle
and fever indicate pyelonephritis. Features suggestive
of chronic kidney disease include hypertension, growth
retardation and normocytic normochromic anemia.
Presence of palpable kidney/s suggests multicystic
dysplastic kidney, polycystic kidney disease and Wilms’
tumor.
Laboratory Examination
Urine Examination
Careful examination, preferably of the first morning
urine is preferred. A midstream specimen is generally
adequate. In infants, a specimen obtained by suprapubic
bladder aspiration or transurethral catheterization is
preferred for culture. The urine specimen should be fresh
and relatively concentrated (appearing yellow). Formed
elements quickly disintegrate in dilute urine. If
processing is likely to be delayed, the sample may be
stored at 4°C.
Urinary protein is measured with heat precipitation
method or with sulfosalicylic acid. The turbidity can be
graded from nil to 4+; 3+ or more indicates heavy
proteinuria. Proteinuria is always abnormal and a cause
should be looked for. Assessment of specific gravity is
required in patients with suspected defects in urine
concentration. Estimation of urine pH is useful in patients
with suspected renal tubular acidosis. Composite
dipsticks are available for urine pH, glucose, protein,
blood, leukocyte esterase and nitrite.
Microscopic examination: A fresh, centrifuged specimen
should be examined. Red cell casts indicate glomerular
inflammation. Clumping of neutrophils (white cell casts)
suggests acute pyelonephritis. Leukocytes may be absent,
despite significant bacteriuria. Red blood cells and
leukocytes can be counted under high power field (HPF)
and more accurately in a counting chamber. Normally,
1 to 2 of either of these may be seen per HPF in midstream
urine. More than 5 neutrophils/HPF with bacteriuria
suggests urinary tract infection. More than 5 red cells/
HPF in a centrifuged specimen is abnormal. Phase
contrast microscopy is helpful to examine red cell
morphology, casts and crystals.
Because of difficulties in accurately collecting 24-hr
specimens of urine, this is resorted to when definitely
needed (e.g. quantitative measurement of calcium,
phosphate, creatinine, magnesium, oxalate) for the
diagnosis of specific conditions and clearance studies.
In nephrotic syndrome and various forms of GN,
semiquantitative tests for protein or protein/creatinine
ratio in spot urine samples are sufficient.
Blood Tests
The normal level of blood urea ranges between 20 and
40 mg/dl. Various factors that reduce renal perfusion,
cause a reversible increase in blood urea levels. The levels
are also increased in excessive tissue breakdown, trauma,
gastrointestinal bleeding and use of corticosteroids and
tetracycline. Urea levels may be low in presence of
hepatic failure and on a low protein diet.
The level of serum creatinine varies inversely with
the glomerular filtration rate (GFR) of which it is a better
indicator than blood urea. Serum creatinine is not readily
affected by prerenal factors. However, serum creatinine
depends on muscle mass and may overestimate GFR in
presence of malnutrition. Hyperbilirubinemia (bilirubin
level > 5 mg/dl) interferes with the measurement of
creatinine. GFR may be estimated in children as follows:
height (in cm)
Glomerular filtration rate = k × _______________________
serum creatinine
(mg/dL)
where, k = 0.33 for preterm infants; 0.45 for children
< 2-yr-old; 0.55 for older children.
Serum albumin is reduced in patients with nephrotic
syndrome proteinuria, occasionally below 1.5 g/dL. In
children with nephrotic syndrome, hypercholesterolemia
is typically present.
The levels of complement factor 3 (C3) in blood are
reduced in postinfectious GN, membranoproliferative
GN and lupus nephritis. In systemic lupus erythematosus
(SLE), C3 levels reflect disease activity; the normal range
is between 70 and 120 mg/dL.

Antinuclear antibodies (ANA) are antibodies directed
against chromatin associated or ribonucleoprotein
particles. They are not specific and may be increased in
many autoimmune diseases like SLE, juvenile rheuma-
toid arthritis, polyarteritis nodosa and autoimmune
hepatitis. Antibodies to double standed DNA (anti-
dsDNA) is specific to SLE, while increased titer of
antineutrophil cytoplasmic antibody (ANCA) is seen in
a group of small vessel vasculitis, including microscopic
polyangiitis, Wegener’s granulomatosis and renal limited
vasculitis.
Imaging Studies
The role of radiological and radionuclide imaging
techniques in discussed in Section 14.3.
Renal Biopsy
A renal biopsy is not necessary in uncomplicated cases
of poststreptococcal GN and corticosteroid responsive
nephrotic syndrome. Indications for kidney biopsy are
listed under specific conditions. The procedure must be
performed early in case of rapidly progressive glomerulo-
nephritis, suspected SLE nephritis and renal vasculitis,
where early institution of specific therapy may improve
outcome.
14.3 Imaging of the Urinary Tract
In the last thirty years the field of diagnostic imaging
has grown tremendously with a multitude of imaging
techniques available to the treating physicians. In view
of the considerable radiation exposure associated with
the use of radiocontrast agents, the use of radionuclide
procedures is preferred, wherever feasible. The indi-
cations for these investigations are discussed.
Plain X-ray of the Abdomen
A plain X-ray film of abdomen has a role in the detection
of small renal calculi and ureteric calculi without
proximal ureteral dilatation. It is also important for
evaluation of the spine in children with neurogenic
Diseases of Kidney and Urinary Tract 719
The availability of disposable Tru-Cut needle and
‘biopsy gun’ has improved the yield of the procedure, with
relatively less risks. Prior to biopsy, a normal coagulation
profile and normal blood pressure must be ensured to
reduce the risk of bleeding. Patients with marked
azotemia should be dialyzed and receive intranasal
desmopressin 30-60 minutes prior to the procedure. The
renal histology is examined by light microscopy and
immunofluorescence. Electron microscopic examination
is useful for precise diagnosis of Alport syndrome,
membranoproliferative GN and thin glomerular
basement membrane disease.
BIBLIOGRAPHY
1. David I. Clinical and laboratory evaluation of renal
function, 2nd edn. In: Edelmann CM, (Ed): Pediatric
Kidney Disease 2000;461-74.
2. Endre SK. Acute proliferative glomerulonephritis. In:
Avner ED, Harmon WE, Niaudet P, (Eds): Pediatric
Nephrology, 5th edn. 2004;543-56.
3. Indian Pediatric Nephrology Group, Indian Academy
of Pediatrics. Consensus statement on evaluation of
hematuria. Indian Pediatr 2006;43:965-73.
4. Srivastava RN, Bagga A. Diagnostic evaluation. In:
Srivastava RN, Bagga A, (Eds): Pediatric Nephrology,
4th edn. New Delhi: Jaypee Brothers 2005;58-69.
Arvind Bagga, Aditi Sinha
bladder, evaluating metastatic bone disease secondary
to malignancies and for changes of renal osteodystrophy.
Intravenous Pyelography (IVP)
The use of intravenous pyelography (IVP) (excretory
urography) has declined due to the advent of ultrasono-
graphy and radionuclide studies. IVP requires bowel
preparation and administration of an ionic contrast
(urograffin, 3-4 ml/kg) with films taken at 1-5 minutes,
10-15 minutes and a late pelvic film for the bladder.
Hydration is necessary to avoid contrast nephropathy.
The test should be avoided in neonates, since they do
not show adequate urinary concentration of the contrast.
720 IAP Textbook of Pediatrics

Figure 14.3.1: Micturating cystourethrogram showing bilateral Figure 14.3.2: Ultrasound study in a 6-yr-old boy showing
grade V vesicoureteric reflux in a 3-yr-old boy with recurrent hydronephrosis; note enlarged kidney and dilated renal pelvis
urinary tract infections. The urethra is not visualized

Current indications for IVP include detailed evaluation

of structural anomalies, e.g. duplex kidneys and
horseshoe kidneys, and for ureteric calculi.

Micturating Cystourethrogram (MCU)

The MCU is an important procedure, necessary for
diagnosis and grading of vesicoureteric reflux (Fig.
14.3.1), and detection of abnormalities of bladder and
urethra. The contrast agent is introduced into the bladder
through a catheter; films are taken while the child is
voiding. Strict aseptic precautions should be observed
during the procedure. The IVP and MCU involve
considerable radiation exposure to the patient.
Figure 14.3.3: Ultrasonography showing dense medullary
nephrocalcinosis in a patient with hyperoxaluria
Ultrasonography
Ultrasound evaluation gives excellent information about parenchymal disease. Measurement of renal size helps
anatomical aspects. It is ideally suited for children since assess its growth. Doppler evaluation is useful for
it is painless and requires no sedation or administration assessment of blood flow in major vessels.
of a contrast agent. It can be carried out even at bedside,
and repeated as often as required. Ultrasound guidance Antenatal Ultrasound
can be used in intervention procedures, e.g. for biopsy Abnormalities routinely picked up during antenatal
or fine needle aspiration. Its major limitation is that it is ultrasonography include hydronephrosis, multicystic
operator dependent. Considerable experience is required kidney and enlarged bladder with posterior urethral
for interpretation of findings in small children (Figs 14.3.2 valves. Particular attention is directed towards the
and 14.3.3). amount of amniotic fluid, anteroposterior diameter of
Change in the renal cortical echotexture and its renal pelvis and pelviectasis, renal echotexture,
comparison with liver, spleen and renal medulla gives appearance of the ureters and urinary bladder. A
non-specific information about the presence of renal distended bladder with bilateral hydronephrosis
 Diseases of Kidney and Urinary Tract 721

suggests distal urinary tract obstruction as seen with of pelviureteric junction obstruction, evaluation of
posterior urethral valves, while unilateral hydronephro- differential and total renal function, assessment of
sis with normal ureters and bladder suggests pelvi- allograft function and perfusion, and diagnosis of
ureteric junction obstruction. renovascular hypertension.
A diuresis renogram in which frusemide is used to
Computerized Tomography (CT) cause rapid diuresis, helps to differentiate obstructive
dilatation from nonobstructive dilatation of the upper
CT gives excellent anatomical details and is especially
urinary tract. In the latter, there is a prompt clearing of
useful in evaluating abdominal or pelvic masses (e.g.
tumors or abscess). Non-contrast helical CT scans are the radionuclide following an injection of frusemide. In
captopril renogram, administration of captopril tempo-
currently the most sensitive and specific technique for
rarily reduces the renal blood flow and GFR, thereby
detecting renal calculi. When used with contrast, CT can
detect a non-functioning or poorly functioning kidney. facilitating the diagnosis of renal arterial stenosis.
The disadvantages are radiation exposure, the need for
Renal Static Imaging
sedation in young children and risks of contrast
nephropathy. Renal static imaging gives a two-dimensional depiction
of the concentration and distribution of the radio-nuc-
Radionuclide Imaging lide. The quality of renal images with 99mTc labeled
dimercaptosuccinic acid (DMSA) and glucoheptonate
Radionuclide methods are replacing conventional
radiocontrast studies such as IVP and renal angiogra- (GHA) is excellent. 99mTc DTPA is an excellent agent for
visualizing the pelvicalyceal collecting system and
phy. Radionuclide procedures are noninvasive, highly
ureters. DMSA attains a high level of concentration in
sensitive and expose the patient to a smaller amount of
radiation. They can be used to assess differential renal renal cortex with a slow rate of urinary excretion and is
therefore particularly useful for demonstration and
function, evaluate kidneys even in advanced dysfunc-
monitoring of renal scarring (Fig. 14.3.4), identifying
tion, assess renal perfusion, identify cortical scars and
intrarenal masses and upper urinary dilatation. ectopic kidneys and in detecting damage to kidneys and
recovery from trauma. GHA is filtered, partially
The radionuclide techniques include: (i) renal
reabsorbed and retained in proximal tubular cells; GHA
perfusion study (renography), (ii) renal static imaging,
(iii) clearance studies, and (iv) radionuclide cystography. imaging is useful when abnormalities in both the cortex
and collecting system need to be evaluated.
Renography
Clearance Studies
Renography monitors the arrival, uptake and elimina-
tion of a radiopharmaceutical by the kidney. 99mTc Radionuclide clearance studies can accurately assess
individual kidney function. Labeled chelating agents like
labeled diethylenetriamine-penta-acetic acid (DTPA), 51Cr-ethylenediamine-tetra-acetic acid (EDTA) and 99mTc
mercaptotriacetylglycine (MAG-3) and LL-ethylene
cysteine dimer (LL-EC) are commonly used agents.
DTPA is a purely glomerular agent, excreted by
glomerular filtration; MAG-3 and LL-EC are excreted by
glomerular filtration and tubular secretion.
A normal renogram has three phases: (i) a rapid rise
and fall, due to first pass perfusion, (ii) slow rise to a
peak due to arrival of the agent into the kidney, and (iii)
declining amplitude due to excretion (Fig. 14.3.4). The
peak of the curve depends on renal blood flow, renal
function, tubular transit and excretion. Therefore, the
Figures 14.3.4A and B: DTPA scintigraphy showing (A) normal
peak is delayed in renal artery stenosis, renal paren- concentration and excretion of the radiolabeled agent through
chymal disease, low urine flow rate or an obstructive both kidneys; (B) delayed image shows clearing of the radio-
process. Renal dynamic scans are useful in identification nuclide from both kidneys and its presence in urinary bladder
722 IAP Textbook of Pediatrics
DTPA are used for estimation of GFR. 131I orthoiodo-
hippurate is used for determination of effective renal
plasma flow.
Direct Radionuclide Cystogram
The diagnosis of vesicoureteric reflux and its grading is
made on radiocontrast MCU. However, radionuclide
cystography is more reliable and sensitive for detecting
VUR. The radiation dose to the patient is greatly reduced,
allowing repeated follow-up examinations. DRCG can
be done by instilling the radionuclide through a urethral
catheter or its direct injection into the bladder. Thereafter,
the patient is asked to void and rapid sequence images
of the urinary bladder are obtained during voiding. These
provide a visual representation of the rate of bladder
emptying, residual urine volume and evidence of VUR.
Clinical Applications
Ultrasound is the initial imaging in most patients with
suspected renal disease. It is often diagnostic or helps
guide the next investigation/s. In patients with suspected
14.4 Developmental Anomalies
INTRODUCTION
Ultrasonographic (USG) examination during the
antenatal period often leads to detection of anomalies of
kidney and urinary tract. About 80 percent of antenatally
diagnosed uropathies are asymptomatic at birth. Some
antenatally detected hydronephrosis may be transient
and regress, while others may be progressive, leading to
severe renal dysfunction.
Fetal urine excretion starts by tenth week, contri-
buting to the volume of the amniotic fluid. Bilateral loss
of renal function causes severe oligohydramnios.
Kidneys are visualized on USG by 15-17 weeks, and after
20 weeks renal growth can be measured. The length of
the kidney (in mm) approximates the fetal age in weeks.
Initially fetal bladder is empty, but if during the later
weeks of gestation, bladder is not visualized a renal
anomaly should be suspected. Table 14.4.1 list the
common anomalies detected on antenatal USG.
renal stones not diagnosed by ultrasonography, non-
contrast helical CT is more useful than IVP or plain
X-ray. A MCU is necessary for the detection and grading
of vesicoureteric reflux and posterior urethral valves. For
follow-up evaluation of vesicoureteric reflux, direct
radionuclide cystography is satisfactory. DTPA scinti-
graphy is useful for assessment of differential kidney
function, detection of pelviureteric junction obstruction
and in allograft dysfunction. DMSA scintigraphy is the
most sensitive technique to detect renal cortical scarring.
BIBLIOGRAPHY
1. Bal CS, Kumar A. Radionuclide imaging. In: Srivastava
RN, Bagga A (Eds). Pediatric Nephrology, 4th edn.
Jaypee Brothers, New Delhi 2005;1-19.
2. Carty H, Wright N. Imaging in pediatric nephrology. In:
Webb N, Postlethwaite R (Eds): Clinical Pediatric
Nephrology, 3rd edn. Oxford University Press, Oxford
2003;113-34.
3. Gupta AK. Imaging of the urinary tract. In: Srivastava
RN, Bagga A (Eds): Pediatric Nephrology, 4th edn.
Jaypee Brothers, New Delhi 2005;30-44.
M Vijayakumar
TABLE 14.4.1: Anomalies detected on fetal USG*
• Hydronephrosis: unilateral, bilateral
• Renal mass: neuroblastoma, renal tumor
• Cystic kidney: solitary cyst, polycystic kidneys, multicystic
kidneys
• Absent kidney: renal agenesis (unilateral or bilateral), ectopic
kidney.
*Hydronephrosis and multicystic kidneys are the most common
anomalies
Fetal Hydronephrosis
Fetal hydronephrosis may be unilateral or bilateral. The
chief cause include pelvi-ureteral junction obstruction
and vesicoureteric reflux (VUR). Severe urinary tract
obstruction result in renal dysplasia and pulmonary
hypoplasia. Postnatally, USG examination is done at 3-7
days of age. Blood levels of urea and creatinine are

measured. Milder degrees of hydronephrosis usally
regress spontaneously. Pelviureteric junction obstruction
is confirmed on DTPA renogram with frusemide
washout. Conservative management is carried out
initially. If there is progression of hydronephrosis with
fall in renal function, surgery is considered.
Posterior urethral valves (PUV) are the most
important cause of distal urinary tract obstruction and
present with dribbling of urine, distended bladder and
recurrent UTI. Occasionally, PUV may present with fetal
hydronephrosis of bilateral nature. The diagnosis is
confirmed by a MCU. Treatment involves resection of
the valves, which is done endoscopically.
Developmental Abnormalities
Presence of any of the clinical features listed in Table
14.4.2 either singly or in combination should lead to the
suspicion of renal anomalies.
TABLE 14.4.2: Clinical features suggestive of
renal anomalies
• Single umbilical artery
• Low set or malformed ears
• Chromosomal disorders (Trisomy 13 and 18)
• Tuberous sclerosis
• Abent abdominal muscles (prune belly syndrome)
• Myelomeningocele, sacral anomalies
• Imperforate anus or genital anomalies
• Aniridia (Wilms tumor)
• Fetal compression syndrome, Potter facies, pulmonary
hypoplasia, oligohydramnios (renal agenesis)
• Family history of renal disease (Alport syndrome, polycystic
kidney disease)
Renal Agenesis
Renal agenesis is the congential absence of identifiable
renal tissue. It may be unilateral or bilateral. Unilateral
renal agenesis is mostly detected incidentally. Bilateral
renal agenesis is a lethal disorder manifesting with
features of Potter syndrome characterized by oligohydra-
mnios, pulmonary hypoplasia, low set ears, receding
chin, and malformed limbs, club feet and dislocated hip
joints.
Renal Hypoplasia and Dysplasia
The hypoplastic kidney is normal in shape and structure
but small in size with reduced number of nephrons and
no dysplastic elements. USG will show normal cortico-
medullary differentiation. The dysplastic kidney is small
Diseases of Kidney and Urinary Tract 723
with primitive tubules and immature glomeruli.
Mesenchymal and cartilaginous tissues are also present.
It may be unilateral or bilateral, and is associated with
obstructive or developmental anomalies of urinary tract.
Patients with severe bilateral dysplastic kidneys may
have features of Potter syndrome and end stage renal
disease sets in early in these cases.
Renal Ectopia and Fusion
Developmental interference with normal ascent and
rotation of the kidneys results in ectopia, malrotation and
fusion. Pelvic kidneys and horseshoe kidneys may be
associated with abnormalities of ureter and renal
vasculature. Various anomalies are often asymptomatic
but careful evaluation for other anomalies and long-term
observations are essential. During ascent into the
abdominal cavity the two kidneys come very near each
other and can fuse occasionally fuse together and the
common form of fusion is horseshoe kidney.
Multicystic Dysplastic Kidneys
A multicystic kidney is a non-functioning, large renal
mass consisting of cysts of varying sizes, which do not
communicate with each other. It is a common cause of
an abdominal mass in the neonate. The kidney tends to
involute and shrink. Surgical removal is rarely necessary.
Polycystic Kidneys
Polycystic kidneys may be inherited as autosomal
recessive or dominant. The severe form is the autosomal
recessive or dominant. The severe form is the autosomal
recessive type in which kidneys are large and palpable.
Renal failure may develop in the first few months of life.
Hepatic fibrosis is a constant associated feature.
Autosomal dominant polycystic kidney disease
(ADPKD) most often presents in the older age group,
but can occasionally be detected in children. Charac-
teristic features include enlarged palpable kidneys,
hematuria, hypertension, urinary tract infection and
calculus formation. Genetic loci for the defect have been
identified on chromosomes 16 and 4. Ultrasound
examination of the parents and siblings should be done.
These children should undergo ECHO evaluation to rule
out mitral valve prolapse syndrome, which is increas-
ingly diagnosed in them. The chances of chronic renal
failure occurring in them should be stressed to the parents
very clearly and early.
724 IAP Textbook of Pediatrics
Other Anomalies
Multiple and aberrant renal arteries are very common
and renal arteriovenous malformation is a rare cause for
hematuria and hypertension. Retrocaval position of
ureter can be noted in few. Ureteral diverticulum and
ureterocele can be documented in few children on
evaluation of UTI and can cause obstruction if it is large.
Ectopic ureters and megacystic-megaureter syndrome
are some of the anomalies seen with ureter and bladder.
14.5 Acute Proliferative Glomerulonephritis
Acute proliferative glomerulonephritis (APGN) is
essentially a histological description denoting a clinical
condition termed as acute nephritic syndrome (ANS). It
is a glomerular injury due to wide spectrum of infectious
agents with glomerular inflammation. APGN is
histologically characterized by diffuse proliferation (all
most all the glomeruli) of all the cell components of the
glomerulus namely endothelial cells, mesangial cells and
minimally epithelial cells; accompanied by invasion of
inflammatory cells into the glomerulus. ANS is clinically
characterized by acute onset of hematuria (micro or
macro) oliguria, edema, proteinuria, arterial hyper-
tension and uncommonly azotemia. It includes a number
of clinical conditions (Table 14.5.1).
Among all causes of ANS, the most frequent is the
postinfectious glomerulonephritis (PIGN). Among the
causes of PIGN, the commonest type is poststreptococcal
glomerulonephritis (PSGN) (Table 14.5.2). PSGN is a
prototype of APGN or ANS and hence discussed in this
chapter. In ANS other than PIGN, the glomerular
proliferation is often focal or segmental and infrequently
diffuse proliferation as in SLE, but even here infiltration
with inflammatory cells is minimal or absent.
Definition
PSGN is characterized by rapid onset of hematuria,
oliguria, edema, proteinuria with or without hyper-
tension. There is often preceding pharyngitis or
pyoderma as a common antecedent infection due to
group A-β hemolytic streptococcus with a latent period.
Pelviureteric junction obstruction and posterior urethral
valves are other anomalies seen in children.
BIBLIOGRAPHY
1. Nammalwar BR, Vijayakumar M. Genetic and develop-
mental renal disease. In: Vijayakumar M, Nammalwar BR,
(Eds): Principles and Practice of Pediatric Nephrology, 1st
Edn, Jaypee Brothers, New Delhi 2004; 424-35.
2. Srivastava RN, Bagga A. Developmental abnormalities.
In: Srivastava RN, Bagga A, (Eds): Pediatric Nephrology,
3rd Edn, Jaypee Brothers, New Delhi 2005;70-80.
BR Nammalwar, T Vasanthi, M Vijayakumar
TABLE 14.5.1: Causes of acute glomerulonephritis
Postinfectious glome- Poststreptococcal glomerulo-
rulonephritis (PIGN) nephritis (PSGN)
Shunt nephritis
Infective endocarditis
Other systemic infections
Systemic vasculitis Henoch Schonlein Purpura (HSP)
Systemic lupus erythematosis (SLE)
Wegener’s granulomatosis (WG)
Polyarteritis nodosa (PAN)
Primary glomerular IgA nephropathy
disease Membranoproliferative glomerulo-
nephritis (MPGN)
Rapidly progressive glomerulonephritis
(RPGN)
Focal segmental glomerulosclerosis
(FSGS)
Familial diseases Alport syndrome
Familial glomerulopathy
Epidemiology
The disease is seen all around the world, but more so in
the tropics secondary to poor hygiene, hot climate and
high humidity. PSGN account for 21% of children
admitted in hospital for acute renal failure in developing
countries. It is endemic in nature but can occur in
epidemic due to intimate contact, overcrowded living
condition and poor sanitation. PSGN is essentially a
disease of preschool and early school age children, rarely
it occurs in children less than 2 years. Recurrence is
uncommon in postpharyngeal infection but may rarely
 Diseases of Kidney and Urinary Tract 725

TABLE 14.5.2: Common infections causing PIGN the inflammatory process resulting in damage to the
glomerular basement membrane and the adjoining
Bacteria Group A-β hemolytic Streptococcus
Streptococcus viridans
cell components.
Streptococcus pneumonia • ‘In situ’ immune complex formation between
Staphylococcus aureus antistreptococcal antibodies and glomerular planted
Salmonella antigens.
Leptospirosis • Molecular mimicry between streptococcal and renal
Viruses Varicella antigen; the normal glomerular tissue acting as auto
Mumps
antigen reacts with the circulating antibody formed
Hepatitis B and C
Cytomegalo virus
against streptococcal antigen.
Ebstein Barr virus • Direct complement activation by streptococcal
Measles antigens deposited in glomeruli.
Echo virus • The autologous IgG becomes autoimmunogenic after
Coxsackie virus being desialysed by streptococcal neuraminidase.
HIV virus
• Cellular immune mechanisms have also been impli-
Parasites Toxoplasma
cated. Macrophages and T-cells were shown to
Plasmodium malariae
Rickettsia
infiltrate the glomeruli. Infiltration of mononuclear
Filariasis cells may be promoted by chemotactic factors of the
Schistosoma mansoni complement system, over expression of the intra-
cellular adhesion molecule-1, and lymphocyte
function-association antigen-1, increased circulating
occur in postpyoderma. The strains of Group A-β levels of IL-6, IL-8, tumor necrosis factor-α, and
hemolytic streptococci associated with APGN are monocyte chemotactic protein-1.
Rebecca Lancefield’s M-types 1,2,4,12,18 and 25 in
pharyngitis and 49, 55, 57 and 60 in pyoderma. These Streptococcal Nephritogenic Antigen
are known as nephritogenic strains. A lipoproteinase that
• In addition to ‘M’ antigen, other antigens related to
makes serum opaque (opacity factor) has been used to streptococcal cell cytoplasm such as endostreptosin,
subdivide M proteins into class I (opacity factor negative)
nephritis-associated streptococcal plasmin receptor,
corresponding to serotypes that cause rheumatic fever
(NAPLr), streptococcal histone-like proteins, cationic
and class II (opacity factor positive) that corresponds to cystenine proteinase-SpeB and its precursor zSpeB
serotypes that cause pyoderma and acute glomerulo-
are antigens against which antibodies are raised
nephritis. In recent years, streptococcus zooepidemicus
which mediate glomerular injury. Streptokinase has
(group C) has been responsible for an epidemic of PSGN. been removed from the list of candidate nephro-
togenic antigens in PSGN.
Pathogenesis
• Certain host factors must play a major and decisive
The symptomatology of PSGN is due to glomerular role in determining who gets post-streptococcal
injury. The exact mechanism is not clear. The most nephritis. ‘Constitutional differences’ among families
accepted mechanism of glomerular injury is immune were assumed to be responsible for a familial
complex mediated but the nephrotogenic antigen is still predisposition.
not definite. Recent evidence has demonstrated that M
protein is not the decisive factor in streptococcal Pathology
nephritogenicity.
It is essentially a diffuse and generalized proliferation of
all cell components of the glomeruli with invasion of
Mechanism of Injury
inflammatory cells (Figs 14.5.1 and 14.5.2). Rarely there
• Trapping of the circulating streptococcal M antigen are epithelial crescents. In PSGN epithelial cell prolife-
with antibody to the antigen in the glomeruli followed ration is minimal or moderate. Most cases exhibit one or
by deposition of complement and the triggering of two layers of hyperplastic parietal epithelial cells focally.
726 IAP Textbook of Pediatrics
Figure 14.5.1: Normal glomeruli. Glomeruli are well spaced
out (blue arrow); Capillary loops are clearly visible with (green
arrow) normal masangium
Figure 14.5.2: Light microscopy showing diffuse proliferative
glomerulonephritis [Glomeruli appears crowded and there is
(green arrow) proliferation of endothelial cells, increase in cells
of (blue arrow) mesangium with mesangial hypercellularity]
Well-formed crescents are seen in a significant proportion
of the glomeruli in a smaller number of pediatric cases.
In this situation, the outcome is less favorable. The
cellular infiltration consists of polymorphs, eosinophils,
T.lymphocytes and macrophages. Immunofluorescent
studies show finely granular staining for IgG, IgM, C4,
C3, C1q, fibrinogen and factor B, along the capillary loops
and within the mesangium. Three types of immune
deposits are described. Stary sky is a fine granular
deposition of C3 and IgG along the capillary walls.
Mesangial pattern is due to deposition of C3 in the
mesangial cells. The garland type is characterized by
dense deposit along the capillary walls. Electron
microscopic studies show subepithelial lumpy bumpy
electron dense deposits in the capillary wall on the sub-
epithelial side of the glomerular basement membrane.
These deposits disappear by about 6 weeks after the onset
of the disease.
Pathophysiology
The diffuse proliferation of the glomeruli leads to
obliteration of the capillary lumen and hence decreased
GFR. In the presence of decreased filtrate, preserved
tubular function and enhanced absorption of fluid with
solute in the distal and collecting tubule, there is
decreased urine production resulting in oliguria. The
decreased filtration leads to retention of fluid and solutes
resulting in increased vascular and interstitial volume
leading to hypertension, azotemia and its associated
complications.
Clinical Manifestations
Typical manifestations consist of preceding streptococcal
infection of throat or skin followed by a latent period of
10-14 days after pharyngitis or 2-3 weeks after pyoderma,
early morning periorbital edema, hematuria with rapid
onset of generalized edema and hypertension. Hematuria
can be gross in about 30% of children while microscopic
hematuria is present in all. Edema is due to retention of
salt and water. Hypertension is the low renin type due to
retention of water and salt which leads to expansion of
the extracellular fluid volume with suppression of the
rennin angiotensin aldosterone axis. Hypertension can
present as headache and drowsiness followed by seizures.
Children can present with orthopnea, tachypnea,
tachycardia and distended jugular vessels and rarely as
cardiac failure. Uncommonly some may present as
isolated hematuria, isolated hypertension with minimal
urine findings and nephrotic syndrome with microscopic
or macroscopic hematuria and rarely as rapidly pro-
gressive renal failure known as RPGN. The urine is dark
reddish brown in color and is described as coco-cola color
or gingili oil colour. Rarely urine may be clear on passing
but becomes reddish brown in color on standing after a
few hours.

Differential Diagnosis
Clinical conditions resembling PSGN are few. Features
like absence of preceding infection, decreased latent
period, recurrence, insidious onset, systemic manifesta-
tions such as fever, rash, arthralgia, organomegaly and
family history of renal disease will rule out PSGN. The
presence of nephrotic proteinuria, renal failure,
macroscopic hematuria or hypertension for more than 4
weeks are unlikely in PSGN. D-negative HUS, IgA
nephropathy and MPGN are three clinical conditions in
children that closely resemble PSGN. MPGN is suspected
when there is recurrence of nephritic features with severe
proteinuria and persistently low serum complement level
even after 6 weeks of the disease. HUS is recognized by
thrombocytopenia, anemia with elevated LDH and
serum bilirubin levels.
Laboratory Findings
• Urine analysis: Proteinuria, mild to moderate is
observed. Massive proteinuria is uncommon.
Presence of dysmorphic or crenated RBCs and RBC
casts are diagnostic. WBCs, hyaline casts and granular
casts are present. Minimal urine findings may be
present in children with severe clinical features.
• Renal function tests: Blood urea, creatinine levels are
usually normal, they may be elevated. Free water
excretion is impaired, leading to hyponatremia.
Decreased GFR and indiscriminate intake of pota-
ssium rich food can cause hyperkalemia. Serum total
proteins can be elevated due to increased gamma
globulins. Serum cholesterol levels are normal.
• Serology: ASO titres will be high in pharyngitis and
can be normal in pyoderma. Use of streptozyme test,
which measures anti-hyaluronidase, ASO titre, anti-
deoxyribonuclease-B, anti-nicotinamide and adenine
dinucleotidase has higher sensitivity particularly in
postpyoderma states. In the future, the etiological
diagnosis of children with ANS due to nephritogenic
streptococcal infection will depend on the demonstra-
tion of rising antibody titres to SpeB/zSpeB or NAPLr
antigens.
• Total hemolytic component, C4 and C3 are low. LE
cells, antinuclear antibody, antinuclear cytoplasmic
antibodies studies are indicated when there are
associated systemic features.
• Low hemoglobin is due to dilution. Occasionally
thrombocytopeia and coagulation abnormalities can
Diseases of Kidney and Urinary Tract 727
be identified.
• Chest skiagram shows pleural fluid and mild
cardiomegaly due to pericardial effusion. Gross
cardiomegaly can be seen with severe volume
overload and is an impending sign of cardiac failure.
Consolidation can be seen in streptococcal pneu-
monia. Presence of pulmonary infiltrates should
suggest systemic vasculitis.
• USG abdomen shows bilaterally enlarged kidneys
with mild parenchymal changes and rarely loss of
corticomedulary differentiation. Free fluid in the
abdomen and pleural fluid are other common
findings.
· Renal biopsy is indicated when any of the above
criteria for PSGN are not met with or when nephrotic
syndrome accompanies acute nephritic syndrome or
in persistent or progressive renal failure.
Treatment
• Children with moderate edema, anuria or oliguria,
hypertension, or moderate renal failure need
hospitalization.
• Bed rest is indicated in the above conditions to
encourage venous return, increased stimulation of
atrial natriuretic hormone and to increase urine
output.
• Fluid intake in the first 24 hours is restricted to
insensible water loss. Subsequently the input is
regulated by urine output added to insensible water
loss.
• Restriction on salt intake is advocated in the presence
of edema, hypertension and renal failure and is
limited to no added salt to the diet during cooking.
• With onset of diuresis to more than 1 ml/kg/hr and
control of hypertension, salt can be gradually
increased by 1 gm every third day and fluid intake
modified to match the urine output.
• Protein is restricted to 0.6-1.0 gm/kg/day in the
presence of renal failure.
• Hypertension should be treated promptly with
parenteral furosemide, calcium channel blockers,
ACE inhibitors or hydralazine. Use of ACE inhibitors
in the presence of renal failure needs monitoring of
serum potassium.
• Volume overload sufficient to produce cardiac failure
can be treated with salt and fluid restriction and IV
furosemide.
728 IAP Textbook of Pediatrics
• Hyponatremia and hyperkalemia should be treated
with restriction of fluid intake and food containing
high potassium. Use of calcium resin salts is helpful
in the presence of fluid overload, wherein sodium
resin salts can worsen hypertension and fluid
retention.
• Antibiotics are indicated in the presence of infection
as infection can prolong the activity of disease and
spread of nephritogenic strains. Ampicillin /
amoxycillin is a good choice.
• Immunosuppressive: There is no clear evidence of
beneficial effects except in RPGN. Pulse methyl
prednisolone 0.5-1.0 g/1.73 m 2 for 3 or 5 days
followed by oral prednisolone has been reported to
have beneficial effect. Use of IV cyclophosphamide
in addition has also been reported.
Complications
• Hypertensive encephalopathy is a consequence of
failure to monitor blood pressure at regular interval
or inadequate treatment. BP monitoring at frequent
intervals is the best way to prevent hypertension.
Control of seizures is followed by use of intravenous
furosemide, salt and fluid restriction. Sublingual/oral
nifedipine (0.25-0.5 mg/kg/dose) can bring down
blood pressure fairly rapidly. It can be repeated on 2
occasions at about 30 minutes intervals. Serious side
effects have been reported in adults hence it should
be administered in children with caution. Fortunately
since hypertension in these children is acute in onset
and cerebral vessels are healthy, cerebrovascular
accidents are unlikely. For hypertensive emergency
in a hospital setting, IV nitroprusside (0.5-2.0 mcg/
kg/min) or IV labetalol (0.5-1.0 mg/kg/hr) in
addition to IV furosemide is recommended.
• Pulmonary edema can at best be managed with
intravenous furosemide at a dose of 2-3 mg/kg given
as slow IV pushes at the rate of 4 mg/mt. This can
avoid the uncomfortable burning sensation in the
body or hypotension.
• Renal failure of mild to moderate degree can be
managed conservatively.
• Dialysis is indicated in the presence of severe
hyperkalemia, acidosis, pulmonary edema, uncon-
trollable hypertension and progressive renal failure.
Peritoneal dialysis is simplest and easily available
method. Other renal replacement therapy such as
continuous renal replacement therapy, slow ultra-
filtration and hemodilaysis are alternate choice.
Prognosis
Spontaneous improvement usually begins in a week’s
time with diuresis followed by loss of edema and
improvement in blood pressure. The total duration of
illness rarely exceeds 4 weeks. Often recurrence of
hematuria occurs associated with URI, a week or two
after resolution of disease and does not require any
intervention. Typically serum complement returns to
normal at about 8 weeks. Proteinuria subsides usually
by about six months and microscopic hematuria may
persists upto one year. Some children with PSGN
develop RPGN and minor sequelae, which may not
become apparent for several years and progress into
chronic renal failure. Some children with systemic
vasculitis can present with isolated renal disease.
Therefore it is in the best interest of children that they be
followed serially for many years for at least a period of
2-5 years.
BIBLIOGRAPHY
1. Endre Sul Yok. Acute proliferative glomerulonephritis.
In: Ellis D Avner, William E Harmone, Patrick Niaudet,
(Eds): Pediatric Nephrology, 5th Edn, Lippincott
Williams and Willkins, Philadelphia 2004;601-13.
2. Mikhael R, Postlethwaite R. Postinfectious glomerulo-
nephritis. In: Chochat P, et al (Eds): ESPN Handbook,
European Society for Pediatric Nephrology 2002;268-74.
3. Rodriguez-Iturbe B, Batsford S. Pathogenesis of post-
reptococcal glomerulonephritis a century after Clemens
von Pirquet. Kidney Int 2007;17:1094-1104.
4. Tasic V. Postinfectious glonerulonephritis. In: Geary DF,
Schaefer F, (Eds): Comprehensive Pediatric Nephrology.
1st Edn, Mosby Elsevier: Philadelphia 2008;309-17.
5. Vijaykumar M, Nammalwar BR. Acute proliferative
glomerulonephritis and crescentic glomerulonephritis.
In: Nammalwar BR, Vijayakumar M (Eds): Principles and
Practice of Pediatric Nephrology. Jaypee Brothers: New
Delhi 2004;167-78.

14.6 Renal Vasculitis
Vasculitis is defined as inflammation of the blood vessels.
The blood vessels involved vary from small vessels like
capillaries to large vessels like aorta. The vessels show
partial or completely obliteration which is often
immunologically mediated or sometimes due to non-
immunological causes like atherosclerosis and throm-
botic obliteration. Symptoms vary depending upon the
type of vessel and the organ system that is involved.
Kidney being a vascular organ is consequently involved
in these disorders as a part of the multiorgan involve-
ment. Renal involvement includes inflammation and
necrosis of the blood vessels, proliferation of the
glomerular cell components, deposition of immunoglo-
bulins and interstitial tissue damage, leading to
malfunction of the kidneys and renal failure. They
commonly present as severe hypertension, chronic
glomerulonephritis, proteinuria and/or hematuria. They
can be classified based on the size of the blood vessel
involved. Hitherto, there has been, with certain
exceptions much reliance on adult classification systems
and criteria that have not proved entirely satisfactory. A
recent International Consensus Conference held at
Vienna in June 2005 proposed an acceptable classification
of childhood vasculitis as well as criteria for classifying
specific subcategories of vasculitic disease affecting the
young (Table 14.6.1 and Fig. 14.6.1).
TAKASAYU ARTERITIS (TA)
Definition
It is a segmental inflammatory vasculitis of unknown
cause that usually begins in the subclavian vessels and
progressively involves the carotids, aorta and renal
arteries and rarely pulmonary vessels (Fig. 14.6.2). It is
known as a pulseless disease, owing to its involvement
of the aortic arch and subclavian vessel, resulting in
reduced blood flow in brachial artery and hence absence
of pulse or poor pulse volume.
Epidemiology
This disease is more common among girls with a female
to male ratio of 9:1. It commonly affects children between
10-20 years.
Diseases of Kidney and Urinary Tract 729
BR Nammalwar, N Prahlad
TABLE 14.6.1: Classification of childhood vasculitis based
on the size of the blood vessels involved
A. Predominantly large vessel vasculitis
Takayasu’s arteritis
B. Predominantly medium-sized vessel vasculitis
Juvenile polyarteritis nodosa
Cutaneous polyarteritis
Kawasaki disease
C. Predominantly small vessel vasculitis
a. Granulomatous
Wegner’s granulomatosis
Churg Strauss disease
b. Non-granulomatous
Microscopic polyangitis
Henoch Scholein purpura
Isolated cutaneous leukocytoclastic vasculitis
Hypocomplementemic urticarial vasculitis
D. Other vasculitis
Behcet’s disease
Vasculitis secondary to infection (including hepatitis
B-associated PAN), malignancy and drugs including hyper-
sensitivity vasculitis
Isolated vasculitis of the CNS
Cogan’s syndrome
Unclassified
Pathology
All three layers of the large vessels and its branches show
mononuclear cell inflammation with variable admixture
of multinucleated giant cells. Focal destruction of the wall
leads to aneurysm formation and occasionally even
rupture. More commonly there is fibrosis of the wall with
narrowing of the vascular lumen with parenchymal
atrophy. Glomerulonephritis is seen occasionally.
Clinical Manifestation
Fifty percent of children present commonly with
hypertension or symptoms of end organ effect due to
hypertension, namely cardiac failure, headache,
dizziness, visual disturbance and seizures. They also
present with asymmetric pulse, bruit over the subclavian,
brachial and abdominal vessels. There are two phases of
the disease. The prepulseless phase is characterized by
nonspecific symptoms like fever, malaise, headache,
730 IAP Textbook of Pediatrics
Figure 14.6.1: Classification of vasculitis based on the size of the blood vessels
Figure 14.6.2: Abdominal aortogram showing area of dilatation
(black arrow) and narrowing (red arrow) in Takayasu arteritis
(Courtesy: Prof. V Tamilarasi)
myalgia, arthralgia and weight loss. As arterial
involvement advances, symptoms of end organ ischemia
appear and signal the start of the pulseless phase. Child
presents with hypertension and end organ dysfunction
like hypertensive encephalopathy and congestive cardiac
failure. The hypertension is secondary to coarctation of
aorta and not due to renal involvement. Due to
compromised arterial blood flow to the brain, children
may present with dizziness, headache, syncope and
stroke. Dermatological manifestations like erythema
nodosum and pyoderma gangrenosum are seen.
Secondary to pulmonary artery involvement, children
may present with hemoptysis, shortness of breath and
pulmonary hypertension. Few can present as angina,
which is due to aortic or coronary arteritis. Any one
criteria listed in the Table 14.6.2 in addition to the
angiographic abnormalities is diagnostic of TA.
TABLE 14.6.2: Diagnostic criteria for Takayasu arteritis
• Decreased peripheral artery pulse(s) and / or claudication of
extremities
• A blood pressure difference of >10 mmHg
• Bruits over the aorta and / or its major branches
• Hypertension
• Presence of angiographic abnormalities of the aorta or its major
branches by conventional, CT or MR (a mandatory criteria)
Laboratory Findings
There may be widening and calcification of aorta on plain
abdominal radiograph. Angiography, demonstrating
narrowing or occlusion with or without aneurysms of the
major arteries makes the diagnosis of TA. Doppler
ultrasound and MRI are other techniques, which have a
role. Digital subtraction angiography has allowed
diagnosis to be made with less contrast. It is classically

anti-nuclear antibody (ANA) and anti- neutrophil
cytoplasmic antibody (ANCA) negative disease. It is
characterized by elevated acute phase reactants like ESR
and CRP and is associated with anemia. Often a positive
mantoux reaction is observed in these children suggesting
a distant possibility of tuberculous etiology. This disease
should be considered in children presenting with
hypertension associated with fever and elevated ESR.
Treatment and Outcome
Therapy with steroids is the first line of treatment. In
situations wherein the child is resistant to steroids,
combination of steroids with cyclophosphamide or
methotrexate has been tried. The combination of steroids
and methotrexate has shown to result in higher remission
rate and the need for lower maintenance dose of steroids.
Reconstructive surgery and percutaneous transluminal
angioplasty used for treating stenosis of the descending
thoracic and or abdominal aorta have been found
moderately successful. Hypertension in children is well
controlled with β blockers, diuretics and vasodilators.
ACE inhibitors have to be used with caution as it can
precipitate renal failure. The long-term prognosis of TA
is generally good but ultimately most of them progress
into severe renal failure or die as a consequence of
uncontrollable hypertension.
JUVENILE POLYARTERITIS NODOSA (PAN)
Definition
Earlier PAN was classified as classical PAN (c PAN),
which was a necrotising vasculitis with aneurysmal
nodules along the walls of medium sized and small sized
muscular vessels like the coronary, hepatic, mesenteric and
renal arteries, without involvement of arterioles, capillaries
and venules, and as microscopic polyarteritis or
polyangitis which involved arterioles, capillaries or
venules. It also defined as PAN where ANCA is negative
and microscopic polyangitis (MPA) where ANCA is
positive. However, in childhood, PAN may also have small
vessel involvement. Hence, it should be classified as
juvenile PAN. Recently new criteria for the classification
of juvenile PAN has been developed (Table 14.6.3).
Epidemiology
PAN is seen in children between 3-16 years with a
median age of 9-10 years. It commonly affects males with
a preponderance of 2.5:1.
Diseases of Kidney and Urinary Tract 731
TABLE 14.6.3: Classification criteria for juvenile
polyarteritis nodosa
A systemic illness characterized by the presence of at least 2 of
the following 7 criteria:
1. Skin involvement (livedo reticularis, tender subcutaneous
modules, other vasculitic lesions)
2. Myalgia or muscle tenderness
3. Systemic hypertension, relative to childhood normative data
4. Mononeuropathy or polyneuropathy
5. Abnormal urinalysis and/or impaired renal function
6. Testicular pain or tenderness
7. Signs or symptoms suggesting vasculitis of any other major
organ system (gastrointestinal, cardiac, pulmonary or central
nervous)
In the presence of (one of the below as a mandatory criteria)
Biopsy showing small and mid-size artery necrotizing vasculitis
Or antiographic abnormalities (aneurysms or occlusions) or
angiographic
From Ozen S, Ruperto N, Dillon MJ, Bagga A et al. EULAR/PRES
endorsed consensus criteria for the classification of childhood
vasculitis. Ann Rheum Dis 65: 936-941, 2006.
Etiopathogenesis
An immune complex mediated mechanism has been
postulated as an initiating factor for the vasculitis.
Another view proposed is the formation of autoantibody
to the vascular endothelium. Similar changes have been
observed with drugs like penicillin, sulfonamide and
amphetamine administration. PAN is also associated
with hepatitis B infection wherein antigen antibody
immune complexes are seen in the walls of the blood
vessels.
Pathology
In the kidney, PAN affects the medium sized muscular
arteries while MPA involves smaller arteries and
arterioles. Renal biopsy of PAN shows necrotising
vasculitis without crescentric or necrotising glomerulo-
nephritis, which differentiate it from MPA wherein there
is evidence of crescentric or necrotising glomerulo-
nephritis.
Clinical Features
PAN is a multisystem disease that has varied presen-
tation. They normally present with fever, weight loss,
weakness, testicular pain, ischemic heart symptoms,
arthalgia and myalgia. PAN can present with cutaneous
features like livedo reticularis or inflammatory nodules
with or without gangrene (Figs 14.6.3 and 14.6.4).
Renovascular hypertension is seen in 1/3 of the affected
732 IAP Textbook of Pediatrics
Figure 14.6.3: Gangrene of fingers in polyarteritis nodosa
Figure 14.6.4: Child with severe arthritis and healing
gangrene in polyarteritis nodosa
children. Renal failure may be seen on presentation or
during the course of the disease. Abdominal pain and
hematochezia signify bowel involvement. It may also
present as peripheral neuropathy or organic psychosis.
Rarely, renal symptoms may be in the form of isolated
proteinuria, nephritic or nephrotic syndrome or renal
failure.
Laboratory Findings
Investigations reveal anemia, polymorphonuclear
leucocytosis, thrombocytosis and elevated ESR and
C-reactive protein positivity. ANCA is detected with both
cytoplasmic and perinuclear patterns. The most valuable
procedure is renal and hepatic angiography, which
shows multiple aneurysms. High-resolution selective
angiography is required to detect small peripheral
aneurysm. Reliable non-aneurysmal signs are perfusion
defect, presence of collateral artery, lack of crossing of
peripheral renal arteries and delayed emptying of small
renal arteries. In the kidney, the interlobar and arcuate
arteries are mainly involved, with rare involvement of
renal arteries. Vasculitis can be confirmed by a biopsy of
the skin, sural nerve, testis or skeletal muscles. Renal
biopsy reveals necrotising vasculitis without evidence
of cresentic or necrotising glomerulonephritis.
Treatment and Outcome
Treatment consists of oral steroids with IV cyclophos-
phamide. Antiplatelet adhesive agents, plasma exchange
and high dose IV immunoglobulins have been tried.
Azathioprine, cyclosporine or mycophenolate mofetil are
useful in maintaining remission. Children with nephrotic
proteinuria, renal insufficiency, cardiomyopathy, and
CNS or GIT involvement have bad prognosis. The
mortality is around 10%, which is mostly due to severe
infections or chronic renal failure.
Cutaneous Polyarteritis
Cutaneous polyarteritis is characterized by the presence
of subcutaneous nodules, painful non-purpuric lesions
with or without livedo reticularis, myalgia, arthralgia and
non-erosive arthritis. Skin biopsy shows necrotizing, non-
granulomatous vasculitis, ANCA tests are negative and
there is often an association with serologic and
microbiologic evidence of streptococcal infection.
Kawasaki Disease (KD)
Kawasaki disease is a systemic childhood vasculitis
characterized by persistent fever of at least 5 days
(mandatory criterion) plus four of the following five
being present: changes in the peripheral extremities or
perianal area, polymorphous exanthem, bilateral
conjuctival congestion, changes in the lips and oral cavity
and/or inflammation of the oral and pharyngeal mucosa
and cervical lymphadenopathy. In the presence of
coronary artery involvement detected on echocardio-
graphy and fever, fewer than four of the five remaining
criteria are considered sufficient. It is a systemic medium
vessel vasculitis. KD is believed to have an infective basis
and may be super antigenic induced. Renal involvement
is characterized by involvement of interlobar arteries and
can present a few months after an episode of Kawasaki

disease as hypertension. They can present as acute renal
failure secondary to interstitial nephritis. Uncommonly
hematuria, proteinuria and pyuria have been reported.
Ultrasonogram has shown nephromegaly, echogenic
kidneys with increased corticomedullary differentiation.
Laboratory investigations will show polymorpho-
nuclear leucocytosis and thrombocytosis. Treatment
involves aspirin, high dose IV immunoglobulins and
antiplatelet adhesive therapy with aspirin given for 2-3
months. Steroids have been tried when no response to
the above treatment is noted.
HENOCH SCHONLEIN PURPURA (HSP)
Definition
HSP is a benign systemic vasculitis which involves small
vessels. It involves multiple organ systems and is
characterized by crops of purpura on the buttock and
lower limbs accompanied by gastrointestinal tract, joints
and renal symptoms (Figs 14.6.5 and 14.6.6). In 1994
Consensus Conference on Nomenclature of Systemic
Vasculitis, defined HSP as a small vessel vasculitis
involving capillaries, arterioles and venules with IgA-
dominant immune deposits typically involving skin, gut
and glomeruli and associated with arthralgia or arthritis.
Recently the European League Against Rheumatism
(EULAR) and the Pediatric Rheumatology Society has
proposed a classification for HSP. Diagnosis of HSP
Figure 14.6.5: Palpable purpuric rash
involving lower limb in HSP
Diseases of Kidney and Urinary Tract 733
Figure 14.6.6: Purpuric rashes involving
the genetalia in HSP
requires at least one of the following four should be
present: diffuse abdominal pain, any biopsy showing
predominant IgA deposition, arthritis or arthralgia and
renal involvement (any hematuria and/or proteinuria)
in the presence of palpable purpura which is a mandatory
criterion.
Epidemiology
It is the most frequent vasculitis seen in children. It
commonly affects males, frequently in the first decade
of life. The median age of presentation is 4-5 years and
the mean age of renal involvement is 6-10 years.
Pathogenesis
The pathogenesis of HSP is believed to be an immune
complex-mediated disease characterized by the presence
of polymeric IgA 1 containing immune complexes in the
dermal, gastrointestinal and glomerulocapillaries. IgA is
the predominant immunoglobulin in secretions acting as
a defence against viral and bacterial agents. HSP and IgA
nephropathy are triggered by respiratory infection.
Though HSP is preceded by a respiratory infection, there
is no clear evidence for a pathogenic role of Group-A
streptococcus. A variety of other infections and food
allergens have been implicated. The principal problem is
persistent depositions of IgA in the mesangium. Various
theories for the IgA deposition are: (1) Immune response
secondary to a specific antigen as evidenced by the
734 IAP Textbook of Pediatrics
presence of IgA immune deposits within the glomeruli,
(2) Affinity of circulating IgA to various molecules like
glycoprotein in the kidney to cause its accumulation and
hence renal involvement, (3) Abnormal glycosylation of
IgA leading to high tendency for self-aggregation and
formation of macromolecules which escape clearance by
hepatic receptors and accumulate in the mesangium of
the kidney. This abnormal accumulation along with
defective catabolism of this abnormal IgA from the
mesangium leads to persistent depositions of IgA in the
mesangium. The interaction of this IgA with Fcα receptor
on mesangial cells results in cellular activation, mediator
synthesis and release of variety of cytokines (IL-6, IL-1,
TNF-α and TGF-β), vasoactive factors (PG, thromboxane,
leukotrienes, nitrous oxide and PAF) by the mesangial
cells, thus leading to glomerular damage. This is worsened
by the increased production of IgA by B cells along with
abnormal activity of T suppressor cells. Several reports
have postulated HLA Class II gene polymorphism to be a
risk factor for HSP.
Clinical Manifestation
In about 2/3 of children, the disease is triggered by
infections (streptococcus, yersinia, mycoplasma,
toxoplasma, varicella, measles, rubella, HIV). The acute
illness starts with fever and malaise. The skin lesions
typically begin as red macules to later become utricarial
and purpuric and involve mainly the extensor surface of
limbs, buttocks, back and occasionally face and genitalia.
The purpura always involves the ankle. Subcutaneous
edema may be seen. Gastrointestinal symptoms like
colicky abdominal pain and hematochezia occur due to
bowel hemorrhage, intussusception or perforation .The
arthritis is moderate to severe involves the ankles and
knees and is oligoarticular in nature. Renal involvement
is noted in 35-65% of these children. Hematuria alone or
with mild proteinuria is always present and is transient.
Some have macroscopic hematuria, which is transient,
but recurs with a respiratory infection. 80% have
nephritic syndrome within 4 weeks of onset of rash.
About 2/3 of children with renal involvement have
nephrotic range of proteinuria and nephrotic syndrome.
Hypertension is noted in 25% of the affected children.
Renal insufficiency is usually mild but acute renal failure
can occur. In severe cases, acute nephritic syndrome,
which progresses to nephrotic syndrome and then to
renal failure occurs (Table 14.6.4).
TABLE 14.6.4: Clinical manifestation of HSP
Skin Palpable purpura
GIT Abdominal pain
Vomiting
Hematemesis
Intussusception
Bowel perforation
Intestinal infarction
Joints Ankle and knee, oligoarticular synovitis
Kidney Nephritis.
Microscopic / Macroscopic hematuria
Mild proteinuria
Nephrotic proteinuria
Renal failure
Hypertension
Nephrotic syndrome
Laboratory Findings
The diagnosis of HSP is essentially clinical and by
demonstrating that purpura is not due to thrombo-
cytopenia or defective clotting mechanism. The serum
IgA may be elevated in 50-70 % of HSP. High levels of
IgA-ANCA may also be seen. A skin biopsy is done only
when the diagnosis is in doubt, which typically shows
leukocytoclastic vasculitis with fragmentation of
leukocyte nuclei in and around arterioles, capillaries and
venules, surrounded by infiltrating neutrophils and
monocytes in the presence of nuclear dust in the walls of
the arterioles. Deposits of IgA and C3 are seen in the
dermal capillaries and IgA deposit in the skin is
diagnostic of HSP. Renal biopsy is neither recommended
nor necessary in all cases of HSP except in case of
nephritis with nephrotic range of proteinuria, renal
failure and nephrotic syndrome. Renal biopsy shows
focal and segmental proliferation with necrotic lesions
and crescents. Tubulointerstitial changes parallel the
severity of glomerular injury. Granular mesangial
deposits of IgA are seen in all glomeruli and are
characteristic of HSP nephritis. Electron dense deposits
may be found in a subendothelial paramesangial location
together with fibrin like material. Severity and prognosis
depends on the histological class as explained in Table
14.6.5.
Treatment and Prognosis
The treatment is essentially symptomatic. In mild cases
treatment is with analgesics like paracetamol for pain
and antispasmodics for relief of abdominal pain. It is

TABLE 14.6.5: HSP nephritis pathology classification of
International Study of Kidney Disease in Children
Class I Minimal change
Class II Pure mesangial proliferation without crescents
Class III Mesangial proliferative glomerulonephritis with
< 50% crescents
a. IIIa Focal
b. IIIb Diffuse
Class IV Mesangial proliferative glomerulonephritis with
50-75% crescents
a. IVa Focal
b. IVb Diffuse
Class V Mesangial proliferative glomerulonephritis >75%
crescents
c. Va Focal
d. Vb Diffuse
Class VI Membranoproliferative (mesangiocapillary)
glomerulonephritis
necessary to monitor urine for active sediments in the
first 2-3 months after the appearance of rashes. When
abdominal pain is severe, a small dose of steroids is
useful. Children who present with nephritic syndrome
unassociated with renal failure, hypertension or massive
proteinuria need no active treatment and can be
monitored. When they present as nephritic syndrome
associated with either nephrotic proteinuria or renal
failure, a renal biopsy is warranted. Endocapillary
proliferation and crescents by renal biopsy warrants more
aggressive therapy with IV methylprednisolone and
cyclophosphamide. The outcome of the disease depends
on the severity of renal involvement. The overall risk of
children with HSP nephritis going into ESRD is 2%. With
more severe renal involvement, the risk increases to 25-
30%. Children with group I to IIIa histological findings
have better outcome with return of normal renal
functions or persistent urinary abnormalities. Children
in groups IIIb, IV and V have persistent proteinuria and
hematuria and may progress to ESRD. When compared
to adults the outcome of children with HSP nephritis is
similar. The overall risk of going into ESRD is 27%.
Wegener’s Granulomatosis (WG)
Wegner’s granulomatosis is a necrotising granulomatous
vasculitis of the upper and lower respiratory tract
associated with glomerulonephritis. It is an idiopathic
inflammatory systemic disease with predilection for the
upper and lower respiratory tract and glomerulo-
Diseases of Kidney and Urinary Tract 735
nephritis. The criteria for WG have been defined as the
presence of 3 of the following 6 criteria: abnormal
urinalysis, granulomatous inflammation on biopsy, naso-
sinus inflammation, subglottic, tracheal or endobronchial
stenosis, abnormal chest X-ray or computed tomography
(CT) and PR3 ANCA or cytoplasmic ANCA staining.
Incidence
It is a rare disease of the pediatric age group. The mean
age of presentation is 15.4 years with a range from 9.3 to
19.4 years.
Etiopathogenesis
WG is an exaggerated immune response to inhaled
antigen. No specific exogenous or endogenous antigens
have been identified. The immune complexes may be
formed in situ or circulating immune complexes may be
deposited. Alternatively cell mediated immune mecha-
nism can be the cause of the granulomatous vasculitis.
Clinical Manifestation
Clinical features include those of PAN with unique
features of subglottic stenosis, opaque sinuses, nasal
septum disease and chronic lower respiratory infection
like symptoms. In less than 10% of the children the
kidneys are not involved. Hematuria, proteinuria and
renal insufficiency are common. Gross hematuria and
hypertension are unusual. Pauci immunenecrotizing
glomerulonephritis is the histological feature. Biopsy of
the involved tissue show ANCA positivity with
granulocytic cytoplasmic pattern and the antibody
directed against proteinase 3.
Treatment and Outcome
Treatment is similar to PAN and MAP. Therapy includes
steroids, cyclophosphamide, antiplatelet adhesive
therapy, plasma exchange and antimicrobial therapy
such as with cotrimoxazole. Remission is maintained
with long-term steroids and azathioprine or cyclosporin.
The long-term mortality and morbidity is high.
CHURG STRAUSS SYNDROME (CSS)
This syndrome is a systemic necrotizing vasculitis with
hypereosinophilia and extravascular granulomas usually
occuring in a patient with asthma. It is a paucimmune
736 IAP Textbook of Pediatrics
small vessel vasculitis characterized by preceding history
of asthma, eosinophilia, parenchymal infiltrates asso-
ciated with rhinitis and nasal polyposis. It is a multisystem
disease involving the GI tract, lungs, kidneys, skin and
peripheral nerves. It has been postulated that CSS occurs
in three phases: a prodromal phase, an allergic phase
(asthma and /or allergic rhinitis), an eosonophilic phase
(tissue and peripheral eosinophilia) and a vasculitis phase
(with multi organ involvement). Six criteria have been
developed by the American College of Rheumatology for
the diagnosis of this condition. The criteria include asthma,
eosinophilia (>10% or absolute eosinophil count of >1500),
mononeuropathy or polyneuropathy, histological
evidence of vasculitis, paranasal sinusitis and non-fixed
pulmonary infiltrates. The kidneys are involved after a
period of 2-30 years. It can present as acute renal failure
due to vasculitis, which responds well to steroids, or
obstructive uropathy due to eosinophilic granuloma.
Laboratory investigations reveal eosinophilia, anemia,
elevated WBC counts, positive CRP, elevated ESR and
high serum IgE levels. Proteinuria and hematuria may be
seen. Steroids form the mainstay of treatment given alone
or in combination with cyclophosphamide. Plasma
exchange has been tried but do not offer any advantage
over steroids. Once remission is attained, cyclophos-
phamide is replaced by azathioprine. Relapses are
common within one year of diagnosis.
Microscopic Polyangitis (MPA)
MPA is a small vessel vasculitis affecting arterioles,
capillaries and post-capillary venules. Clinically children
presents with glomerulonephritis, purpura and occa-
sionally pulmonary hemorrhage. It is difficult to
distinguish it from WG and RPGN.
Clinical features
Usually presents with proteinuria, hematuria, hyper-
tension and renal impairment. The presenting features
are more of glomerulonephritis with hypertension while
in PAN it is essentially systemic features and hyper-
tension without evidence of crescentric or necrotising
glomerulonephritis by renal biopsy. Investigations reveal
positive ESR and a high titre of myeloperoxidase ANCA
or positive perinuclear ANCA staining. Renal biopsy is
diagnostically valuable revealing characteristically pauci
immune crescentic necrotizing glomerulonephritis.
Treatment and Prognosis
Treatment is similar to that of PAN utilizing steroids,
cyclophosphamide and antiplatelet adhesive agents.
Plasma exchange has been tried. Long-term alternate day
steroid therapy, azathioprine have been tried for
maintenance. The mortality with ESRD is more than 50%.
A protective effect is seen with cyclophosphamide.
Renal Limited Disease
These are rare situations wherein a child presents with
isolated progressive renal failure with clinical features
of glomerulonephritis. The renal biopsy will show a
crescentic glomerulonephritis with no immune comple-
xes but have a positive ANCA.
BIBLIOGRAPHY
1. Bakkaloglu A, Ozen S. Wegener’s Granulomatosis,
Microscopic polyangitis, and childhood polyarteritis
nodosa. In: Geary DF, Schaefer F (Eds): Comprehence
Pediatric Nephrology. 1st Edn, Mosby Elsevier,
Philadelphia 2008;353-8.
2. Dillon KJ, Sirin A. Systemic vasculitis. In: Chochat P,
et al. (Eds): ESPN Handbook, European Society for
Pediatric Nephrology 2002;291-5.
3. Dillon MJ, Ozen S. A new international classification of
childhood vasculitis. Pediatr Nephrol 2006;21:1219-22.
4. Rudolph P Valentini, William E Smoyer. Renal vasculitis.
In: Ellis D Avner, William E Harmone, Patrick Niaudet
(Eds): Pediatric Nephrology, 5th Edn, Lippincott
Williams and Willkins, Philadelphia 2004;835-63.
5. Vasanthi T, Nammalwar BR, Vijayakumar M. Renal
vasculitis and lupus nephritis. In: Nammalwar BR,
Vijayakumar M (Eds): Principles and Practice of Pediatric
Nephrology, 1st edn, M/s.Jaypee Brothers, New Delhi
2004;216-24.
 Diseases of Kidney and Urinary Tract 737

14.7 Acute Renal Failure

Arvind Bagga, Aditi Sinha

INTRODUCTION urinary tract obstruction and dehydration should be

Acute renal failure (ARF) is characterized by a rapid
deterioration of renal function, resulting in retention of
nitrogenous wastes and biochemical derangements.
Anuria or oliguria (urine volume less than 500 ml/1.73
m2/24 hours; in infants less than 0.5 ml/kg/hr) is the
most prominent feature of ARF. However, in a propor-
tion of patients the urine output may be normal or only
slightly reduced (non-oliguric ARF). An increase in the
blood levels of urea and creatinine suggests the diagno-
sis in such cases. ARF usually occurs in patients with
previously normal renal function, but it occasionally may
be superimposed on preexisting renal disease (acute-on-
chronic renal failure).
A lack of a standard definition of ARF has resulted
in failure to identify the condition early enough to
implement appropriate action. The lack of a definition
also makes it difficult to compare data across the world.
Recently, the term ‘acute kidney injury’ (AKI) has been
proposed to represent the spectrum of acute renal
dysfunction. Criteria for diagnosis and staging of AKI
have been recommended (Table 14.7.1). AKI is consi-
dered to be present when there is an abrupt (within
48 hours) reduction in kidney function, defined as an
absolute increase in serum creatinine of > 0.3 mg/dl or a
percentage increase of creatinine by > 50% or a reduction
in urine output (< 0.5 ml/kg/hr for > 6 hr). The diagnosis
of AKI thus requires that two values of creatinine be
estimated within 48 hours; in cases where the diagnosis
is based on urine output alone, reversible causes like
excluded. Common causes of ARF are listed in Table
14.7.2.
Geographical and Regional Variations
The etiology of ARF varies regionally. In infants, acute
gastroenteritis with severe dehydration used to be the
commonest cause of ARF. Widespread use of oral
rehydration in the management of diarrhea has led to a
marked decline in the incidence of severe dehydration.
For several years, hemolytic uremic syndrome (HUS) was
a leading cause of ARF at most referral centers, but its
incidence has recently declined. Acute glomerulo-
nephritis and acute tubular necrosis (each due to various
underlying causes) are presently the commonest
conditions associated with ARF. In coastal regions of
India, Orissa and in rural areas, snakebite is a major cause
of ARF. In some parts of Kerala, leptospirosis is
frequently encountered. Acute intravascular hemolysis
following exposure to oxidant drugs in G-6-PD deficient
subjects and falciparum malaria, may lead to acute
tubular necrosis. Major surgical proce-dures especially
open heart surgery and road traffic accidents, are other
important causes. Post-renal causes are uncommon in
children.
Pre-renal ARF
In pre-renal type of ARF, the functional integrity of the
kidney is preserved and renal dysfunction is reversible with
restoration of the underlying hemodynamic abnormality.

TABLE 14.7.1 Staging of acute kidney injury*

Stage Serum creatinine criteria Urine output criteria

1 Increase in serum creatinine of >0.3 mg/dl or >150% to 200% Less than 0.5 ml/kg per hour for >6 hr
(1.5- to 2- fold) from baseline
2 Increase in serum creatinine to >200% or 300% (>2- to 3-fold) Less than 0.5 ml/kg per hour for >12 hr
from baseline
3** Increase in serum creatinine to >300% (>3-fold) from baseline Less than 0.3 ml/kg per hour for >24 hr, or
(or serum creatinine of >4.0 mg/dl with acute increase of >0.5 mg/dl) anuria for 12 hr

* Only one criterion (creatinine or urine output) should be fulfilled for definition and staging
**Patients receiving renal replacement therapy (RRT) are considered in stage 3
738 IAP Textbook of Pediatrics
TABLE 14.7.2. Causes of acute renal failure
Pre-renal Acute gastroenteritis, blood loss, shock,
sepsis, fulminant hepatitis, congestive
heart failure
Renal
Acute tubular Prolongation of pre-renal insult, malaria,
necrosis intravascular hemolysis, sepsis, nephro-
toxic drugs, snakebite and other enveno-
mations
Glomerulonephritis Acute glomerulonephritis (poststreptococ-
cal, other infections), crescentic glome-
rulonephritis
Interstitial nephritis Acute interstitial nephritis (drugs,
infections)
Vascular Thrombotic microangiopathy (hemolytic
uremic syndrome), small vessel vasculitis,
renal vein thrombosis, renal artery
obstruction
Post-renal Obstructive uropathy, neurogenic bladder
Characteristically, there is severe decrease in renal
perfusion and a fall in glomerular filtration but tubular
function is maintained with increased reabsorption of
sodium, water and urea. The renal perfusion is restored
following correction of pre-renal factors, e.g. repletion of
fluids in hypovolemia.
Although various conditions that lead to pre-renal
failure can progress to acute tubular necrosis, it is difficult
to predict when that transition may occur or the duration
of circulatory impairment necessary for its development.
More than one factor is often operative. Thus, renal injury
is compounded when dehydration is associated with the
administration of nephrotoxic agents.
Post-renal ARF
Bilateral obstruction at pelviureteric junction or ureters,
and obstruction at the bladder outlet or urethra by calculi,
blood clots and pus debris may cause post-renal ARF.
Renal Causes
Renal causes of ARF may be grouped into that invol-
ving the tubules, glomeruli, interstitium and blood
vessels and microvasculature.
Acute Tubular Necrosis
Renal hypoperfusion leads to a spectrum of conditions
ranging from typical pre-renal ARF, to an intermediate
stage, which is slowly reversible over 1 to 3 days, and
established ARF with acute tubular necrosis. In more
extreme instances, cortical necrosis may be present. Thus,
there is progressively severe renal injury, which is
inversely related to the chances of recovery.
A variety of renal insults can lead to acute tubular
necrosis. Common causes include renal hypoperfusion
following extracellular fluid volume contraction, e.g. in
acute gastroenteritis, severe renal vasoconstriction,
nephrotoxic agents, sepsis and shock.
G-6-PD deficiency with intravascular hemolysis: Exposure
to oxidant drugs, most notably antimalarials (chiefly
primaquine), sulphonamides, nitrofurantoin and
naphthaquinolones, and occasionally infections may
result in acute intravascular hemolysis in patients who
are G-6-PD deficient. The extent of hemolysis depends
upon the amount of drug taken and the degree of enzyme
deficiency. In severe cases, there is rapid onset of pallor,
weakness, mild jaundice and hemoglobinuria. Renal
tubular damage is indicated by elevation of blood urea
and creatinine levels. Occasionally, G-6-PD deficiency
with intravascular hemolysis may develop in a child
having viral hepatitis; extremely high levels of serum
bilirubin and other features of liver dysfunction may be
seen.
Snakebite: Snakebites are serious in children because of
the relatively large volume of venom injected. ARF may
develop due to intravascular hemolysis, shock and direct
tubular injury. Prompt administration of antivenom and
supportive treatment may reduce the severity of the
manifestations.
Sepsis: Serious infections and septicemia account for a
large proportion of ARF in the neonates and infants.
Shock and consumption coagulopathy are often asso-
ciated.
Hemolytic Uremic Syndrome (HUS)
HUS is characterized by a triad of microangiopathic
hemolytic anemia, thrombocytopenia and acute renal
failure. On peripheral smear, red cells show fragmenta-
tion and schistocyte formation, which is caused by
mechanical injury as these cells traverse the damaged
microvasculature. HUS is mostly seen in infants and
young children. In India, and other developing countries,
HUS is associated with dysentery due to Shigella
dysenteriae 1. Shigella (shiga) toxin enters the circulation

and leads to endothelial cell damage in the renal micro-
vasculature, followed by local coagulation. In developed
countries, HUS follows a diarrheal illness caused by
strains of verotoxin producing enterohemorrhagic E. coli
(verotoxin being similar to shiga toxin).
The patients present with acute onset of pallor,
oliguria, hypertension, occasional petechiae and sensorial
changes. Biochemical abnormalities, in addition to
hematologic features, reflect the severity of renal
insufficiency. Urinalysis may show microscopic hema-
turia and mild proteinuria, but heavy proteinuria and
gross hematuria are rare. There is no specific treatment
for HUS. The management consists of standard measures
for ARF, and treatment of anemia and hypertension. The
prognosis is related to the severity of renal involvement;
those with extensive damage and renal cortical necrosis
have a poor outcome. Even patients who recover from
the acute illness may develop progressive renal
insufficiency.
Occasionally, HUS is seen without a preceding
diarrheal illness (D negative, atypical HUS). The
underlying etiology is heterogeneous and includes
disorders of complement regulation, infection with
S. pneumoniae, systemic lupus erythematosus and medi-
cations (quinine, cyclosporine, oral contraceptives). The
clinical features are similar to typical HUS; hypertension
is severe and renal failure may be prolonged. The long-
term outcome of patients with D- HUS is unsatisfactory.
ARF in the Newborn
Because of the immaturity of the kidney with a low renal
blood flow, the tubules are particularly susceptible to
injury. Birth asphyxia, respiratory distress syndrome,
shock, sepsis and use of nephrotoxic drugs are important
causes of ARF. Obstructive lesions such as bilateral pelvi-
ureteric junction obstruction and posterior urethral
valves are frequently detected in this age group.
Diagnostic Approach to ARF
In a child having oligoanuria, it is important to look for
pre-renal factors that lead to renal hypoperfusion. A
history of diarrhea, vomiting, fluid or blood loss should
be sought and an assessment of fluid intake in the
previous 24 hours made.
In pre-renal ARF, renal blood flow and glomerular
filtration rates decline but tubular reabsorption of salt
and water continues. Thus, there is oliguria with low
Diseases of Kidney and Urinary Tract 739
urine sodium, high urine osmolality, increased plasma
urea to creatinine ratio and low fractional excretion of
sodium. In intrinsic renal failure (acute tubular necrosis)
in a setting of renal hypoperfusion, there is diminished
tubular function with high urine sodium and dilute urine.
Several indices (Table 14.7.3) help to differentiate pre-
renal from established renal failure. Fractional excretion
of sodium is the most sensitive and reliable index. These
indices are however, not useful in patients with non-
oliguric renal failure, and those receiving diuretics.
TABLE 14.7.3: Differences between pre-renal ARF and
established ARF (indices for neonates are in parentheses)
Indices Pre-renal Established
ARF ARF
Urinary sodium (mEq/L) <20 (<30) >40 (>60)
Urinary osmolality (mOsm/kg) >500 (>400) <300 (<350)
Blood urea to creatinine ratio >20 :1 <20 :1
Urine osmolality/plasma >1.5 (>2) <0.8-1.2 (<1.1)
osmolality
Fractional excretion of <1 (<3) >1 (>10 )
sodium (percent)
Fractional excretion of sodium (percent) =
urine sodium × serum creatinine × 100
__________________________________________________
serum sodium × urine creatinine
In pre-renal ARF, expansion of the intravascular
volume leads to improved renal perfusion and an
increase in urine output. Dehydration is corrected by
infusion of 20 ml/kg of an isotonic solution (0.9% saline
or Ringer’s lactate) over 45 to 60 minutes. During this
period, the patient’s vital signs are monitored and care
taken to avoid overhydration. If there is still no clinical
improvement, a clinical decision should be made
regarding the patient’s intravascular volume status, as
further fluid administration could be potentially
hazardous in a child with oligoanuria. Assessment of the
central venous pressure may be needed, since clinical
assessment may be difficult. If urine output has not
improved despite volume repletion or if the patient
shows features of overhydration, frusemide (1-2 mg/kg)
may be administered intravenously to induce diuresis.
If these measures fail to result in diuresis, a diagnosis of
established ARF is made.
Varieties of interventions have been examined to
prevent ARF and reduce the need for renal replacement
740 IAP Textbook of Pediatrics
therapy. Current evidence suggests that there is no
indication for the use of intravenous mannitol, low-dose
dopamine and diuretics for this purpose. In view of lack
of benefit and presence of adverse effects, their use is
not recommended.
Clinical Features
The child with ARF may have altered sensorium and
convulsions due to advanced uremia or hypertensive
encephalopathy. The breathing may be rapid and deep
due to acidosis. There may be peripheral or pulmonary
edema. Blood pressure may be elevated, or there may be
hypotension indicating volume depletion.
Clinical features that suggest an underlying cause,
include a history of fluid or blood loss with severe
dehydration (acute tubular necrosis); edema, hematuria
and hypertension (acute glomerulonephritis); dysentery,
pallor and petechiae (HUS), or sudden pallor, passage
of dark red urine and jaundice (acute intravascular
hemolysis). Severe hypertension is suggestive of
glomerulonephritis or atypical HUS. A history of
interrupted urinary stream and palpable bladder or
kidney, suggests an obstructive uropathy, and that of
abdominal colic, hematuria and dysuria suggests a
urinary tract calculus or infection. Anuria may occur in
urinary tract obstruction, renal cortical necrosis, bilateral
vascular occlusion, severe glomerulonephritis or
vasculitis.
ARF may occasionally be superimposed on chronic
renal disease. Features such as failure to thrive, hypo-
calcemia, hyperphosphatemia, hypertensive retino-
pathy, renal osteodystrophy and small contracted
kidneys indicate an underlying chronic renal disease. Use
of nephrotoxic drugs, rapid increase in hypertension,
infections and hypovolemia may precipitate ARF in a
child with pre-existing renal damage.
Laboratory Investigations
Appropriate investigations should be performed to
confirm the diagnosis. Peripheral blood smear exami-
nation showing features of microangiopathic hemolysis,
thrombocytopenia, increased reticulocyte count and
elevated levels of LDH suggests HUS. Throat swab
culture for Streptococcus, titers of ASO and other
streptococcal antibodies and serum complement should
be done in patients suspected to have acute glomerulo-
nephritis. In glomerular and vascular disease, urinary
protein excretion is increased to 3+ or 4+, along with red
cells and red cell casts. Presence of eosinophils in the
urinary sediment suggests interstitial nephritis.
Ultrasonography is a useful imaging tool in renal
failure because of its non-dependence on renal function.
It allows visualization of the size of kidneys and the
pelvicalyceal system, structural anomalies and calculi.
Renal biopsy is indicated in the following:
i. Patients where the etiology of ARF is not identified,
especially in context of a systemic disease, e.g.
vasculitis.
ii. Unremitting ARF lasting longer than 2-3 weeks:
biopsy may identify a cause such as crescentic
glomerulonephritis, or assess the extent of damage
and outcome, e.g. acute cortical necrosis.
iii. Suspected drug toxicity, e.g. interstitial nephritis, or
in a renal transplant recipient treated with cyclo-
sporine.
Immediate Management of ARF
Immediate attention should be directed towards
detection and management of life-threatening complica-
tions. Clinical evaluation includes measurement of blood
pressure, fundus examination and a search for signs of
congestive heart failure and fluid overload, acidosis and
anemia. Immediate investigations include estimation of
levels of hemoglobin, urea, creatinine, electrolytes and
bicarbonate. An electrocardiogram (ECG) is done to
detect potassium cardiotoxicity and an X-ray film of the
chest for pulmonary edema.
Hyperkalemia
Urgent treatment is instituted depending upon the blood
potassium levels and ECG changes. If serum potassium
is below 6.5 mEq/L or there are mild ECG changes, such
as peaked T waves, administration of 7.5 percent solution
of sodium bicarbonate in a dose of 1-2 ml/kg over 15 to
30 minutes may reduce serum potassium level. If the level
is more than 6.5 mEq/L or more ominous ECG changes
(widened QRS complex or sine wave) are present slow
infusion of 0.5 ml/kg of 10 percent calcium gluconate
over 5 to 10 minutes should be given, with ECG being
monitored. This should be followed by the adminis-
tration 0.5-1 g/kg of 50 percent glucose solution and 0.2
units of insulin for each gm of glucose administered. The
administration of bicarbonate and insulin-glucose will
acutely reduce the serum potassium level, and calcium

infusion will prevent fatal cardiac arrhythmias without
lowering serum potassium level. Intravenous or inhaled
salbutamol also lowers the levels of serum potassium.
The action of potassium binding resins (calcium or
sodium resonium 1 g/kg orally or rectally) is slow and
these are used in chronic situations to prevent hyper-
kalemia.
Pulmonary Edema and Heart Failure
The child may have overhydration, pulmonary edema
and congestive heart failure, which result from adminis-
tration of excessive amount of fluid either orally or
intravenously. The child should be placed in a sitting
position and given oxygen. The CVP should be moni-
tored. If the patient is in shock, dopamine 5-10 mg/kg
body weight per minute is administered by IV infusion,
using minimum amount of fluid that contains no sodium
or potassium. If the condition does not rapidly improve,
the patient should be managed by endotracheal
intubation and assisted ventilation with positive end-
expiratory pressure. Administration of IV frusemide (2-
3 mg/kg) may induce some diuresis. Rotating tourni-
quets and venesection may occasionally be life-saving.
While these measures are being carried out, peritoneal
dialysis with hypertonic glucose should be started.
Hypertensive Encephalopathy
A rapid rise in blood pressure, usually associated with
retention of sodium and water (as in acute glomerulo-
nephritis), may lead to encephalopathy presenting with
headache, vomiting and altered sensorium. Loss of
vision, hemiparesis and seizures may be present. The
immediate management aims at reducing the blood
pressure to safe levels (95th percentile for age, sex)
without causing it to fall precipitously and produce
cerebral ischemia. The medication of choice is IV infusion
of sodium nitroprusside (labetalol or nicardipine are
preferred alternatives, if available) in incremental doses
until the desired effect is produced. During infusion,
blood pressure levels are monitored closely. If the above
agents are not available, oral nifedipine (0.25-0.5 mg/
kg) may be used with careful measurements of blood
pressure. If there is evidence of fluid overload, co-
administration of IV frusemide is useful.
Acidosis
A patient with a blood pH of below 7.2 and serum
bicarbonate level less than 12 mEq/L needs prompt
Diseases of Kidney and Urinary Tract 741
correction of acidosis. The estimated deficit is adminis-
tered according to the formula: 1/2 deficit × weight in
kg × 0.5 = mEq of sodium bicarbonate. If severe acidosis
is present as indicated by deep and rapid breathing and
blood gas measurements are not available, sodium
bicarbonate 2 to 3 mEq/kg should be administered by
an IV infusion over 15-30 minutes.
Anemia
Packed red cells in aliquots of 3 to 5 ml/kg should be
infused. In the presence of fluid overload, partial
exchange transfusion may be required. Blood pressure
should be carefully monitored.
Standard Supportive Care of ARF
In a child with ARF in whom serious complications are
absent or have been adequately treated, standard
supportive care is instituted. Such management is based
on close attention to the intake of fluid and electrolytes,
provision of proper nutrition, prevention and treatment
of infections, careful monitoring and dialysis.
Diet
Adequate nutrition improves survival in ARF. A diet
containing 0.8 to 1 g/kg protein of high biologic value
and 80 to 120 Cal/kg should be given. Carbohydrates
and fats are allowed liberally. Volume restriction during
oliguria often imposes severe limits on the calories that
can be provided. Dietary restrictions are eased once
dialysis is instituted.
Management of Infections
Various infections (respiratory and urinary tract,
peritonitis and septicemia) are the immediate cause of
death in many patients. All procedures must be performed
with strict aseptic techniques, IV lines should be carefully
watched and skin puncture sites cleaned and dressed. Oral
hygiene should be ensured. Devitalized tissue and
collections of blood should be surgically removed. Sepsis
is suggested by hypothermia, persistent hypotension,
hyperkalemia and a disproportionate rise of blood urea
as compared to creatinine (indicating a catabolic state).
Once infection is suspected, appropriate specimens should
be taken for culture and antibiotics started.
Standard charts should be consulted to modify the
dose and dosing interval of various antibiotics.
742 IAP Textbook of Pediatrics
Fluid and Electrolyte Balance
Fluid and electrolyte intake in a patient with ARF is cru-
cial. The daily fluid requirement amounts to insensible
water losses (300-400 ml/m2) and the urinary output.
The former should be replaced with 10 percent glucose
solution. Urinary losses and those from vomiting,
diarrhea and aspiration should be replaced with 0.45
percent sodium chloride in 5 percent glucose solution.
Potassium containing fluids should not be given. It is
usually possible to administer the required amounts of
fluid by mouth, unless there is persistent vomiting.
Hyponatremia: Serum sodium less than 130 mEq/L may
be present at the initial diagnosis of ARF or develop later
during the course of management. In both instances,
hyponatremia is the result of excessive fluid adminis-
tration rather than increased sodium loss. Profound
hyponatremia when associated with sensorial alteration
or seizures requires prompt correction. Serum sodium
concentration should be increased by 5 to 10 mEq/L over
a 60 to 120 minute period by infusion of 3 percent saline;
12 ml/kg of this solution will raise serum sodium by 10
mEq/L. It is emphasized that sodium administration is
usually not required to correct hyponatremia associated
with ARF and fluid restriction is the primary mode of
therapy. Sodium administration is hazardous in patients
with excessive body water and may cause hypertension
and congestive heart failure.
Hyperkalemia: Serum potassium levels should be
measured daily. Ion exchange resin (sodium or calcium
resonium) may be used to prevent hyperkalemia.
Hyperphosphatemia, hypermagnesemia and hypocalcemia:
Once ARF has persisted for a few days, hyper-phos-
phatemia (5-8 mg/dl) and hypermagnesemia may occur.
Hypocalcemia is usually asymptomatic because of
associated acidosis. However, tetany or convulsions may
be precipitated by excessive alkali therapy. Calcium
gluconate or carbonate may be administered with meals
at a dose of 30-50 mg/kg elemental calcium. Hyperphos-
phatemia is treated with aluminum hydroxide gel, which
chelates and prevents absorption of ingested phosphate.
Specific therapy: Therapy with high dose IV cortico-
steroids initially, followed by oral prednisolone is
recommended in patients with ARF secondary to rapidly
progressive glomerulonephritis, systemic vasculitis and
acute interstitial nephritis. Plasmapheresis and/or
infusion of fresh frozen plasma may be indicated in a
subset of subjects with atypical HUS.
Monitoring
The child should be closely monitored. Accurate record
of intake and output, and weight should be maintained.
Laboratory tests are carried out depending upon the
stability of the condition, progression of ARF and pre-
sence of complications. A careful physical examination
should be done at least twice a day.
Diuretic Phase in ARF
The clinical course of acute tubular necrosis is often
characterized by 3 phases: oligoanuria, diuresis and
recovery. The duration of oliguria may be just a few hours
to several weeks; in uncomplicated acute tubular
necrosis, it usually lasts for 5 to 10 days. Subsequently
there is a progressive rise in urine output, which may
reach 2-3 liters per day accompanied by increased losses
of electrolytes since tubular reabsorption is still impaired.
The diuretic phase should be managed by replacement
of urinary output with 0.45 percent saline. Potassium
supplementation may be necessary.
Renal Replacement Therapy
The absolute indications for dialysis include severe or
persistent hyperkalemia, congestive heart failure,
pulmonary edema, severe acidosis (total CO2 content
<10-12 mEq/l) and encephalopathy secondary to uremia
or hyponatremia. Early dialysis should be performed in
HUS and in hypercatabolic states, e.g. extensive trauma
and infections.
All modalities of renal replacement (peritoneal
dialysis, hemodialysis, continuous hemofiltration) can
be used during ARF. The choice of the procedure
depends on the age and size of the patient, cardiovascular
status, availability of vascular access, integrity of
peritoneal membranes and the expertise available at the
center. In young children, peritoneal dialysis is preferred
since it is simple to perform, requires minimum
equipment and does not require vascular access.
Critically sick children often tolerate this mode better
than hemodialysis due to the slow rate of fluid removal
and correction of metabolic abnormalities. A wide range
of PD catheters is available, permitting dialysis at all ages
and for different durations. Hemodialysis is more

effective in ARF associated with hypercatabolic states
(e.g. extensive trauma, sepsis, burns).
Continuous hemofiltration is a technique whereby
excessive fluid is removed without dialysis. It is
particularly useful for the management of critically sick
patients with hemodynamic instability, severe fluid
overload and in patients with major surgical procedures,
burns, heart failure and septic shock, especially when
conventional hemodialysis or peritoneal dialysis is not
possible. The procedure is hemodynamically gentler and
fluid is removed in a controlled manner. Different modes
include continuous arteriovenous hemofiltration
(CAVH), continuous venovenous hemofiltration (CVVH)
and continuous arteriovenous hemodiafiltration
(CAVHD).
Prognosis and Outcome
The derangements caused by ARF can be reversed by
optimal management and dialysis. The eventual recovery
and the long-term outcome depend upon the underlying
condition. The prognosis is good in acute tubular necrosis
and intravascular hemolysis, when complicating factors
are absent. The outcome is poor in infants with sepsis,
presence of multi-organ failure, cardiac surgery and
delayed referral. The outcome, in crescentic glomerulo-
14.8 Nephrotic Syndrome
INTRODUCTION
Nephrotic syndrome is characterized by heavy protein-
uria, hypoalbuminemia (serum albumin < 2.5 g/dL),
hyperlipidemia (serum cholesterol > 200 mg/dL) and
edema. The clinical and biochemical features of nephrotic
syndrome result from heavy proteinuria (more than
40 mg/m2/hour). Sustained proteinuria is followed by
hypoalbuminemia, lowered plasma oncotic pressure and
edema.
In about 95 percent cases of nephrotic syndrome, there
is a primary glomerular abnormality. The remainder is
caused by renal involvement in diverse conditions, such
as systemic lupus erythematosus, Henoch-Schönlein
purpura, amyloidosis and hepatitis B. More than
Diseases of Kidney and Urinary Tract 743
nephritis and HUS, depends on the severity of renal
injury.
If ARF is prolonged beyond 2 to 3 weeks, multiple
dialyses may be required. Maintenance of nutrition and
prevention of infections become crucial as patients may
die of infection and inanition before significant recovery
of renal function. Many survivors of ARF in the neonatal
period and childhood continue to have some degree of
functional abnormality, which may not be immediately
apparent. It is therefore necessary that survivors of ARF
in childhood remain under long-term observation with
monitoring of urinalysis and measurement of blood
pressure.
BIBLIOGRAPHY
1. Andreoli SP. Acute renal failure. Curr Opin Pediatr
2002;14:183-8.
2. Bagga A. Management of acute renal failure. Indian J
Pediatr 1999;66:225-39.
3. Besbas N, Karpman D, Landau D, Loirat C, et al. A
classification of HUS and TTP and related disorders.
Kidney International 2006;70:423-31.
4. Gulati A, Bagga A. Acute kidney injury: Standardizing
terminologies. Indian J Pediatr 2008;75:526-7.
5. Moghal NE, Embleton ND. Management of acute renal
failure in the newborn. Semin Fetal Neonatal Med
2006;11:207-13.
RN Srivastava, Arvind Bagga
80 percent children with idiopathic nephrotic syndrome
show insignificant glomerular abnormalities on light
microscopy (minimal change nephrotic syndrome,
MCNS), whereas others have several distinct glomerular
lesions. The former usually respond to corticosteroid
therapy with complete remission and have an excellent
long-term prognosis. Those with significant glomerular
abnormalities usually do not respond to corticosteroids
and in a majority of cases, there is increasing renal damage
and a poor outcome.
Mechanisms of Proteinuria
The glomerular capillary wall consists of three layers:
fenestrated endothelium, glomerular basement
744 IAP Textbook of Pediatrics

membrane (GBM) and epithelium. The endothelial lining

contains pores of 70 to 100 nm diameter. The endothelial
surface is negatively charged due to the presence of
polyanionic surface glycoprotein, podocalyxin. The
endothelium prevents blood cells from being filtered and
contributes to the charge selective barrier.
The GBM contains a meshwork of negatively charged
molecules rich in heparan sulfate, proteoglycans and
sialoproteins. These negative sites are important for
maintaining the normal structure and function of the
filtration barrier. The GBM acts as a semipermeable filter,
preventing the passage of macromolecules while
allowing fluid and low molecular weight solutes. The
slit diaphragm between adjacent podocytes is also an
important component of the ‘glomerular filter’.
Normally, negligible amounts of albumin and
globulin are excreted in urine. Small molecules, which
are less than 20,000 daltons such as beta-2 microglobulin
are freely filtered, but almost completely reclaimed by Figure 14.8.1: A 2-year-old girl with nephrotic syndrome and
the proximal tubule. Heavy proteinuria is usually due anasarca. Note ascites and facial puffiness
to a glomerular abnormality. As a result, proteins that
are not normally filtered or filtered in very small amounts
Clinical Features
pass readily into the urinary space and are excreted in
the urine. The disease usually starts between the ages of 2 to 6 years;
60 to 70 percent are boys. When the disorder first occurs
Pathogenesis of Nephrotic Syndrome after the age of 10-12 years, the chances of presence of a
In minimal change nephrotic syndrome (MCNS), light significant underlying glomerular lesion are greater.
microscopy does not disclose significant abnormalities. The onset is insidious with swelling around the eyes
Deposits of immune reactants are not seen on immuno- and facial puffiness, which may be mistakenly ascribed
fluorescence examination, serum levels of complement to allergy, conjunctivitis, mumps or dental infection. The
(C3) are normal and circulating immune complexes are swelling gradually increases to involve the extremities
absent. However, immunologic mechanisms seem to be and abdomen and if untreated, may become massive
involved in the pathogenesis of MCNS. The remission (Fig. 14.8.1). Occasionally, generalized swelling over the
that occasionally follows measles, association with body may develop acutely and be associated with gross
allergy, and response to immunoactive agents (steroids, hematuria and oliguria. Such cases present a mixed
immunosuppressive and immunomodulatory drugs) picture of nephrotic syndrome and acute nephritis, which
suggest an underlying immune dysfunction. However, requires urgent detailed investigations and a renal
the precise mechanism of proteinuria is not clear. biopsy.
A proportion of patients with nephrotic syndrome
Evaluation
show genetic mutations of proteins (nephrin, podocin,
actinin) required for integrity of the slit diaphragm. Such The patient should be examined to detect any associated
patients do not respond to therapy with corticosteroids. infection. The height, weight and blood pressure is
Finally, some patients with nephrotic syndrome show recorded. Regular weight record helps monitor the
histological abnormalities of the glomerulus (focal decrease or increase of edema. Physical examination is
segmental glomerulosclerosis, membranoproliferative done to detect infections and underlying systemic
glomerulonephritis), which disrupt the glomerular filter disorder, e.g. systemic lupus erythematosus and Henoch
resulting in proteinuria. Schonlein purpura.

Urinalysis
Nephrotic range proteinuria is present if early morning
urine protein is 3+/4+ (on dipstick or boiling test), spot
protein/creatinine ratio > 2 mg/mg, or urine albumin
excretion > 40 mg/m2 hr. Precise quantitative assessment
of proteinuria, including 24-hr urine protein measure-
ment is seldom necessary. Urine microscopy is done to
look for red cells; persistent microscopic hematuria
suggests the likelihood of an underlying significant renal
histologic lesion.
Blood Examination
Blood is examined for levels of urea, creatinine, proteins
and cholesterol. In MCNS, blood urea levels are normal
unless edema is massive with associated oliguria.
Persistently elevated urea and creatinine suggest the
presence of significant renal histologic lesions. Hypo-
albuminemia (serum albumin < 2.5 g/dl) and hyperlipi-
demia (total cholesterol > 200 mg/dl) are present. Serum
IgG levels are usually low and IgM raised. Serum C3
levels may be decreased in patients with membranopro-
liferative GN.
Appropriate laboratory tests should be done when a
collagen vascular disorder or renal vasculitis is suspected.
An X-ray film of chest and a Mantoux test are carried
out to exclude tuberculosis.
MANAGEMENT
Clinical and laboratory evaluation identifies children
likely to have MCNS. In such patients, a standard course
of prednisolone is instituted. Indications for renal biopsy
are listed in Table 14.8.1.
TABLE 14.8.1: Indications for kidney biopsy
At onset
Age at onset less than one year
Gross hematuria, persistent microscopic hematuria or low
serum C3
Sustained hypertension
Renal failure not attributable to hypovolemia
Suspected secondary cause of nephrotic syndrome
After initial treatment
Proteinuria persisting despite 4 weeks treatment with daily
corticosteroids
Before treatment with cyclosporine A or tacrolimus
Diseases of Kidney and Urinary Tract 745
Treatment of the Initial Episode
Adequate treatment of the initial episode, both in terms
of dose and duration of corticosteroids, is necessary.
Evidence from multiple studies suggests that appropriate
therapy of the initial episode is an important determinant
of long-term outcome. It is recommended that the initial
episode be treated with prednisolone at a dose of 2 mg/
kg body weight given daily for 6 weeks. The dose of
prednisolone is then reduced to 1.5 mg/kg administered
on alternate days, as a single morning dose, for another
6 weeks, after which it is discontinued. Shorter duration
of initial therapy is not recommended and may predis-
pose to a higher risk of subsequent relapses.
Prednisolone should preferably be given after meals;
treatment with antacids is necessary in patients with
gastritis. Most patients respond to prednisolone with
complete disappearance of proteinuria within 2 weeks;
only a minority responds beyond 4 weeks of treatment.
The use of other corticosteroid preparations, including
methylprednisolone, dexamethasone, betamethasone,
triamcinolone, hydrocortisone or deflazacort is not
recommended.
A small proportion of patients has only one episode
of the disease, and is then cured. However, most patients
suffer from relapses for several years. About 30 percent
patients have infrequent relapses (three or fewer relapses
in one year), 40 percent frequent relapses and the
remainder needs almost continuous treatment with
prednisolone to maintain remission (steroid depen-
dence). Table 14.8.2 lists standard definitions used for
defining the course of nephrotic syndrome.
Treatment of Relapse
A relapse is often precipitated by an upper respiratory
infection. The patient should be examined for infections,
which should be treated before initiating corticosteroid
therapy. Appropriate therapy of an infection might rarely
result in spontaneous remission, avoiding the need for
treatment with corticosteroids.
Prednisolone is administered at a dose of 2 mg/kg/
day (single or divided doses) until remission. Subse-
quently, prednisolone is given in a single morning dose
of 1.5 mg/kg on alternate days for 4 weeks, and then
discontinued. The usual duration of treatment for a
relapse is thus 5-6 weeks. In case the patient is not in
remission despite two weeks treatment with daily
746 IAP Textbook of Pediatrics
TABLE 14.8.2: Definitions related to nephrotic syndrome
Remission Urine albumin nil/ trace (proteinuria
< 4 mg/m2/h) for 3 consecutive morning
specimens
Relapse Urine albumin 3+/4+ (proteinuria > 40 mg/
m 2 /h) for 3 consecutive morning
specimens, having been in remission
previously
Frequent relapses Two or more relapses in initial 6-months,
or more than three relapses in any
12-months
Steroid dependence Two consecutive relapses when on
alternate day steroids or within 14 days of
its discontinuation
Steroid resistance Absence of remission despite therapy with
daily prednisolone at a dose of 2 mg/kg
per day for 4 weeks
prednisolone, the treatment is extended for two more
weeks. Patients showing no remission despite 4 weeks’
treatment with daily prednisolone are labeled as steroid
resistant and managed accordingly.
Infrequent Relapses
Patients with infrequent relapses are managed using the
aforementioned regimen for each relapse. Such children
are at a low risk for developing steroid toxicity.
Frequent Relapses and Steroid Dependence
Patients having frequent relapses or steroid dependence
require repeated courses of prednisolone may develop
serious steroid toxicity, including cushingoid features
(obesity, hirsutism, striae), hypertension, impaired
glucose tolerance, posterior subcapsular cataract,
emotional problems and growth retardation. Alternative
regimens in such patients are listed below:
i. Long-term alternate day prednisolone: Following
treatment of a relapse, prednisolone is tapered to
maintain the patient in remission on alternate day
dose of 0.5-0.7 mg/kg, which is administered for
9-18 months. Long-term alternate day prednisolone
is effective in maintaining a remission or reducing
the number of relapses. It has few side effects and
does not seem to interfere with growth. Break-
through relapses are treated with standard treat-
ment of relapse. If the prednisolone threshold, to
maintain remission, is higher or if features of steroid
toxicity are seen, additional use of the following
immunomodulators is recommended.
ii. Levamisole: Levamisole is beneficial in reducing
relapse rates in patients with frequent relapses and
steroid dependence. It is administered at a dose of
2 mg/kg on alternate days for 12-24 months. Co-
treatment with prednisolone at a dose of 1.5 mg/kg
on alternate days is given for 2-4 weeks; its dose is
gradually reduced by 0.25 mg/kg every 4 weeks to
a maintenance dose of 0.5 mg/kg that is continued
for six or more months. Occasionally, it might be
possible to discontinue treatment with cortico-
steroids. The chief side effect of levamisole is
leukopenia; flu-like symptoms, liver toxicity,
convulsions and skin rash are rare.
iii. Cyclophosphamide: Treatment with cyclophospha-
mide may induce sustained remission in some
patients. Cyclophosphamide is given at a dose of
2-2.5 mg/kg/day for 12 weeks. Prednisolone is co-
administered at a dose of 1.5 mg/kg on alternate
days for 4 weeks, followed by 1 mg/kg for the next
8 weeks; steroid therapy is tapered and stopped over
the next 2-3 months. Total leukocyte counts should
be monitored every 2 weeks; treatment with
cyclophosphamide is held if the count falls below
4000/mm3. An increased fluid intake and frequent
voiding help prevent hemorrhagic cystitis. Other
side effects are alopecia, nausea and vomiting; the
risk of gonadal toxicity is limited with a single
(12-week) course of cyclophosphamide. Therapy
with a related agent, chlorambucil, is currently not
recommended.
iv. Calcineurin inhibitors: Cyclosporine (CsA) causes
specific and reversible inhibition of T-helper
lymphocytes. The dose of CsA is 4 to 5 mg/kg per
day (100-150 mg/m2 per day) and is given for
12-24 months. Prednisolone is co-administered at a
dose of 1.5 mg/kg on alternate days for 2-4 weeks;
its dose is gradually reduced by 0.25 mg/kg every
4 weeks to a maintenance dose of 0.25-0.5 mg/kg
that is continued for six or more months.
Occasionally, treatment with corticosteroids may be
discontinued. Relapses often occur when therapy
with CsA is discontinued. Side effects of therapy
include hypertension, gum hypertrophy, hirsutism
and nephrotoxicity; hypercholesterolemia and
elevated transaminases rarely occur. Tacrolimus is
an alternative agent, preferred in adolescents
because of lack of cosmetic side effects.
 Diseases of Kidney and Urinary Tract 747

Figure 14.8.2: Management of steroid sensitive nephrotic syndrome. The evidence for efficacy is strongest for cyclophosphamide
and cyclosporin. Levamisole has a modest steroid sparing effect and is a satisfactory initial choice for patients with frequent
relapses or steroid dependence. Treatment with cyclophosphamide is preferred in patients showing steroid toxicity or severe
relapses. The lack of renal, hemodynamic and metabolic toxicity with mycophenolate mofetil makes it an attractive alternative to
calcineurin inhibitors (Indian Pediatric Nephrology Group. Management of steroid-sensitive nephrotic syndrome. Indian Pediatr
2008; 45:203-14; with permission)

v. Mycophenolate mofetil: Prolonged therapy with this
agent, an inhibitor of purine metabolism, is found
effective in reducing relapse rates in patients with
frequent relapses and steroid dependence. Principal
side effects include gastrointestinal discomfort and
leukopenia.
A protocol summarizing the specific management of
patients with steroid sensitive nephrotic syndrome is
shown in Figure 14.8.2.
INITIAL STEROID RESISTANCE
A renal biopsy is carried out in patients with steroid
resistance to determine the underlying glomerular lesion.
Mesangial proliferative glomerulonephritis, focal
segmental glomerulosclerosis (FSGS) and membrano-
proliferative glomerulonephritis (MPGN) account for
most of these cases. An occasional patient with minimal
change nephrotic syndrome may show initial steroid
resistance.The treatment of these conditions is not well
established. Treatment with oral cyclophosphamide is
not satisfactory. Other regimens that have been used with
variable success include high dose IV pulse methyl-
prednisolone with oral cyclophosphamide, monthly
pulses of IV cyclophosphamide, and oral treatment with
cyclosporine or tacrolimus. Patients with persistent
proteinuria have an unsatisfactory long-term outcome
and are at risk of progressive kidney failure.
CONGENITAL NEPHROTIC SYNDROME
The features of nephrotic syndrome may be present
rarely at birth or develop within the first 3 months of
life. Congenital syphilis and other intrauterine infections
are rare causes. The Finnish type, an autosomal recessive
condition, is relatively more common and is caused by
748 IAP Textbook of Pediatrics
mutations in the nephrin (NPHS1) gene. There is no
specific treatment and chronic renal failure develops
quite early. A correct diagnosis is important for
prognosis, therapy and genetic counseling. The Finnish
type of congenital nephrotic syndrome can be diagnosed
antenatally at 15 to 18 weeks gestation by elevated alpha-
fetoprotein concentration in the amniotic fluid and
maternal serum.
Advances in genetic diagnostic techniques including
positional cloning and sequencing have enabled us to
identify genes in several forms of familial and congenital
nephrotic syndrome. Denys Drash syndrome (infantile
nephrotic syndrome, male pseudohermaphroditism,
Wilms’ tumor; biopsy showing diffuse mesangial
sclerosis) and Frasier syndrome (nephrotic syndrome, XY
females, increased risk of gonadoblastoma, biopsy
suggestive of FSGS) are two forms of nephrotic syndrome
associated with WT1 gene mutation. Other genes
implicated include NPHS2 (podocin), α actinin 4 (ACT4)
and laminin.
GENERAL CARE
Diet
A balanced diet, adequate in protein (1.5-2 g/kg) and
calories is recommended. Not more than 30% calories
should be derived from fat and saturated fats avoided.
Salt restriction is not necessary in most patients with
steroid sensitive nephrotic syndrome, but may be
recommended in those with persistent edema. Unneces-
sary restrictions in diet, salt intake and physical activity
are avoided. Diuretic induced losses of potassium may
be replaced by potassium supplements.
Edema
Hypoalbuminemia with reduction in colloid osmotic
pressure results in hypovolemia, which triggers various
sodium retaining mechanisms leading to accumulation
of salt and water in the body. Since treatment with
corticosteroids usually leads to diuresis within 5-10 days,
diuretics are avoided unless edema is significant.
Diuretics should also not be given to patients with
diarrhea, vomiting or hypovolemia.
Patients with persistent edema might require
treatment with oral frusemide (1-3 mg/kg daily). Patients
requiring higher doses and prolonged duration of
treatment with frusemide should receive potassium
sparing diuretics, e.g., spironolactone (2-4 mg/kg daily).
Blood pressure should be monitored frequently. A
gradual reduction of edema, over one week, is preferred.
Use of large doses of diuretics carries a hazard of inducing
sudden diuresis, which may aggravate hypovolemia and
precipitate acute renal failure. Therapy with IV albumin
(20%) is costly and the results are transient since most of
the infused albumin is rapidly lost in the urine. However,
it is necessary in patients with refractory edema, where
repeated administration might be necessary.
Infections
Bacterial infections in children with nephrotic syndrome
cause considerable morbidity, and are the commonest
cause of death. The factors responsible for the high
susceptibility to infections include urinary loss of factor
B and immunoglobulins, inadequate antibody response
and defective opsonization. Immunosuppressive
therapy, edema and ascites are contributory factors.
Peritonitis is the most common serious infection.
Others include pneumonia, meningitis, osteomyelitis,
arthritis and cellulitis. A majority of infections are due
to Streptococcus pneumoniae, but Gram-negative
organisms such as E. coli and Hemophilus influenzae are
also responsible. Tuberculosis also is more common in
children with nephrotic syndrome, particularly those
requiring prolonged corticosteroid therapy.
The clinical features of infections are often masked
and subtle. Infections must be suspected in any patient
with nephrotic syndrome who looks sick, has fever and
abdominal pain, vomiting and diarrhea. Appropriate
investigations should be done and treatment instituted.
Ascites predisposes to peritonitis and it is important to
treat relapses early and prevent edema. The administra-
tion of pneumococcal and varicella vaccines is recom-
mended. Immunocompromised patients with varicella
should be administered oral/IV acyclovir depending on
its severity.
Immunization
The child should receive all recommended vaccines.
Patients receiving prednisolone at a dose of 2 mg/kg/
day or greater, or 20 mg/day or greater (if weighing
>10 kg) for more than 14 days are considered immuno-
compromised. Live agents should not be administered
to these patients. Live vaccines are administered once
the child is off immunosuppressive medications for at

least 6 weeks. Administration of some vaccines, e.g.
hepatitis B, measles-mumps-rubella or meningococcal
vaccines may rarely precipitate a relapse.
All children with nephrotic syndrome should receive
immunization against pneumococcal infections and
against varicella.
Coagulation Abnormalities
Nephrotic syndrome may be complicated by thrombosis
of major veins or arteries. An increase in platelet
aggregation and hepatic synthesis of clotting factors, and
urinary loss of clotting inhibitors contribute to the
hypercoagulable state. Renal vein is a common site of
thrombosis and is suspected in patients with oligoanuria,
hematuria or flank pain, especially following an episode
of dehydration. Major arteries (femoral and mesenteric)
and axillary and subclavian veins and cerebral venous
sinuses may also be involved. Saggital sinus and cortical
venous thrombosis may follow episodes of diarrhea and
present with convulsions, vomiting, altered sensorium
and neurological deficits. The diagnosis can be confirmed
by ultrasound examination, angiography or in suspected
pulmonary vein thrombosis by ventilation perfusion
scans. Treatment consists of correction of dehydration
and other complications, and use of heparin (IV) or low-
molecular-weight heparin (subcutaneously) initially,
followed by oral anticoagulants on the long-term. There
is no role for prophylactic treatment with anticoagulants
in patients with hypoalbuminemia.
Blood sampling in children with nephrotic syndrome
should be done only from superficial veins. Diarrhea and
volume depletion should be promptly treated.
Hypertension
This may occur due to the disease state or secondary to
steroid therapy. Initial drugs used include ACE
inhibitors, calcium channel blockers or β adrenergic α
antagonists, keeping the blood pressure at less than the
90th percentile.
Hyperlipidemia
Hyperlipidemia is an important feature of nephrotic
syndrome. Patients with severe and persistent hyper-
lipidemia should maintain normal weight for height. The
diet should contain less than 30 percent fat, with equal
amounts of polyunsaturated and saturated fatty acids
Diseases of Kidney and Urinary Tract 749
and low cholesterol. Persistent, severe hyperlipidemia
in steroid resistant nephrotic syndrome may be treated
with lipid lowering agents.
Calcium, Vitamin D Metabolism
Hypocalcemia in nephrotic syndrome is due to a
reduction in protein bound calcium secondary to
hypoalbuminemia. Occasionally, low ionized calcium
levels are seen, which result from urinary loss of vitamin
D binding globulin and 25-hydroxyvitamin D3, and may
cause tetany. Patients on prolonged (> 3 months)
treatment with steroids should receive daily supplements
of oral calcium (250-500 mg daily) and vitamin D (125-
250 IU).
Hypovolemia and Acute Renal Failure
Patients with nephrotic syndrome in relapse are sensitive
to a reduction of blood volume. This complication can
occur due to unsupervised use of diuretics especially if
accompanied by septicemia, diarrhea or vomiting.
Prolonged renal hypoperfusion may result in renal
tubular necrosis. The diagnosis is suggested by moderate
to severe abdominal pain, hypotension, tachycardia, cold
extremities and poor capillary refill; hematocrit and blood
levels of urea and uric acid are elevated. Management
consists of rapid infusion of normal saline at a dose of
15-20 mL/kg over 20-30 minutes; this is repeated if
clinical features of hypovolemia persist. Infusion of 5%
albumin (10-15 mL/kg) or 20% albumin (0.5-1 g/kg) may
be used in subjects who do not respond despite two
boluses of saline.
Corticosteroid Side Effects
Prolonged therapy may be associated with significant
side effects including increased appetite, impaired
growth, behavioral changes, risk of infections, salt and
water retention, hypertension and bone demineraliza-
tion. All patients should be monitored for cushingoid
features and blood pressure; 6-monthly record of height
and weight, and annual evaluation for cataract is
recommended.
Steroids during Stress
Patients who have received high-dose steroids for more
than 2 weeks in the past year are at risk of suppression
of the hypothalamo-pituitary-adrenal axis. These
children require supplementation of steroids during
surgery, anesthesia or serious infections. Corticosteroids
750 IAP Textbook of Pediatrics
are supplemented, as parenteral hydrocortisone at a dose
of 2-4 mg/kg/day, followed by oral prednisolone at 0.3-
1 mg/kg/day. This is given for the duration of stress
and then tapered rapidly.
Reduction of Proteinuria
Persistent heavy proteinuria in steroid resistant nephrotic
syndrome itself may cause progression of glomerular
injury. Angiotensin converting enzyme inhibitors, such
as enalapril, reduce the amount of filtered protein, by
causing efferent arteriolar dilation and reducing
glomerular filtration pressure. Thus, proteinuria is
reduced which leads to rise in serum albumin levels.
Patient and Parent Education
Parental motivation and involvement is essential in the
long-term management of these children. They should
learn how to examine urine for protein at home (using
dipstick, sulfosalicylic acid or boiling test) and maintain
a diary showing results of urine protein examination,
medications received and intercurrent infections. Parents
should also ensure a normal activity and school
attendance; the child should continue to participate in
all activities and sports.
OUTCOME IN NEPHROTIC SYNDROME
The outcome in patients with minimal change nephrotic
syndrome is satisfactory. Most patients stop getting
14.9 Urinary Tract Infection, Vesicoureteric
Reflux and Reflux Nephropathy
URINARY TRACT INFECTIONS
Urinary tract infections (UTI) are common during
childhood and often associated with congenital
anomalies of the urinary tract and vesicoureteric reflux
(VUR), which together consititute an important cause of
chronic renal failure.
UTI is identified by significant bacteriuria on culture
of urine. It may be confined to the bladder and urethra
and is known as lower tract infection or dysuria
frequency syndrome. It is indiacated by dysuria,
relapses between the ages of 12-15 years, and recover
without any residual renal dysfunction. However, in a
given case, it is not possible to predict when the relapses
would cease. In a small proportion, there is development
of late steroid resistance and renal biopsy may show
abnormalities other than minimal change. In such cases,
the prognosis is guarded. The outcome of nephrotic
syndrome in patients with significant renal pathology
or steroid resistant nephrotic syndrome is variable.
Patients with persistent nephrotic range proteinuria are
at risk for progressive kidney disease. The long-term
outcome of congenital nephrotic syndrome, secondary
to mutations involving the NPHS1 gene, is unsatisfactory.
BIBLIOGRAPHY
1. Bagga A, Mantan M. Nephrotic syndrome in children.
Indian J Med Res 2005;122:13-28.
2. Hodson EM, Willis NS, Craig JC. Corticosteroid therapy
for nephrotic syndrome in children. Cochrane Database
Syst Rev 2007 Oct 17;(4):CD001533.
3. Hodson EM, Willis NS, Craig JC. Non-corticosteroid
treatment for nephrotic syndrome in children. Cochrane
Database Syst Rev 2008 Jan 23;(1):CD002290.
4. Indian Pediatric Nephrology Group, Indian Academy
of Pediatrics. Management of steroid-sensitive nephrotic
syndrome: Revised guidelines. Indian Pediatr 2008;
45:203-14.
5. Vats AN. Genetics of idiopathic nephrotic syndrome.
Indian J Pediatr 2005;72:777-83.
M Vijayakumar, RN Srivastava
frequency and suprapubic pain. In renal parenchymal
involvement (pyelonephritis), otherwise known as upper
tract infection, there are fever, chills and flank pain.
occasionally, asymptomatic bacteriuria is identified on
screening of healthy children.
UTI is more frequent in male neonates due to a higher
incidence of urinary tract anomalies. In older girls, lower
tract UTI is common, because of the short female urethra,
which is readily colonized with pathogenic organisms,
In the newborn period, renal involvement occurs by the

hematogenous route. Thereafter, in infants and older
children, bacteria enter the urethra and ascend into the
bladder. E.coli is the most common organism causing
UTI. E.coli that most often produce pyelonephritis have
special fimbriae on their surface through which they
attach to the uroepithelium. Bacteria have several
virulence factors, which leads to cell invasion and
inflammation. Other pathogens include Proteus
(common in uncircumcised boys), Streptococcus faecalis,
Klebsiella and Pseudomonas.
Predisposing Factors
Obstruction to urine flow anywhere along the urinary
tract, VUR, instrumentation, urinary calculi, constipation
and pinworm infestation predispose to UTI. The host
defense mechanism chiefly consists of a normal urine
flow, which washes away the bacteria. The presence of
secretory IgA and antibacterial property of bladder
mucosa may have some role.
Clinical Features
Newborn period: The neonate may have features of
septicemia, jaundice, vomiting and shock.
Infant: There may be nonspecific symptoms such as
unexplained fever, diarrhea, vomiting and failure to
thrive.
Older child: The child has dysuria, frequency and
suprapubic pain. Fever, flank pain and toxic appearance
suggest renal parenchymal involvement.
Diagnosis
The diagnosis of UTI is suggested by detection of bacteria
and neutrophils on microscopic examination of a
carefully collected fresh sample of urine. Mild protein-
uria, leukocyturia (>5 WBC/HPF in centrifuged urine
and >10 WBC/mm3 in uncentrifuged urine) and bacteria
on gram stain can indicate UTI. Enhanced urinalysis
using uncentrifuged urine and Neubauer counting
chamber along with gram staining of urine sediment is
found useful to get at the suspicion of UTI early. More
than 10 WBCs/mm3 with a positive gram staining will
indicate the possibility of UTI to a very reasonable extent.
The popular rapid tests like Nitrite or Greiss test and
leucocyte esterase tests have problems of false positivity
and negativity. Bacterial enzyme nitrate reductase can
convert the urinary nitrate to nitrite, which can be
Diseases of Kidney and Urinary Tract 751
detected. If sufficient time is not allowed for incubation
of bacteria with urine, the tests become negative as in
children with increased frequency. Even if UTI is caused
by a bacterium that does not contain nitrate reductase as
in streptococcal species, false negative results are seen
Similarly leucocyte esterase test detects leucocytes in
urine, which can be present in UTI as well as in other
conditions like interstitial nephritis or glomerulo-
nephritis. A better method of utilizing these rapid tests
is by getting a combined positive tests for leucocyte
esterase and nitrite in a child with clinico-biological
features of upper tract UTI. A positive enhanced
urinalysis with positive rapid test will definitely indicate
UTI with certainty.
In urine culture, more than 105 colonies/ml indicates
significant bacteriuria whereas a colony count less than
104 is usually due to urinary contamination. A colony
count between 104 to 105/ml may be significant, if the
child has polyuria or has received antibiotics. In older
children, a midstream urine specimen is obtained. Urine
samples may be obtained by suprapubic bladder
aspiration or urethral catheterization in neonates and
infants where collecting midstream urine sample is
difficult. Imaging studies are considered in all children
with UTI. A child below the age of 2 years should have
an ultrasound (USG) study, DMSA renal scan and a
micturation cystourethrogram (MCU) with first attack
of UTI. Recent evidences state that this can be extended
up to 5 years of age. Older children are usually screened
by an USG following the first UTI. MCU should be done
in all children with recurrent UTI, and where USG or
DMSA scan shows anomalies or cortical scarring. A plain
X-ray film of abdomen detects bony deformities like spina
bifida and calculi. USG demonstrates renal anomalies,
dilated or irregular plevicalyceal system and renal
parenchymal scars. MCU may show VUR, bladder
thickening due to lower tract obstruction, posterior
urethral valves and can help in the assessment of residual
urine. Direct radionuclide cystogram is found useful as
a repeat test for documenting VUR on follow-up and
should not be used as the initial screening test as it
may not give details of the anatomy of bladder and
urethra.
Delay in diagnosis results in delayed treatment which
causes extensive morbidity. Most of the times, this is due
to vague symptomatology of UTI in young children and
infants. Young age, delay in initiating antibacterial
therapy, wrong choice of antibiotics, short duration of
752 IAP Textbook of Pediatrics
therapy, recurrences and associated disorders like
vesicoureteric reflux are essential risk factors for renal
scarring. Growing kidneys up to 2 years of age and even
up to 5 years of age are at the risk of developing renal
scars and utilimately ending up with end stage renal
disease in adulthood due to renal parenchymal damage
that can occur in early childhood with upper tract
infection or otherwise known as acute pyelonephritis.
Management
If UTI is suspected clinically and suggested by urine
microscopy, treatment should be started promptly
without waiting for the result of urine culture. The initial
treatment is based on clinical evaluation of the severity
of UTI and the age of the patient.
Neonate and infant: Ampicillin and gentamicin are given
for a period of 10-14 days; cefotaxime or ceftriaxone may
be used instead.
Older children: Amoxicillin or co-trimoxazole orally are
the drugs of choice; oral cephalosporins may be also used.
The duration of therapy is 7-10 days. Patients who have
high fever, systemic toxicity or flank pain should receive
parenteral drugs as described for infants above.
Fever should be controlled and a liberal fluid intake
provided. The antibiotics may be modified, once the
culture and sensitivity results are available. With effective
treatment, symptoms disappear within 24-48 hours,
urine microscopy does not show bacteria and the culture
becomes sterile. Failure to respond suggests bacterial
insensitivity to the drugs, lack of compliance to treatment
or presence of complicating factors such as obstructive
urotpathy.
Chemoprophylaxis: Drugs used for chemoprophylaxis are
co-trimoxazole (1-2 mg/kg/daily) or nitrofurantion
(1-2 mg/kg daily), which is given in the night as a single
dose. The chief indication is in the management of VUR;
the aim is to keep the bladder urine sterile. The duration
of chemoprophylaxis is 6 months to two years, depen-
ding upon the associated anomalies and the problem of
recurrence.
Management of recurrent UTI: Recurrent UTI indicate
presence of complicating factors such as VUR, obstruc-
tion, neurogenic bladder or other abnormalities. A
through clinical examination and imaging studies are
mandatory.
Asymptomatic bacteriuria: On screening of normal school
children, significant bacteriuria occasionally is detected.
The organisms are of low virulence that colonise the
lower tract. No treatment is necessary. But adolescent
females presenting with asymptomatic bacteriuria need
USG evaluation of the urinary tract to rule out renal
anamolies as chances of acute pyelonephritis occurring
during pregnancy in these individuals should be
remembered.
VESICOURETERIC REFLUX (VUR) AND
REFLUX NEPHROPATHY
VUR implies passage of urine into the ureter and kidney
during micturition. Normally, the long submucosal and
intravesical segment of the ureter at the ureterovesical
junction closes when bladder contracts, effectively
preventing VUR. Incompetence of ureterovesical junction
due to shortening and lack of obliquity of the submucosal
and intravesical segments results in VUR. VUR can be
primary as an isolated defect or secondary associated
with other anomalies like posterior urethral valve or
neurogenic bladder. Voiding dysfunction should be
remembered in a child with VUR as this is recently
considered to complicate the disorder of VUR.
Thirty to forty percent of all children and 40-60
percent of neonates with UTI have VUR. UP to one-third
of children with UTI having VUR, develop renal scars.
Primary VUR may have a genetic basis and occur in
siblings.
Pathogenesis of Renal Scars
During micturition VUR allows the rise in intravesical
pressure to be transmitted to the ureter and renal pelvis,
which enables urine to enter papillary collecting ducts
and renal tubules (intrarenal reflux). Thus, pathogenic
organisms present in the bladder urine reach the renal
parenchyma and initiate inflammation and subsequent
scar formation. Reflux nephropathy indicates renal
parenchymal damage due to VUR.
The calyceal clubbing seen on IVP is a result of
papillary distortion and retraction following scar
contraction. The DMSA renal scan is a sensitive technique
to detect renal scars (Fig. 14.9.1).
Diagnosis
VUR is diagnosed and graded by a conventional MCU
done with radio contrast. Radionuclide cystogram using

Figure 14.9.1: 99mTc DMSA renal scan. Posterior view at 4
hours, following an intravenous injection of the radiotracer
showing bilateral cortical scarring (arrows)
DTPA also detects VUR, but the MCU can clearly show
abnormalities of the bladder and urethra. Hence
radionuclide cystogram is not useful in male infants as a
screening procedure as it will miss anatomical anomalies
of the urethra and bladder, which is more common in
females. Radionuclide cystogram is found to detect VUR
in some children where MCU failed to detect it as
radionuclide cystogram is more sensitive and specific
compared to MCU.
In mild to moderate VUR (grade I-III), there is reflux
into the non-dilated ureter or dilated ureter and upper
collection system. In severe VUR (grade IV-V), there is
reflux into grossly dilated ureter, pelvis and calyces.
Clinical Features
The child may have recurrent UTI with or without a
structural anomaly of the urinary tract. Those with reflux
nephropathy and marked renal parenchymal scarring
may present with chronic acidosis, hypertension or renal
failure.
Management of VUR
Children with VUR and otherwise normal urinary tract
are treated with long term chemoprophylaxis with
nitrofurantion (1-2 mg/kg body weight, as a single daily
night dose) or co-trimoxazole (1-2 mg/kg/day trimetho-
prim). Training the child for double or triple micturition
to reduce the residual urine is also beneficial. Urine
examination (microscopic and culture) is done if UTI is
suspected on follow-up. Yearly radionuclide cystography
is done to assess VUR. Grade I-III VUR resolves and even
Diseases of Kidney and Urinary Tract 753
higher grades may disappear in 80-90 percent of children.
Surgical indications will include non-resolution of VUR
by 5 years of age, VUR grades III-V associated with
bilateral renal scarring after 2 years of age, recurrent
breakthrough UTI’s in children with VUR on uropro-
phylaxis, parents who are living in remote communities
and are not very confident about giving uroprophylaxis
or convinced about it and these are the same people who
in the event of suspected UTI will not do cultures, VUR
associated with paraureteric diverticulum or in duplex
systems as resolution in uncommon in this subset. Today
there are two options for correction of VUR. Subureteric
injection of Deflux or Macroplastique; is a day care or
out patient technique which is 70% effective in elimi-
nating VUR which is grade III or IV. Cost of the implant
is the only limiting factor. A day care minimal access
extravesical ureteric reimplant technique is now quite
popular in the US. This is also suitable only for Grade III
or IV VUR. The most effective method of reflux
eliminating is surgery by ureteric reimplantation. The
scar can be placed in a transverse direction just above
the public symphysis so that it becomes obscured by the
pubic hair line.
The problem of voiding dysfunction should be
remembered in recurrent UTI as well as in children with
VUR and failure to manage this will not eliminate the
problem of recurrent UTI and will lead to failure of VUR
management done either medically or surgically.
Treatment of constipation and voiding dysfunction play
a major role in the management of VUR in children in
the present day care.
BIBLIOGRAPHY
1. Indian Pediatric Nephrology Group: Indian Academy
of Pediatrics, Consensus statements on management of
urinary tract infection. Indian Pediatr 2001;38:1106-15.
2. Srivastava RN, Bagga A. Urinary tract infection. In:
Srivastava RN, Bagga A (Eds): Pediatric Nephrology, 3rd
Edn, Jaypee Brothers, New Delhi 2005;235-64.
3. Vijayakumar M, Prahlad N, Sharma NL, Nammalwar
BR. Urinary tract infection (UTI). In: Suraj Gupta (Ed):
Recent advances in Pediatrics-17-Hot topics. 1st Edn,
Jaypee Brothers Medical Publishers, New Delhi 2007;
348-57.
4. Vijayakumar M, Prahlad N. Urinary tract infection in
children. In: Vijayakumar M, Nammalwar BR (Eds):
Principles and Practice of Pediatric Nephrology, 1st Edn,
Jaypee Brothers, New Delhi, 2004;348-57.
754 IAP Textbook of Pediatrics
14.10 Obstructive Uropathy
Obstructive lesions of urinary tract, i.e. the pelvis, ureter,
bladder or urethra can be congenital or acquired (calculi,
ureteral stricture due to tuberculosis, postoperative
fibrosis). A list of common lesions is given in Table 14.10.1.
Obstruction may be partial or complete requiring surgery
for relief of back pressure, dilation and progressive renal
damage. Obstructive uropathy is an important cause of
end-stage renal disease (ESRD). The age of the child, and
severity and duration of obstruction, determine the extent
of renal damage. The increase in ureteric pressure is
transmitted to renal pelvis and tubules, causing a fall in
glomerular filtration rate. There is impairment of tubular
function characterized by decreased ability to concentrate
and acidify urine, decrease in potassium excretion and
reduced responsiveness to ADH. These abnormalities lead
to polyuria, hyperkalemia, hyperchloremic metabolic
acidosis with inappropriately high urine pH (distal renal
tubular acidosis type IV).
The mechanical effects of high pressure on the ureters
and pelvicalyceal system result in their dilatation,
tortuosity and loss of peristalsis. Urinary infection causes
further loss of peristalsis. Obstruction below the level of
the bladder results in distension of the bladder with
thickened walls and later, formation of diverticuli that
may obstruct the ureters. In cases of posterior urethral
valve the proximal urethra dilates. Due to poor emptying,
stagnation of urine occurs which predisposes to infection
and stone formation.
Obstruction in utero can cause irreversible renal
damage and renal dysplasia, due to adverse effect of
obstruction on the development of kidneys. Relief of
obstruction usually does not improve renal function in
such cases.
TABLE 14.10.1: Common obstructive lesions
• Pelviureteric junction (unilateral or bilateral)
• Calculi in pelvis, ureter or urinary bladder
• Diverticuli or ureteroceles (obstructing ureter or uretero-
vesical junction)
• Posterior urethral valves
• Bladder neck obstruction
• Phimosis, paraphimosis, meatal stenosis
• Neurogenic bladder, neuropathic bladder
Kumud P Mehta
Diseases of spinal cord like meningomyelocele, lipo-
meningocele, tethered cord can lead to functional
obstruction due to detrusor, sphincter dyssynergia.
Clinical Features
A neonate with obstructive uropathy may present with:
i. Distention of abdomen due to unilateral or bilateral
renal masses (hydronephrosis) and poor urinary
stream with distended firm bladder;
ii. Excessive crying and irritability, poor feeding, and
occasionally hematuria.
In older children there may be abdominal pain due
to distention of kidney or bladder, voiding dysfunction
such as straining, dribbling, daytime enuresis, polyuria,
frequency and urinary tract infections.
It is possible to diagnose obstructive uropathy by
antenatal US around 25 to 26 weeks of gestation.
Investigations
US can demonstrate dilation of the pelvicalyceal system,
ureters and bladder, hydronephrosis, cortical thickness
and scarring. MCU is done to detect posterior urethral
valves. Radionuclide renal scan using 99mTc DTPA can
confirm obstruction at pelviureteric junction and provide
differential renal function. Failure of radiotracer pooling
in renal pelvis to “washout” after an intravenous injection
of frusemide indicates organic obstruction. Intravenous
pyelography is useful in older children, to define
accurately the anatomical site of obstruction or detect
radiolucent calculus in pelvis or ureter.
Treatment
Appropriate surgical treatment is done to relieve the
obstruction. Long-term follow-up is necessary to look for
urinary tract infections and treat associated compli-
cations. Renal dysplasia and renal scars already present
before the relief of obstruction may eventually lead to
ESRD over a period of 10 to 15 years.
BIBLIOGRAPHY
1. Koff SA. Obstructive uropathy: Clinical. In Pediatric
Barratt TM, Avner, Harman WE, (Eds): Nephrology (4th
edn). Williams & Wilkins, Baltimore 1999;887-96.

14.11 Disorders of Micturition
Disorders of micturition result from abnormal bladder
function. Main functions of urinary bladder are storage
of urine at low pressure till maximum capacity is reached
and then complete evacuation of bladder at a convenient
time and place. Periodic voiding occurs due to co-
ordinated contraction of detrusor muscle with relaxation
of bladder sphincter under the influence of nervous
system both somatic, sympathetic and parasympathetic.
Centers in brain, brain stem and spinal cord send
inhibitory and facilitatory impulses to detrusor and
sphincter muscles in a cycle. Disruption of this cycle
results in disorders of micturition.
Bladder Innervation
The chief nerve supply to the bladder is through pelvic
nerves (S 2-3 segments), which contain both sensory and
motor fibers. The former detect the degree of stretch of
the bladder wall and posterior urethra, which serves to
initiate the reflexes, leading to bladder emptying. The
motor nerve fibers are parasympathetic and innervate
the external sphincter muscle and control its voluntary
contraction. Once the bladder is full, stimuli reach the
external sphincter through the pudendal nerves.
Voluntary relaxation of that sphincter leads to mictu-
rition. Higher centers in pons and cortex also control
micturition. These are mostly inhibitory and override the
micturition reflex, until it is convenient to void.
Causes of disorders of micturition are:
1. Congenital anomalies of spine—meningomyelocele,
lipomeningocele, tethered spinal cord, sacral
agenesis.
2. Congenital anomalies of urinary tract—posterior
urethral valves, vesicourteral reflux, duplex kidney,
ectopic ureter.
3. Urinary tract infections, calculi.
4. Non-neurogenic bladder dysfunction, Hinmann’s
syndrome or Ochoa syndrome (facial dysmorphism
and bladder dysfunction) are associated with daytime
incontinence.
Common clinical manifestations of disorders of micturition
are poor stream, dribbling, straining in infants with
posterior urethral valves. Early diagnosis by ultrasono-
Diseases of Kidney and Urinary Tract 755
Kumud P Mehta
graphy of KUB and micturating cystourethrography
helps in early repair of valves with release of obstruction
that can prevent progressive renal damage. In older
children night time or day time enuresis is commonly
associated with functional disorders of micturition.
Children with enuresis should be evaluated for specific
cause as suggested in the flowchart given in Figure
14.11.1
Enuresis
Bladder control is normally achieved between 1-5 years.
A majority of children are dry during the day by the age
of 2-3 years and at night by 3-5 years.
Nocturnal enuresis (involuntary voiding at night with
daytime control), is a common condition affecting 10-15
percent children above the age of 5 years. It is three times
more common in boys. There is a spontaneous tendency
to remit and the prevalence is about 3 percent at the age
of 10 years and less than 1 percent in adults. Enuresis is
a benign condition but often leads to significant
emotional and psychological problems in the child and
the family.
The etiology of nocturnal enuresis is not well
understood. The disorder is often familial and in a large
proportion, one of the parents or siblings was also
enuretic. Inadequate or inappropriate toilet training may
play a role. Emotional stress may precipitate bedwetting
in a previously continent child. It has been suggested
that children with enuresis have smaller maximum
bladder capacities which become normal after they
recover.
Enuretic children tend to be heavy sleepers. More
recently, it was observed that enuretic children had lower
noctural ADH secretion rate, as compared to normal
subjects. It is more likely that enuresis is due to a delay
in the maturation of the neurological mechanisms
involved in the bladder control, which improve with
increase in age. Psychological and behavior problems are
common in such children and disappear after enuresis
is no longer present.
Treatment of Nocturnal Enuresis
Reassurance and sympathetic handling of the problem
are important. Punishment or humiliation of the child
must be avoided.
756 IAP Textbook of Pediatrics
Figure 14.11.1: Algorithm for evaluation of enuresis
in a child
Strict fluid restriction at and after the evening meal and
waking the child during night may be effective, but
compliance with such a regimen is difficult. Imipramine
in a dosage of 50 mg daily for a child below the age of
10 years is beneficial but most children relapse when the
drug is stopped. Higher doses, more than 75 mg/day,
are of no additional benefit. The side effects of
imipramine include restlessness, headache, abdominal
pain and weight loss; accidental poisoning may cause
coma, convulsions and arrhythmias. In general,
imipramine therapy should be discouraged.
A moisture alarm is a conditioning device, in which
an alarm is activated when the child passes urine. The
response of urination is inhibited when the child wakes
up. Eventually, a conditioning process is established and
the child wakes up before the micturition-induced alarm
goes off. The parents and the child should be explained
the use of the alarm device. If the alarm does not awake
the child, imipramine may be added to the therapy.
Administration of arginine vasopressin (desmopres-
sin) as a nasal spray is also effective. Relapse occurs in
more than half of the cases when it is stopped. Hypo-
natremia is an uncommon side effect.
Daytime Incontinence
Wetting during the daytime is uncommon. It may be a
manifestation of a behavior disturbance. Fecal soiling
may be associated. In some cases, there is a dysfunction
of detrusor which may be hyperactive and may contract
on stress or physical exercise. Urgency of micturition
may be present. The child is unable to hold urine
and voids precipitately. Oxybutinin is beneficial in some
cases.
Pollakiuria
Rarely a child begins to void extremely frequently, at
30-60 minutes intervals. There is no dysuria or pain. It
creates great anxiety in the parents and interferes with
schooling. No organic cause seems to be present. The
disorder is most probably related to some stressful
situation. The condition resolves gradually. In persistent
cases, psychiatric evaluation may be carried out.
Giggle Micturition
Involuntary voiding during sudden laughter or straining
is occasionally seen in schoolgirls and adolescents, and
may cause considerable embarrassment. The underlying
abnormality may be an instability of bladder with
inappropriate detrusor contraction. The precipitating
event if identified, should be avoided and the child asked
to empty the bladder regularly.
Infrequent Voiding (Lazy Bladder Syndrome)
In this rare disorder, the child does not void until the
bladder is stretched to the limit. Gradually, the bladder
enlarges, and may not empty completely. Recurrent UTI
may develop. Chronic constipation may occur for the
same reason. Regular voiding should be advised.
Neuropathic Bladder
Important causes of neuropathic bladder include spina
bifida, sacral agenesis, autonomic neuropathy, transverse
myelitis, spinal cord tumors and trauma.
The treatment aims to prevent deterioration of renal
function and achieve continence. Any associated
anomaly should be appropriately treated. Medical
management is essentially based on clean intermittent
catheterization. Regular bladder emptying at 3-4 hourly
intervals may improve continence and increase bladder
capacity. In children with VUR, long-term chemoprophy-
laxis or surgery should be considered.
 Diseases of Kidney and Urinary Tract 757

Urodynamic study is useful in selected cases in BIBLIOGRAPHY

providing details of bladder function and capacity,
co-ordinated action of detrusor muscle contraction and
sphincter relaxation to decide therapy with oxybutynin,
bethacholine and clean intermittent catheterization to
reduce post-void urine and back pressure that can cause
progressive kidney damage.
1. Atala A, Bauer SB. Bladder dysfunction In: Barratt (Ed):
Pediatric Nephrology, 4th ed, Avner Harmon Lippincott
William and Wilkins, 1999;913-31.
2. Churchill BM, Abramson RP, Washl EF. Dysfunction of
lower urinary tract PCNA 2001;48:1587-1630.
3. Dharnidharka VR. Primary nocturnal enuresis. Indian
Pediatr 2000;37:135-49.

14.12 Chronic Kidney Disease

KD Phadke, Pankaj Hari

Chronic kidney disease (CKD) implies persistent renal Etiology

damage or decreased glomerular filtration rate (GFR)
The important causes of CKD are listed in Table 14.12.1.
with a risk of developing progressive loss of renal
In infancy and early childhood congenital renal
function. It is usually of gradual onset and there may be
anomalies predominate, whereas the incidence of
no symptoms in the early stages.
acquired renal diseases progressively increases through-
CKD signifies structural or functional abnormalities
out childhood.
of the kidneys for ≥ 3 months, as manifested by either:
Obstructive uropathy (23%), renal aplasia/dysplasia
1. Kidney damage, with or without decreased GFR, as
(18%), reflux nephropathy (9%) and FSGS (8%) are more
defined by:
common disorders progressing to CKD. Recent studies
• Pathologic abnormalities
have shown that FSGS is emerging as a more common
• Markers of kidney damage
etiology leading to CKD. Regardless of the primary cause,
— Urinary abnormalities (e.g. proteinuria)
glomerular and tubular adaptive changes to initial insult
— Blood abnormalities (e.g. renal tubular
syndromes) TABLE 14.12.1: Important causes of CKD
— Imaging abnormalities
Congenital disorders
2. GFR < 60 min/1.73 m 2, with or without kidney
damage. Malformations Renal hypoplasia, dysplasia
Obstructive uropathy
CKD has been staged into five stages according to GFR.
Neurogenic bladder

Stage Description GFR (ml/min/ Hereditary disorders Nephronophthisis

1.73 m2) Polycystic kidney disease
Alport’s syndrome
1 Kidney damage with normal or ↑ GFR ≥ 90 Congenital nephrotic syndrome
2 Kidney damage with mild ↓ in GFR’ 60-89
3 Moderate ↓ in GFR 30-59 Acquired disorders
4 Severe ↓ in GFR 15-29 Glomerular Focal segmental glomerulosclerosis
5 Kidney failure (end stage renal disease) < 15 or disorders (FSGS)
dialysis Crescentic glomerulonephritis
Membrano proliferative glomerulonephritis
The above staging is not applicable for children
Vascular disorders Hemolytic uremic syndrome
below 2 years of age since GFR will progressively
increase from birth to reach adult values by 2 years of Tubulointerstitial Reflux nephropathy
age. disorders Interstitial nephritis
758 IAP Textbook of Pediatrics

occur in the remaining nephrons. These changes finally

lead to global deterioration of kidney function. Final
histopathology findings are similar regardless of cause
which reveals global sclerosis, tubular atrophy and
interstitial fibrosis.

Clinical Features
The symptoms of CKD may be due to metabolic
derangements resulting from renal dysfunction or due
to the specific features of the underlying disease. The
early symptoms are vague and non-specific such as
weakness, anorexia, nausea and failure to thrive. When
renal function deteriorate significantly; anemia,
osteodystrophy and growth failure are noticed. The late
manifestations of CKD are gastrointestinal bleeding,
pericarditis, congestive cardiac failure, altered sensorium
and seizures. A careful history and clinical examination
provides useful clues to the diagnosis of the underlying
etiology (Table 14.12.2). Important signs to be looked for
in chronic kidney disease are growth failure, pallor,
rickets (Fig. 14.12.1), hypertension, altered sensorium and Figure 14.12.1: A 10-year-old body with chronic kidney
fluid overload. disease with short stature and deformities of the lower limbs

Laboratory Evaluation
The laboratory investigations are aimed at assessing the
severity of renal dysfunction, associated metabolic
abnormalities, and identifying the cause of CKD
(Fig. 14.12.2).

Baseline Investigations
Urine: Proteinuria, hematuria, microscopy
24 hours protein or protein/creatinine ratio
Blood: Hb, peripheral smear, transferrin saturation,
serum ferritin; urea, creatinine, electrolytes,
bicarbonate
calcium, phosphorous, alkaline phosphatase
HbsAg; renal ultrasound.

TABLE 14.12.2: Clinical assessment of the etiology of CKD

History Diagnosis Figure 14.12.2: Algorithm for evaluation of CKD

Recurrent fever, dysuria,
pyuria
Poor urinary stream, urinary
retention, incontinence
polyuria, polydipsia, acidosis
Positive family history
Edema, hematuria,
hypertension
Reflux nephropathy
Obstructive uropathy, neurogenic
bladder
Tubulointerstitial disease
Alport’s syndrome, polycystic
kidney disease, cystinosis
Glomerulonephritis
(MCU—micturating cystourethrography,
DMSA—dimercaptosuccinic acid scan)
Additional Investigations for Etiology
Micturating cystourethrogram
Radionuclide imaging
Renal biopsy.

MANAGEMENT OF CKD
The action plan for the various stages of CKD has been
outlined in Table 14.12.3.
Conservative Management
Aims of conservative management are:
• Correction of the reversible component of renal
dysfunction
• Preservation of renal function
• Treatment of metabolic problems
• Addressing psycho-social issues
• Optimization of growth
• Preparation for treatment of end stage renal disease
(ESRD).
Infections, accelerated hypertension, volume
depletion, obstruction to urine flow, congestive cardiac
failure and drug nephrotoxicity can acutely exacerbate
renal dysfunction (acute-on-chronic renal failure).
Correction of these factors may improve renal function.
The measures for retarding the progression of CKD
are—treatment of hypertension, prevention and
treatment of recurrent urinary tract infections, use of
proteinuria lowering agents like angiotensin convert-
ing enzyme inhibitors and avoidance of nephrotoxic
drugs.
Dietary Advice
Dietary therapy is aimed at allowing normal growth and
development. Protein restriction may produce protein
calorie-malnutrition and hence is not recommended in
children. A CKD diet should therefore consist of
100 percent recommended dietary allowance for calories
and proteins. As renal function declines, dietary
TABLE 14.12.3: Stages of CKD and action plan
Stages GFR (ml/min/ Action
1.73 m2)
1 > 90 Diagnosis and treatment
Treatment of comorbid conditions
Slowing of progression
2 60-89 Estimating progression
3 30-59 Evaluating and treating complications
4 15-29 Preparation for kidney replacement
therapy
5 < 15 Replacement
(or dialysis)
Diseases of Kidney and Urinary Tract 759
restrictions in potassium and phosphorous become
necessary. Hyperkalemia usually occurs when the GFR
falls below 10 ml/min/1.73 m2. Salt should be restricted
in patients with hypertension and fluid overload.
Appropriate daily supplementation of minerals and
vitamins should be provided, especially when child is
started on dialysis.
Renal Osteodystrophy (ROD)
Bone and mineral metabolism is affected early in CKD.
Several factors contribute to development of ROD which
is now called as mineral bone disease. These include
phosphate retention, hypocalcemia, impaired renal
calcitriol synthesis, alteration in PTH secretion, calcium
sensing receptors, and aluminium toxicity. The spectrum
of disease ranges from high turnover state (hyper-
parathyroidism, osteitis fibrosa) to low turnover state
(rickets/osteomalacia, adynamic bone disease). Early
symptoms are nonspecific and include bone pain, muscle
weakness. Long standing disease results in growth
retardation and skeletal deformities.
Laboratory and radiological studies are routinely
done; confirmation with bone biopsy is rarely required.
Aim of therapy is to prevent or reverse hyperpara-
thyroidism, maintain normal mineralization and growth.
Restriction of dietary phosphate and administration of
phosphate binders such as calcium carbonates lower
serum phosphate and suppresses hyperparathyroidism.
The serum levels of phosphorus should be maintained
between 3.5-5.5 mg/dl (1.13-1.78 mmol/L) during
adolescence and between 4-6 mg/dl for children between
the ages of 1-12 years. Aluminium hydroxide should be
avoided due to the risk of aluminium toxicity. Vitamin D
is essential to raise the serum calcium and suppress
parathormone secretion. Therapy with short acting
vitamin D analogs such as calcitriol or 1-alpha-hydroxy
D is preferred. Care should be taken that the product of
calcium and phosphorous does not exceed 55 mg2/dl2 in
child above 12 years and 65 mg2/dl2 in younger children.
Osteotomy may be required to correct bony deformities.
Hypertension
Hypertension is a common complication of advanced
stages of CKD. Some patients remain hypertensive
despite salt and fluid restriction and diuretics and may
require treatment with antihypertensives drugs.
Hypertension in patients with proteinuria and glome-
760 IAP Textbook of Pediatrics
rular filtration rate >30 ml/min/1.73 m 2 should
preferably be treated with angiotensin converting
enzyme inhibitors (e.g. enalapril). Beta-adrenergic
blockers (atenolol,) and calcium channel antagonists
(nifedipine, amlodipine) are also effective. Patients with
severe hypertension, uncontrolled with the above
medications, may require addition of clonidine or
prazosin. Angiotensin converting enzyme inhibitors may
help in retarding the progression of CKD; however, they
should be cautiously used as they may cause reduction
in GFR and worsen hyperkalemia.
Metabolic Acidosis
Metabolic acidosis occurs when the GFR falls below
25 percent of the normal. It should be corrected with
sodium bicarbonate (2-3 mEq/kg/day). The dose should
be titrated to maintain a serum bicarbonate level of
20 mEq/l.
Anemia
Several clinical features like fatigue, anorexia, poor
cognitive performance, decreased exercise capacity along
with left ventricular hypertrophy has been associated
with anemia. Inadequate production of erythropoietin
by peritubular interstitial cells in cortex is the most
important cause for anemia. Other contributing factors
include nutritional deficiency of iron, folic acid, decreased
RBC survival, and increased blood loss.
Administration of recombinant human erythro-
poietin (rHuEpo) along with adequate iron supplementa-
tion results in dose dependent increase in hemoglobin
level and cessation of transfusion requirement. The initial
dose varies between 50 to 150 IU/kg/dose thrice a week
given subcutaneously. The selected hemoglobin target
should generally be in the range of 11.0 to 12.0 g/dL.
Patient should be monitored for worsening of hyper-
tension. After the desired hematocrit is achieved, the dose
is adjusted to maintain that level. Supplements of iron
and folic acid are given. Patients on hemodialysis should
receive intravenous iron supplementation. Inadequate
response to erythropoietin may occur due to iron
deficiency, chronic infection, aluminum toxicity and
severe hyperparathyroidism. Blood transfusions should
be avoided to prevent sensitization and blood borne
infections.
Growth
Inadequate calorie intake, acidosis, salt depletion and
secondary hyperparathyroidism result in poor growth.
Abnormalities of the growth hormone-insulin like
growth factor (GH-IGF) axis are also reported. With
optimum dietary management, children with GFR > 25
ml/min/l.73 m2 grow steadily. The administration of
recombinant human growth hormone improves height
velocity of children with CKD. The high cost of this
treatment, however, limits its use.
Children with CKD should be immunized against
hepatitis B. Those planning to undergo renal trans-
plantation should also receive varicella vaccine.
RENAL REPLACEMENT THERAPY
Once ESRD is reached, renal replacement like dialysis
or transplantation becomes essential to sustain life.
Dialysis Treatment
In peritoneal dialysis (PD), the peritoneum is the semi-
permeable membrane across which the exchange of
solutes and fluid takes place (blood in the peritoneal
capillaries on one side and the dialysis fluid in the
peritoneal cavity on the other side). The major types of
PD are intermittent peritoneal dialysis (IPD), continuous
ambulatory peritoneal dialysis (CAPD) and continuous
cyclic peritoneal dialysis (CCPD). The parents can be
trained to perform exchanges. The cost of this treatment
is high. Peritonitis is likely to occur if aseptic precautions
are not followed meticulously.
Hemodialysis requires institutional facility having
dialysis machines, dialyzers (artificial kidney) and
technical expertise. It also needs a vascular access which
is difficult to obtain in young children weighing less than
20 kg. During a hemodialysis session blood is circulated
through an extracorporeal circuit that includes a hollow
fiber dialyzer. Anticoagulation of the circuit is usually
achieved by systemic heparnization. The procedure
requires continuous monitoring. The procedure needs
to be performed three times every week.
Renal Transplantation
Renal transplantation is the ideal treatment of ESRD in
children. Dialysis treatment is offered till transplantation
becomes possible. An adult kidney can be successfully
transplanted into a child. The donor can be living related

or a deceased donor. The Indian government passed
“Human Organ Transplantation Act” in 1994, recogniz-
ing “brainstem death”. This act has paved way for
cadaveric organ transplantation (Deceased donor
transplantation). Intensive hemodynamic monitoring is
needed during intraoperative and immediate post-
operative period. The major complications of trans-
plantation include rejection, infection, hypertension,
drug toxicity and recurrence of the primary disease.
Lifelong immunosuppression is required to prevent
rejection. The usual immunosuppressive therapy is a
combination of prednisolone, azathioprine or myco-
phenolate mofetil and a calcineurin inhibitor such as
cyclosporin A or tacrolimus. Excellent rehabilitation is
obtained in most children with functioning grafts. They
can attend their school normally and lead a near normal
life. The results of pediatric renal transplantation at
experienced centers are excellent and 1 year graft survival
rate has been more than 90% giving children a fresh lease
of life.
Deterrent factors for pediatric transplantation in India
include lack of awareness regarding renal transplantation
among the general public as well as medical pro-
fessionals, financial issues, lack of experienced centers,
lack of suitable donors, ill developed deceased donor
program.
14.13 Hypertension
INTRODUCTION
Hypertension in children is defined as blood pressure
values above the 95th percentile for the corresponding
age, height and sex. Values beyond 99th percentile denote
severe hypertension.
An acute rise in blood pressure is a usual feature of
acute glomerulonephritis and also may be associated
with hemolytic uremic syndrome, Guillain-Barré
syndrome, severe burns, disorders of central nervous
system, lead poisoning and porphyria. Important causes
of sustained (chronic) hypertension are listed in Table
14.13.1. They can be chiefly grouped into renal paren-
chymal, renal vascular and endocrine disorders. Essential
hypertension is being increasingly recognized in
children.
Diseases of Kidney and Urinary Tract 761
PREVENTION OF CKD
A significant proportion of cases of CKD can be
prevented by early detection and appropriate manage-
ment of the underlying condition, e.g. prompt relief of
urinary tract obstruction and early diagnosis and
treatment of vesicoureteric reflux. Early immuno-
suppressive therapy can reverse renal dysfunction due
to crescentic glomerulonephritis and prevent its
progression to CRF. Routine antenatal sonography and
systematic evaluation of children with urinary tract
infection are other useful strategies.
BIBLIOGRAPHY
1. Fine RN, Whyte DA, Boydstun I. Chronic renal failure.
In: Avner Ed, Hartnan WE, Niaudet P (Eds): Pediatric
Nephrology (5th edn). Williams and Wilkins, Baltimore,
2004.
2. Hari P, Singla IK, Kanitkar M, Bagga A. Chronic renal
failure in children. Indian Pediatr 2003;40:1035-42.
3. Moudgil A, Bagga A. Evaluation and treatment of chronic
renal failure. Indian J Pediatr 1999;66:241-53.
4. NKF K/DOQI clinical practice guidelines for chronic
kidney disease 2000.
5. Phadke K, Iyengar A, Karthik S, Kumar A, Olakkengil S.
Pediatric renal transplantation: The Bangalore
experience. Indian Pediatr 2006;43:44-7.
Kumud P Mehta
Sustained hypertension in children is mostly secon-
dary to an underlying renal or other disorder.
Diagnostic evaluation of a child with hypertension
includes identifying the cause, demonstrating target
organ damage and identifying risk factors for cardiovas-
cular injury. A thorough history and clinical examination
can give clues to the underlying etiology (Table 14.13.2).
Clinical Features
Chronic hypertension is often asymptomatic and
detected on incidental examination. Headache is an
important feature, although in a majority of children who
complain of headache, some cause other than hyper-
tension is responsible. More often the presenting feature
is related to a complication of hypertension. These
762 IAP Textbook of Pediatrics

TABLE 14.13.1: Causes of sustained hypertension

Renal parenchymal Primary or secondary
glomerulonephritis
Reflux nephropathy
Obstructive uropathy
Polycystic kidney disease
Hereditary nephritis

Renovascular Renal artery stenosis, arteriovenous

fistulae, aorto arteritis (Takayasu’s
disease) (Fig. 14.13.1)

Endocrine Cushing's disease, congenital adrenal

hyperplasia, hyperaldosteronism,
pheochromocytoma

Miscellaneous Essential hypertension,

neuroblastoma, Wilms’ tumor,
coarctation of aorta Figure 14.13.1: Renovascular hypertension.
Arrow indicates renal artery stenosis

TABLE 14.13.2: Evaluation of a child with hypertension

TABLE 14.13.3: Clinical features consistent with
Clinical Investigations Diagnosis
hypertension
Edema, hematuria Urine for hematuria, Glomerulo- Neonates
Purpura, joint proteinuria, RBC casts, nephritis; Post Respiratory distress Vomiting, seizures
pains BUN, S. creatinine streptococcal, Irritability, lethargy Palpitations/tachycardia
ASO Titer, Serum C3 lupus, HSP, Congestive heart failure Sweating, pallor or cyanosis
ANA other chronic Cardiomegaly Failure to thrive
GN
Recurrent UTI Urine culture ultrasound Chronic/recur- Older children
(USG) for pelvicalyceal rent pyelo- (In addition to above)
dilatation nephritis Fatigue, nausea
99Tc DMSA renal scan Headache Epistaxis
Renal scars,
reflux nephro- Encephalopathy Facial nerve palsy
pathy Blurred vision Polydipsia, polyuria
Weak femorals USG, color Doppler Renal artery
stenosis
Abdominal bruit Digital subtraction Aorto arteritis lead to hypertensive encephalopathy (manifested by
angiography sensorial disturbance, seizures), left ventricular failure
Renal lump/s USG of KUB Hydronephrosis
and pulmonary edema.
Polycystic
kidneys
Renal tumors
Treatment of Hypertensive Emergency
If no clinical CT scan for adrenals Adrenal causes Hypertensive emergency may be treated with nifedipine
clues but urinary VMA, MIBG
0.25 to 0.5 mg/kg per dose orally or sublingually which
symptomatic scan
hypertension reduces blood pressure within 10 minutes. However, the
fall of blood pressure is not controlled and is often
BUN—Blood urea nitrogen, ASO—Antistreptolysin O,
C3—Complement factor 3, ANA—Antinuclear antibody, unpredictable. Intravenous sodium nitroprusside
HSP—Henoch Schonlein purpura, GN—Glomerulonephritis, (0.5–8 μg/kg/minute) by continuous infusion has a
DMSA—dimercaptopuric luceinic acid, CT—Contrast tomography, potent hypotensive effect and is the method of choice.
VMA—Varillylmandelic acid, MIBG—131I metaiodobenzyl guanidine
Intravenous labetalol infusion is also effective. Intra-
include epistaxis, facial paresis, and ocular symptoms venous frusemide removes excess water and sodium and
such as momentary loss of vision (Table 14.13.3). is particularly useful in patients with acute glomerulo-
Uncommonly, a rapid increase of blood pressure may nephritis.

Treatment of Chronic Hypertension
In a large majority of patients with hypertension, the
underlying causative disorder is not curable (e.g. chronic
glomerulonephritis, reflux nephropathy). In such cases,
appropriate antihypertensive medications are given. The
aim of the treatment is to reduce the blood pressure levels
to below 90th percentile for the age. The most commonly
used agents are beta blockers (propranolol, atenolol),
calcium channel blockers (nifedipine), and angiotensin
converting enzyme inhibitors. A diuretic such as
hydrochlorthiazide is usually added. The cost of drugs
is an important consideration, since the treatment must
be given for long periods. A list of important drugs is
given in Table 14.13.4.
Essential Hypertension
Often an underlying cause cannot be identified in an
obese older child or adolescent with a family history of
essential hypertension. The blood pressure values are
only mild to moderately elevated, and there is no target
organ damage. Such cases are labeled as essential
hypertension. The treatment consists of weight reduc-
14.14 Renal Tubular Disorders
INTRODUCTION
In comparison to glomerular diseases, renal tubular
disorders are rare. Because of their non-specific or vague
manifestations, tubular disorders are frequently missed
or detected late. With early diagnosis, satisfactory
treatment is possible in several of them. A correct
diagnosis is also necessary for genetic counseling. In a
primary tubular renal disorder, there is no significant
impairment of glomerular filtration or tubulointerstitial
involvement. A tubular disorder may be congenital or
acquired. It may involve a single function of the tubule
(e.g. renal glucosuria, nephrogenic diabetes insipidus)
or multiple functions (e.g. Fanconi syndrome). A primary
tubulopathy is usually congenital and hereditary and
often involves a single tubular function. Secondary
derangements of tubular function are usually acquired,
and involve multiple functions.
Common renal tubular disorders are listed in
Table 14.14.1.
Diseases of Kidney and Urinary Tract 763
TABLE 14.13.4: Drugs for long-term
treatment of hypertension
Drug Initial Maximum
(mg/kg/day)
Nifedipine 0.25-0.3 1-3
Captopril 0.3 5
Enalapril 0.1 0.5
Propranolol 1-2 6-8
Atenolol 1 3
Hydrochlorthiazide 1 2
tion, increased exercise, salt restriction and potassium
supplementation in the diet. If necessary, appropriate
medications may be used to keep the blood pressure
levels below the 90th percentile for the age.
BIBLIOGRAPHY
1. Mehta KP. Hypertension. In Gupte S (Ed): Recent Advan-
ces in Pediatrics. Jaypee Brothers, New Delhi, 1996;
270-97.
2. National High Blood Pressure Education Program.
Working group on hypertension control in children and
adolescent. Update on the 1987 Task Force Report of
Blood Pressure. Pediatrics 1996;98:649-58.
Aditi Sinha, Arvind Bagga
The diagnosis of a tubular disorder requires accurate
measurements of GFR and quantitative determinations
of various substances in the blood and urine for the
evaluation of functions of the proximal tubule (i.e. tubular
handling of sodium, glucose, phosphate, calcium,
bicarbonate and amino acids) and distal tubule (urinary
acidification and concentration).
Renal Tubular Acidosis
Renal tubular acidosis (RTA) comprises a group of
tubular transport defects characterized by an inability
to appropriately acidify the urine with resultant
metabolic acidosis. The underlying abnormalities consist
of an impairment of bicarbonate reabsorption or
excretion of H+ ions or both. Two major varieties are
observed: distal RTA (type I) and proximal RTA (type
II); type IV characterized by hypoaldosteronism and
hyperkalemia is rare. In all forms of RTA, plasma anion
gap (Na+ - [Cl- + HCO3-]) is normal (8-16 mEq/L). The
764 IAP Textbook of Pediatrics
TABLE 14.14.1 Common disorders of renal tubule functions
Segment Function
Proximal tubule Phosphate transport
Glucose transport
Amino acid transport
Bicarbonate transport
Ascending limb of Henle Sodium, potassium, chloride transport
Distal tubule Proton secretion
Sodium, chloride transport
Collecting duct Sodium, potassium transport
Water transport
*Dysfunction of the proximal tubule (Fanconi syndrome) may be primary or secondary to various disorders (e.g., galactosemia, Lowe
syndrome)
urine anion gap (Na+ + K+ - Cl-), which provides an
estimate of renal ammonium production, is positive.
Type I RTA: Distal RTA is characterized by severe
rachitic deformities, failure to thrive and features of
hypokalemia. There is a severe metabolic acidosis due
to impaired capacity of the distal nephron to secrete H+
ions. The urine is inappropriately alkaline; proximal
tubular reabsorption of bicarbonate is normal. Persistent
acidosis results in buffering of H+ ions in the bone with
release of calcium, hypercalciuria and nephrocalcinosis.
Investigations show blood pH below 7.2, bicarbonate
below 15 mEq/L and low serum potassium (often below
2.5 mEq/L). The urine pH is more than 6 and there is
mild bicarbonaturia; hypercalciuria and hypocitraturia
are often associated.
Hypokalemia should be corrected before correction
of acidosis. Acidosis is treated by administration of alkali
solution, 2 to 3 mEq/kg/day and increased until the
blood bicarbonate levels become normal. Adequate long-
term treatment results in healing of rickets and
improvement in growth. The alkali therapy is required
lifelong.
Type II RTA: Proximal RTA is characterized by impaired
proximal tubular reabsorption of bicarbonate, the
fractional excretion of bicarbonate being more than
15 percent. In children proximal RTA is usually seen as
a part of global proximal tubular dysfunction (Fanconi
syndrome) when glucosuria, amino-aciduria, phosphat-
uria and low molecular weight proteinuria are present
in addition to bicarbonaturia.
Disorder
Hypophosphatemic rickets
Renal glucosuria
Isolated, generalized amino aciduria
Proximal renal tubular acidosis, Fanconi syndrome*
Bartter syndrome
Distal renal tubular acidosis
Gitelman syndrome
Pseudohypoaldosteronism
Liddle syndrome
Nephrogenic diabetes insipidus
Clinical features include failure to thrive, and growth
retardation. Irritability, anorexia and listlessness are
present. Rachitic deformities are rare in isolated proximal
RTA but common in Fanconi syndrome. The blood pH
and bicarbonate levels are low and urine pH is relatively
alkaline. However, if the blood bicarbonate level is below
15 mEq/L (spontaneously or following an acid load), the
urine pH reduces to 5.5 or lower.
Sodium bicarbonate is given, initially at a dose of
5-8 mEq/kg/day; part of the alkali may be given as
potassium citrate. The requirement of bicarbonate
supplements is higher in patients with proximal RTA.
Correction of acidosis results in striking increase in the
growth velocity.
Type IV RTA: It is associated with hypoaldosteronism
or resistance to the action of aldosterone, either isolated
or in the context of chronic kidney disease, e.g.
obstructive uropathy. Nephrocalcinosis and urolithiasis
are absent and bone lesions are rare. Older children may
develop type IV RTA due to advanced tubulointerstitial
renal diseases leading to mineralocorticoid resistance,
drugs or with mineralocorticoid deficiency. In younger
children, genetic defects like pseudohypoaldosteronism
may be suspected.
A summary of the findings in different types of RTA
and their differences is provided in Table 14.14.2.
Fanconi Syndrome
In Fanconi syndrome, there is global dysfunction of the
proximal tubule. Glucosuria, phosphaturia and generali-
zed amino aciduria are present. There is, in addition,
impaired reabsorption of bicarbonate (type II RTA),

TABLE 14.14.2: Investigations to differentiate types of renal tubular acidosis (RTA)
Proximal RTA
Plasma potassium Normal/low
Urine pH* <5.5
Urine anion gap Positive
Urine ammonium Low
Fractional bicarbonate excretion >10-15%
Urine calcium excretion Normal
Other tubular defects Often present
Nephrocalcinosis Absent
Bone disease Common
*Urine pH should be assessed during the state of metabolic acidosis
sodium, potassium and organic acids. The plasma
concentrations of glucose and amino acids are within the
normal range, but those of phosphate are low. Fanconi
syndrome may be primary (idiopathic) or secondary
(associated with various conditions, e.g. cystinosis, lead
toxicity, galactosemia and Wilson disease).
During infancy polyuria, polydipsia, growth
retardation and fever are common symptoms. Vitamin
D refractory rickets is a striking feature.
Treatment: The underlying primary condition should be
detected and appropriately managed. Urinary losses of
various substances should be replaced orally. Supple-
ments of sodium, potassium, bicarbonate and phosphate
are often required; ad lib water intake is allowed. Some
patients require an additional supplemental dose of
vitamin D3. Rickets may heal with correction of
hypophosphatemia and acidosis.
Cystinosis
Cystinosis is an autosomal recessively inherited
condition characterized by deposition of cystine crystals
in the cornea, conjunctiva, bone marrow, leukocytes,
lymph nodes and other organs. There is an enzymatic
defect in the transport of cystine from lysosomes to
cytosol, leading to very high levels of free cystine within
the lysosomes. The chief symptoms are polyuria,
polydipsia, failure to thrive, vitamin D resistant rickets
and photophobia. End-stage renal disease develops
before the age of 10 years.
The diagnosis is confirmed by the demonstration of
elevated leukocyte cystine levels. Cystine crystals are
seen in the cornea on slit-lamp examination and in the
bone marrow. Management of manifestations of Fanconi
Diseases of Kidney and Urinary Tract 765
Distal RTA Type IV RTA
Low/normal High
>5.5 <5.5
Positive Positive
Low Low
<5% 5-10%
High Normal/low
Absent Absent
Present Absent
Often present Absent
syndrome and oral therapy with cysteamine is beneficial.
Renal transplantation is successful but does not correct
the disorder, and cystine continues to accumulate in non-
renal tissues resulting in late-onset of hypothyroidism
and diabetes mellitus.
Renal Glucosuria
Renal glucosuria is a benign disorder in which there are
large amounts of glucose in the urine, with normal blood
glucose levels. The renal threshold for glucose reabsorp-
tion is lowered to variable degrees. There is no other
defect of proximal tubular function. No treatment is
necessary.
Nephrogenic Diabetes Insipidus
Nephrogenic diabetes insipidus (NDI) is a rare, X-linked
recessive disorder, characterized by tubular unrespon-
siveness to the antidiuretic hormone. Clinical features
include polyuria and polydipsia, irritability, poor
feeding, failure to thrive and recurrent episodes of
dehydration and fever. The patients often undergo
extensive investigations to find a cause for fever.
The urinary osmolality is usually less than 150
mOsm/kg. Serum sodium levels are high in infancy,
when they may be more than 160 mEq/L, with corres-
ponding increase in osmolality. Hypernatremia is less
common once the child has free access to water. The
diagnosis is confirmed by failure of urinary osmolality
to rise, following either water deprivation or adminis-
tration of vasopressin. The presence of low urine
osmolality (< 300 mOsm/kg) in patients with elevated
plasma osmolality (>300 mOsm/kg, serum sodium >145
mEq/L), either at baseline or after water deprivation, is
766 IAP Textbook of Pediatrics
diagnostic of diabetes insipidus. Following adminis-
tration of vasopressin, the increase of urine osmolality
in patients with nephrogenic DI is nil or minimal. The
urine osmolality increases by >50% in patients with
central DI.
Treatment consists of provision of adequate amounts
of water to compensate for the urinary losses. Hydro-
chlorothiazide at a dose of 1-3 mg/kg/day combined
with sodium restriction leads to significant reduction of
urine volume. Co-treatment with indomethacin or
amiloride is useful.
Bartter Syndrome
Bartter syndrome is characterized by variable presenta-
tion with polyuria, failure to thrive, normal to low blood
pressure, hypokalemia, hypochloremia and metabolic
alkalosis; plasma levels of renin and aldosterone are
raised. There is urinary wasting of potassium, sodium
and chloride.
Treatment with supplementation of potassium and
administration of indomethacin is usually satisfactory,
although serum K + levels may not increase above
3.5 mEq/L.
Urolithiasis
Patients with stones either in the bladder or upper
urinary tract may present with hematuria, pain abdomen
and urinary tract infections. Isolated vesical calculi are
seen in children consuming a cereal based diet lacking
in animal proteins. They are chiefly composed of
ammonium acid urate and calcium urate.
Renal stones are usually secondary to an underlying
disorder, chiefly idiopathic hypercalciuria, hyperoxaluria
and recurrent urinary tract infections. Hypercalcemia,
renal tubular acidosis, cystinuria and hyperuricosuria are
rare causes. A metabolic cause is more likely if there is a
positive family history, nephrocalcinosis, sterile urine,
recurrent stones or presence of clinical features like
failure to thrive, rickets or polyuria. All patients
presenting with renal stones or nephrocalcinosis should
be evaluated to determine the etiology. Investigations
include estimation of blood levels of urea, creatinine,
electrolytes, calcium, phosphorus, magnesium, pH and
bicarbonate. Urine is examined for crystals and casts;
estimation of spot and 24-hr urine calcium, creatinine,
uric acid and protein is recommended. Sodium nitro-
prusside test for cystine and 24-hr urinary oxalate is
required in patients with recurrent or multiple stones.
Treatment should be directed at the underlying cause;
a high fluid intake and low salt diet is advised in all
patients. Patients with idiopathic hypercalciuria benefit
from modest salt restriction, and administration of
potassium citrate; refractory cases might need treatment
with thiazide diuretics.
Cystinuria
Cystinuria is an autosomal recessive disorder characteri-
zed by a defect in transport of the four dibasic amino
acids: cystine, ornithine, lysine and arginine, causing
their increased urinary excretion. Cystine is relatively
insoluble and may lead to calculus formation. The stones
are typically radiopaque and urinalysis shows hexagonal
cystine crystals. The urinary cyanidenitroprusside test
gives a magenta red color. The four amino acids can be
identified on paper chromatography; plasma concentra-
tions are usually normal. A high fluid intake and
alkalization of urine increase the solubility of cystine. D-
penicillamine may dissolve calculi as well as prevent
their formation.
BIBLIOGRAPHY
1. Bagga A, Bajpai A, Menon S. Approach to renal tubular
disorders. Indian J Pediatr 2005;72:771-6.
2. Bagga A, Sinha A. Evaluation of renal tubular acidosis.
Indian J Pediatr 2007;74:679-86.
3. Soriano RJ. Renal tubular acidosis. Pediatr Nephrol 2000;
14:1121-36.
4. Srivastava RN, Bagga A. Urolithiasis. In: Srivastava RN,
Bagga A, (Eds): Pediatric Nephrology, 4th edn. New
Delhi: Jaypee Brothers 2005;379-89.
 15.1 Anemia in Children: MR Lokeshwar, VP Choudhry ............................................................................................................................. 768
15.2 The Value of a Complete Blood Count in Children: Zeenat Currimbhoy .......................................................................................... 771
15.3 Anemia in the Newborn: Jayashree A Mondkar, Mamta Manglani, Armida Fernandez ..................................................................... 775
15.4 Nutritional Anemias in Infancy and Childhood: Niranjan Shendurnikar, Omprakash Shukla, Sushil Madan .................................. 780
15.5 Nutritional Anemias in Adolescence: Sushil Madan .......................................................................................................................... 785
15.6 Thalassemia: MR Lokeshwar, Nitin Shah, Swati Kanakia, Mamta Manglani ....................................................................................... 794
15.7 Sickle Cell Disease: VS Dani ................................................................................................................................................................ 816
15.8 Red Cell Membrane Disorders: Rashmi Dalvi, Bharat Agarwal, R Agarwal ....................................................................................... 820
15.9 Autoimmune Hemolytic Anemia: Bharat Agarwal, Rashmi Dalvi ....................................................................................................... 822
15.10 Bone Marrow Failure Syndrome: Nitin Shah, MR Lokeshwar ............................................................................................................ 824
15.11 Physiology of Hemostasis: Approach to a Bleeding Disorder: Renu Saxena ................................................................................ 828
15.12 Platelet and Bleeding Disorders: VP Choudhry, Amit Upadhyay ....................................................................................................... 831
15.13 Disseminated Intravascular Coagulation (DIC): Anupam Sachdeva, VP Choudhry ......................................................................... 843
15.14 Bleeding Disorders in the Newborn: Jayashree A Mondkar, Mamta Manglani, Armida Fernandez ................................................. 854
15.15 Hematopoietic Growth Factors: Purvish M Parikh, MR Lokeshwar .................................................................................................... 858
15.16 Transfusion Medicine and Component Therapy in Pediatrics: RK Marwaha, Sudeshna Mitra, Deepak Bansal ........................... 861
768 IAP Textbook of Pediatrics

15.1 Anemia in Children

MR Lokeshwar, VP Choudhry

INTRODUCTION the oxygen dissociation curve and deviation of blood

Anemia is global problem of immense public health flow towards vital organs and tissues.
significance. It is an ancient disease, and commonest
chronic malady of mankind and seen all over the world. CLASSIFICATION
Anemia is defined as reduction of red blood cell Anemia is not a specific entity but an indication of an
volume or hemoglobin concentration, and hematocrit underlying pathologic process or disease.
below the range of values occurring in healthy persons, Anemia may be classified as
or two standard deviations below the mean for the • Mild Anemia < 10 gm%, but < normal for the
normal population, age and sex. age.
Anemia is reduction in oxygen carrying capacity of • Moderate Anemia 7-10 gm%
blood as a result of reduction in: • Severe Anemia < 7 gm%
• Red cell mass -Red cell count / HCT • Very Severe Anemia < 5 gm%
• Hb. concentration.
Although a reduction in the amount of circulating Useful classification of the anemia of childhood divides
RBCs and hemoglobin decreases the oxygen carrying them into two broad groups—
capacity of the blood, few physiological disturbances • Those resulting primarily from decreased or
occur until hemoglobin level falls below 7 to 8 g/dl. ineffective (inadequate) production of red blood cells
Below this level pallor becomes evident in the skin and or hemoglobin;
mucus membrane. Physiologic adjustment to anemia • Those in which increased destruction or loss of red
includes tachycardia, increased cardiac output, shift in cells is predominant mechanism.

TABLE 15.1.1: Shows age specific Indices

Hb (g %) Hct(%) MCV(fl) MCHC % Retic(%) WBC/mm3x 1000, Platelets
Mean (2SD) Mean(-2SD) Mean(-2SD) Mean(-2SD) Mean(+2SD) (103/mm3)
Term (Cord) 16.5 (13.5) 51 (42) 108 (98) (33.0)(30) (3-7) 18.1 (9-30) 290
1-3 days 18.5 (14.5) 56 (45) 108 (95) 33.0 (29) (1.8-4.6) 18.9 (9.4-34) 192
2 wks 16.6 (13.4) 53 (41) 105 (88) 31.4 (28.1) — 11.4 (5-20) 252
1 month 13.9 (10.7) 44(33) 101 (91) 31.8 (28.1) (0.1-1.7) 10.8 (4-19.5) —
6 mth-2 yr 12.0 36 78 33.0 — 10.6 (150-350)
2-6 yrs 12.5 (11.5) 37(34) 81(75) 34(31) (0.5-1.0) 8.5(5-15.5) —
6-12 yrs 13.5(11.5) 40 (35) 86(77) 34(31) (0.5-1.0) 8.1(4.5-13.5) —
12-18 yr Male 14.5 (13) 43(36) 88(78) 34(31) (0.5-1.0) 7.8 (4.3-13.5) —
12-18 yr Female 14.0(12) 41(37) 90(78) 34(31) 0.5-1 7.8(4.5-13.5) —

Adapted from Harriet Lane Handbook, Kevin B Johnson, Jaypee Brothers Medical Publishers, New Delhi, India, pp 231.(1)

TABLE 15.1.2: Shows hemoglobin and hematocrit cut off values used to define anemia in
people living at sea level (WHO criteria)
Age/Sex Group Hb. level below Gm/dl. HCT level below%
6 months – 5 yrs. <11.0 33
5 – 11 yrs. <11.5 34
12 – 13 yrs. <12.0 36
Non-pregnant women <12 36
Pregnant women <11 33
Men <13 39

From WHO/UNICEF/UNO 1997

 Pediatric Hematology 769

TABLE 15.1.3: Shows the important causes of anemia in childhood

• Anemia resulting primarily from inadequate production of red blood cells or hemoglobin.
1. Marrow failure
• Aplastic anemia involving more than one cell line with or without congenital anomalies.
– Congenital
- Fanconie’s Anemia, Dyskaratosis Congenita, etc.
- Acquired
- Idiopathic.
– Infection, Chronic inflammatory disorder, Renal disease, Liver disorders, and Endocrine disorders, Chemicals, Physical
agents, Metabolic products, Immune mechanism.
• Decreased numbers of red blood cell precursors in the marrow.
– Pure red blood cell anemia - Congenital pure red blood cell anemia (Diamond Blackfan Syndrome)
– Acquired pure red blood cell anemia-Transient erythroblastopenia of childhood. (e.g. TEC)
2. Marrow replacement
• Malignancies and infiltrative disorders, Leukemia, Hodgkin’disease. Neuroblastoma
• Osteopetrosis,
• Storage disorders (Gaucher, Nimennpick),
• Myelofibrosis
• Congenital dyserythropoietic anemia
• Ineffective erythropoiesis-Thalassemia.
• Chemotherapy
3. Deficiency of specific factors
• Megaloblastic anemia
– Folic acid deficiency or malabsorption
– B12 deficiency - malabsorption or transport disorders, orotic aciduria
• Microcytic anemia
– Iron deficiency
– Pyridoxine responsive and X-linked hypo chromic anemia
– Lead poisoning
– Copper deficiency.
4. Impaired erythropoietin production
– Chronic renal disease
– Hypothyroidism
– Hypopitutrism
– Chronic infection and inflammation
– Malignancy
– Protein malnutrition
Anemia resulting primarily from increased destruction or loss of red cells
1. Loss of red cells from the body.
• Acute Hemorrhage
• Chronic Hemorrhage
2. Hemolytic anemia- Excess Destruction
• Intracorpuscular Defect (Intrinsic defect of red blood cells)
• Extracorpuscular Defect (Extrinsic defect of red blood cells)
Intra Corpuscular Defect (Intrinsic defect of red blood cells)
• Membrane defect (Membranopathy)
– Hereditary spherocytosis / Elliptocytosis / Stomatocytosis.
– Paroxysmal Nocturnal Hemoglobinuria.
– Pyropyknocytosis.
• Enzymatic defect (Enzymopathy) -Non-spherocytic Hemolytic anemia
– Defect in enzymes of Glycolytic Pathway - Pyruvate Kinase, Hexokinase and other enzyme defects.
– Defect in enzymes of the Pentose phosphate pathway and glutathione Complex -G6PD deficiency.
• Defect in Synthesis of Hemoglobin (Hemoglobnopathy)
– Hb S, C, D, E, etc alone or in combination.
– Thalassemia group of disorder.
• Extra-corpuscular Defect (Extracellular defect of red blood cells)
– Immunologic disorder
Contd...
770 IAP Textbook of Pediatrics

Contd...
• Passive acquired antibodies (Hemolytic disease of New born).
– Rh. isoimmunization
– A/B isoimmunization
– Other minor blood group incompatibility
• Active antibody formation
– Idiopathic autoimmune hemolytic anemia
– Warm and cold agglutinin diseases
– Symptomatic-Lupus, Lymphoma
– Drug induced
• Non-immunologic disorder
– Toxic drugs, Chemical agents-Heavy metals, Oxidants,
– Infections –Malarial, Clostridia, Bacterial Toxins
– Physical trauma-Microangiopathic,Thermal injury, HUS’
– Miscellaneous-Hypersplenism

Modified from Nelson’s Textbook of Pediatrics and Hematology of Infancy and Childhood—Nathan and Oski, Smiths Disease of
Infancy and Childhood

MORPHOLOGICAL CLASSIFICATION
Anemia can be evaluated by complete blood count
(Table 15.1.1).
1. Hemoglobin (Hb) values are expressed in gm/liter
2. Mean corpuscular volume (MCV) represents mean
size of RBC.
3. Mean corpuscular Hb concentration (MCHC) detects
cellular dehydration.
4. Increased MCHC occurs in hereditary spherocytosis
and other membrane abnormalities like eliptocytosis
(ovalocytosis), stomatocytosis, and sickle cell
anemia.

Figure 15.1.2: Microcytic Hypochromic RBC

(MCV < 80 Fl, MCH < 29 pg)

Figure 15.1.1: Normocytic Normochromic (MCV = 80-94Fl.

MCH - 29pg-34pg) Figure 15.1.3: Macrocytic Hypochromic Anemia MCV > 94Fl
 Pediatric Hematology 771

MORPHOLOGIC CLASSIFICATION TABLE 15.1.4: Proposed classification of anemic disorders

based on MCV and RDW
Morphologic classification is often used, the red blood
cell being characterized by their mean corpuscular Low MCV Normal MCV High MCV
volume (MCV) as
RDW Normal Thalassemia Normal Aplastic
Microcytic Hypochromic anemia trait anemia
• MCV < 80 Fl, RDW High IDA Chronic liver Megaloblastic
• MCH < 29 pg disease anemia
• MCHC < 30% Malignancies, Immune
myelofibrosis, hemolytic
Macrocytic anemia myelotoxic anemia
• MCV > 94 cmm. drugs

Normocytic Normochromic anemia (Modified from Nelson’s Textbook of Pediatrics)

• MCV - 80-94 cmm.

• MCH - 29 pg to 34 pg
• MCHC - 30-36%
Classification of anemia based on red cell parameter
derived from blood cell counter. (RDW and MCV as a
diagnostic aid in anemia).
Anemia in childhood may also be classified by
variation in cell size and shape, as reflected by alteration
in the red blood cell distribution width. A knowledge of
both the MCV the RDW can be helpful in the initial
classification of the anemia of childhood (Table 15.1.4)
RDW Values in Various Diseases
RDW is the coefficient of variation of red cell volume
distribution. RDW is the objective documentation of
subjective anisocytosis. It gives degree of red cell
anisocytosis. Normal range: 11.5 to 14.5 %.
It helps in distinguishing Iron Deficiency Anemia
(IDA) from beta thalassemia trait, two common causes
of microcytic anemia in clinical practice.
Reticulocyte count: Reticulocyte count (corrected), is the
mirror image of bone marrow activity which is markedly
reduced (<1%) in hypoplastic or aplastic anemia whereas
reticulocyte count is increased in hemolytic anemia.
BIBLIOGRAPHY
1. Bertil Glader. The Anemias Nelson’s Textbook of
Pediatrics Ed. R Klingman, HB Gleson, RE Burman
Bonita Stanton, 18th Edition.
2. Denis Miller. Anemias: General considerations on
Smith’s Blood Diseases of Infancy and Childhood. Denis
R Miller, Howard A Pearson. 4th Edition. P91, The CV
Mosby Company: Saint Louis, 1978.
3. Harriet Lane Handbook, Kevin B Johnson. Jaypee
Brothers Medical Publishers: New Delhi, India, 231.
4. Hematology of Infancy and childhood-Nathan and Oski,
5. Philip Lanzkowasky Hematologic references Manual of
Pediatric Hematology and Oncology, 630-31.
6. SM Lewis, BJ Bain, I. Bates Reference ranges and normal
values. Dacie and Lewis Practical Hematology. P13.
7. WHO/UNICEF/UNO, 1997.

15.2 The Value of a Complete

Blood Count in Children
Zeenat Currimbhoy

MEASUREMENT OF COMPLETE
BLOOD COUNT (CBC)
The components of CBC are hemoglobin (Hb), hematocrit
(HCT/PCV), mean corpuscular volume (MCV), mean
corpuscular hemoglobin concentration (MCHC), red
blood cell (RBC) Count, red cell distribution width
(RDW), WBC count and platelet count. In addition a
blood smear is examined for cellular morphology and
for a WBC differential count. A reticulocyte count
completes the examination. Instruments are available
today to do CBC.
772 IAP Textbook of Pediatrics
HEMOGLOBIN, MCV, RBC COUNT AND MCHC
Hemoglobin level more then 2 SDs below the mean
constitutes anemia. Mean corpuscular volume (MCV)
and red cell distribution width (RDW) show size and
size distribution respectively. Increased RBC size or
macrocytosis (increased MCV) points to hemolysis or
marrow failure or folic acid/Vit B12 deficiency, and
decreased RBC size or microcytosis (decreased MCV) to
iron deficiency or anemia of chronic disease or
thalassemia. Normal or elevated MCV in anemic children
with increased reticulocyte (retic) counts is the result of
hemolysis and without increased retics is due to acquired
aplastic anemia. Mean corpuscular Hb concentration
(MCHC) detects cellular hydration and although not
picked up by electric impedance instruments, e.g. Coulter
counter /Sysmax, it can be measured by light scatter
instruments e.g. Technicon Series, Cell dyne. Increased
MCHC occurs in hereditary spherocytosis and sickle cell
anemia and normal newborns. It is low in iron deficiency.
INTERPRETATION
For interpretation, the clinician must have a working
knowledge of normal values of the components of the
CBC. Hemoglobin (Hb) values vary with age. The
normally high Hb of 19 gm/dl at birth decreased to 18
gm/dl at one week of age. Thereafter it falls gradually
to reach a nadir of 10.5 g/dl by 7 to 10 weeks of age.
(Prematures reach their nadir earlier and recover later).
Thereafter, Hb remains initially around 11 g/dl and later,
after the age of 6 months, over 12g/dl.
To keep any cell number constant, the amount of cell
destruction must equal the amount effectively produced.
In case of RBCs, if this balance is upset in favor of former
TABLE 15.2.1: The RBC balance
(excessive cell destruction) or the latter (decreased
production), anemia results which is reflected in a
decrease in Hb concentration (Table 15.2.1). A third
reason why the cell counts may be upset is
maldistribution as occurs when the spleen is enlarged
and hence contains an increased amount of blood
(hypersplenism).
When Hb is decreased, further RBC parameters that
prove helpful in diagnosis are MCV, MCH, RDW and
retic count. Iron deficiency appears if external iron is not
supplied and the diet is poor in iron by 6 months of age;
hence Hb screening is valuable if routinely done at 9
to 12 months of age. MCV and RDW estimations aid in
the diagnosis of iron deficiency and RDW differentiates
it from thalassemia minor (Table 15.2.2). Additionally,
Hb is normal or near normal in a thalassemia trait, but
the RBC count is higher than normal to explain
hypochromia in red cell.
Iron deficiency and thalassemia major are usually
detected between 6 months and 2 years of age. Both show
hallmark of hypochromia on peripheral blood (PB)
smears and a low MCV, but unlike iron deficiency,
several nucleated red cells (NRs) are present in a major
thalassemic smear.
If iron deficiency is on the way of being corrected
with iron therapy (at least 1g/dl of Hb rise within one
month), and then the Hb gets “stuck” at 8 to 9g/dl,
suspect and underlying chronic infection which may
show hypochromia. Serum ferritin solves this problem.
It is low in iron deficiency (<15 mg/dl).
Reticulocyte is evident when the marrow attempts
to make up for the blood loss. If RBC destruction
(hemolysis) is due to malaria, retic count rises to
compensate, unless there is a complication iron and/or

folic acid deficiency. In congenital hemolytic anemias
with continuous hemolysis, Hb is low only if the bone
marrow cannot compensate for red cell destruction, e.g.
in congenital spherocytosis, if the Hb normal and the
retic count is elevated, it implies a state of a compensated
hemolytic anemia. Peripheral blood smears are helpful
in diagnosing nonspecific and specific types of hemolysis
by the presence of nucleated red cells (NRs),
polychromatophilia, Howell-Jolly bodies, fragmented
cells, spiculated RBCs, sickle cells, basophilic stippling,
rouleaux formation, spherocytes, macrocytes etc.2 The
MCV is high with severe hemolyis and there may also
be an increase in WBC and platelet counts. If in a
peripheral blood smear NRs are increased, a correction
must be made in the WBC count thus:
NR
Corrected WBC count = —————— × WBC count
NR + 100
Increased MCV (macrocytosis) if due to extravascular
RBC loss from hemolysis, will show a reticyulocytosis
and hyperbilirubinemia, but if due to bone marrow
failure (aplastic anemia), will show a reticulocytopenia.
Anemia with a normal MCV and reticulocytes can also
be due to hemolysis, and in the absence of reticulocytes,
it may be due to chronic infection or chronic
inflammation.
WBC, Granulocytes, Lymphocytes
WBC counts lack sensitivity and specificity, hence must
be viewed in the context of the illness. An erroneous
TABLE 15.2.2: RDW and MCV as an aid in diagnosis
MCV low MCV normal
RDW RDW RDW
normal high normal
Thalassemia trait Iron deficiency Normal
Chronic disease S-beta thalassemia Chronic disease
HbH Sickle/Hbc trait
Fragmentation Hereditary
(HUS, DIC) speherocytosis,
Chemotherapy,
CML, hemorrhage
(Ref. Waters, MC and Abelson, HT Pediatric Clinics of North America 1996;43:599-622)
MCV low (67m3) and RDW high = Iron deficiency
MCV low (67m3) and RDW normal = Thalassemia trait and
The low MCV cannot be corrected with iron therapy
Pediatric Hematology 773
concept is that polymorphonuclear (PMN) leukocytosis
exclusively implies a bacterial infection.
Normal WBC counts and differentials are given in
Table 15.2.3.
If after the neonatal period (i.e. after 1 month of age)
children display over 500 bands/mm3 (non-segmented
neutrophils), it suggests an infection, often bacterial, but
may be viral, irrespective of the WBC count.
Leukopenia is frequently associated with viral
infections. Lymphocytes with atypical lymphocytes
(which should be counted separately from regular
lymphocytes) are encountered in EBV, CMV, HBV, HAV
and HIV infections.
Eosinophilia is seen in parasitic infections and allergic
reactions (Table 15.2.3).
In a suspected immunodeficiency, absolute
lymphocyte count (WBC count × lymphocyte %) is
frequently less than normal for age, and demands
further specific investigations (Table 15.2.3). Testing for
Primary Immunodeficiency Disease (PID) should be
considered in any infant/child presenting with recurrent
infections. Its later consequences are autoimmunity and
malignancy.
If NRs and immature granulocytes are present in a
peripheral blood smear (i.e. a leuko-erythroblastic
reaction), beware of an underlying malignancy (e.g.
neuroblastoma).
A leukemoid reaction is a WBC count of more than
50,000/mm3 and with an increase in immature granulo-
cytes or in lymphocytes A granulocytic leukemoid
reaction with myelocytes, metamyelocytes, bands and
MCV high
RDW RDW RDW
high normal high
Mixed deficiency Aplastic anemia Folate deficiency
Early iron or folate Pre-leukemia B12 deficiency
deficiency
Hemoglobinopathy — Immune hemolysis
Myelofibrosis — Cold
agglutinins
Sideroblastic
anemia
HUS = Hemolytic uremic syndrome
DIC = Disseminated IV coagulation
CML = Chronic myelogenous leukemia
774 IAP Textbook of Pediatrics

TABLE 15.2.3: Age-specific leukocyte differential

Total leukocytes* Neutrophils Lymphocytes Monocytes Eosinophils

Age Mean (range) Mean (range) % Mean (range) % Mean % Mean %

Birth 18.1 (9-30) 11 (6-26) 61 5.5 (1-11) 31 1.1 6 0.4 2

12 hrs 22.8 (13-38) 15.5 (6-28) 68 5.5 (2-11) 24 1.2 5 0.5 2
24 hrs 18.9 (9.4-34) 11.5 (5-21) 61 5.8 (2-11.5) 31 1.1 6 0.5 2
1wk 12.2 (5-21) 5.5 (1.5-10) 45 5.0 (2-17) 41 1.1 9 0.5 4
2wks 11.4 (5-20) 4.5 (1-9.5) 40 5.5 (2-17) 48 1.0 9 0.4 3
1mth 10.8 (5-19.5) 3.8 (1-8.5) 35 6.0 (2-5-16.5) 56 0.7 7 0.3 3
6mths 11.9 (6-17.5) 3.8 (1-8-5) 32 7.3 (4-13.5) 61 0.6 5 0.3 3
1yr 11.4 (6-17.5) 3.5 (1.5-8.5) 31 7.0 (4-10.5) 61 0.6 5 0.3 3
2yrs 10.6 (6-17) 3.5 (1.5-8.5) 33 6.3 (3-9.5) 59 0.5 5 0.3 3
4yrs 9.1 (5.5-15.5) 3.8 (1.5-8.5) 42 4.5 (2-8) 50 0.5 5 0.3 3
6yrs 8.5 (5-14.5) 4.3 (1.5-8) 51 3.5 (1.5-7) 42 0.4 5 0.2 3
8yrs 8.3 (4.5-13.5) 4.4 (1.5-8) 53 3.3 (1.5-6.8) 39 0.4 4 0.2 2
10yrs 8.1 (1.5-13.5) 4.4 (1.5-8.5) 54 3.1 (1.5-6.5) 38 0.4 4 0.2 2
16yrs 7.8 (4.5-13.0) 4.4 (1.8-8) 57 2.8 (1.2-5.2) 35 0.4 5 0.2 3
21yrs 7.4 (4.5-11.0) 4.4 (1.8-7.7) 59 2.5 (1-4.8) 34 0.3 4 0.2 3

From Dallaman PR. In Rudolph AM, editor, Pediatrics, 20th ed. New York: Appleton-Century-Crofts; 1996.
Numbers of leukocytes are x 103 /mm3; ranges are estimates of 95% confidence limits; percents refer to differential count.
Neutrophilis include band cells at all ages and a small number of metamyelocytes and mydelocytes in the first few days of life.

neutrophils has to be distinguished from chronic autoimmune idiopathic thrombocytopenic purpura

myelogenous leukemia (CML). Heperleukocytosis (AITP) in which platelet count often falls below
increases Hb, HCT, RBC and MCV value in electronic 20,000/mm3 . For rough calculations 1 platelet/oil
cell counters. immersion field corresponds to 10,000 to 15,000
Infants with a low absolute lymphocyte count (ALC) platelets/mm3. It is worthwhile to look for evidence of
of <1500/ mm3 suggests a diagnosis of severe combined leukemia (blasts/high WBC count, and low PMN count)
immunodeficiency (SCID), which ends up in early death when thrombocytopenia is present. In leukemia or in
if not treated-hence, SCID is a pediatric emergency, and aplastic anemia, a pancytopenia (RBC, WBC and platelet
ALC is considered to be the most useful screening cytopenia) is present. Thrombocytosis is commonly
diagnostic test of SCID from birth (Tabel 15.2.4). associated with infections, and can occur in iron
Peripheral blood smears may reveal leukocyte deficiency and hemolytic anemias and post-splenectomy.
abnormalities, e.g. cytoplasmic inclusions, or a marked
shift to the left with immature granulocytes or blasts, or
TABLE 15.2.4: ALC at various ages (absolute counts
a leuko-erythroblastic reaction, or decreased lympho- (× 109/L): Median and percentiles (5th to 95th percentiles)
cytes or thrombocytopenia thereby emphasizing the
Age ALC
importance of blood smears in the detection of both RBC
and WBC abnormalities. Neonatal 4.8 (0.7-7.3)
1wk – 2 moths 6.7 (3.5-13.1)
2-5 moths 6.9 (3.7-9.6)
Platelet Count
5-9 moths 6.0 (3.8-9.9)
The previously neglected platelet size and counts are now 9-15 moths 5.5 (2.6-10.4)
being easily done in CBC machines. Large platelets are 15-24 moths 5.6 (2.7-11.9)
2-5 yrs 3.3 (1.7-6.9)
picked up by CBC machines (mean platelet volume) and
5-10 yrs 2.8 (1.1-5.9)
visually in PB smears. They occur in immunomediated
10-16 yrs 2.2 (1.0-5.3)
platelet destruction as new young platelets produced by Adult 1.8 (1.0-2.8)
the marrow enter the peripheral blood in an effort to
compensate. Thrombocytopenia is commonly due to ALC—Absolute lymphocyte count
 Pediatric Hematology 775

In conclusion, the often routinely done CBC and PB
smears provide an excellent framework on which the
clinician can recognize and diagnose a disease,
direct therapy, prognosticate, and also counsel patients
and parents with genetic conditions, e.g. Thalassemia
major.
Infants with a low absolute lymphocyte count (ALC)
of < 1500/mm3 suggests a diagnosis of Severe Combined
immunodeficiency (SCID) which ends up in early death
if not treated-hence SCID is a pediatric emergency, ALC
is considered to be the most useful screening diagnostic
test of SCID from birth.
Testing for primary immunodeficiency diseases (PID)
should be considered in any infant/child presenting with
recurrent infections. Its later consequences are auto-
immunity and malignancy.
BIBLIOGRAPHY
1. Brugnara C and Platt OS. The Neonatal Erythrocyte and
its disorders. 519-55 Nathan and Oski’s Hematology of
Infancy and Childhood. Philadelphia: WB Saunders 2003.
2. Harriet Lane Handbook. 16th ed. VI Gunn C. Nechyba
Mobsy 2002.
3. Walter MC and Abelson HJ, Pediatric Clinics of North
America 1996;43:599-622.

15.3 Anemia in the Newborn

Jayashree A Mondkar, Mamta Manglani, Armida Fernandez

INTRODUCTION is rapid. Reticulocyte counts are 3-7% reflecting

erythropoiesis. With improved oxygen saturation to 95%
Anemia during the first week of life is defined as a
after birth, the erythropoietin levels become undetectable
hemoglobin value less than 14 gram/dl.
hence RBC production stops, reticulocyte counts are low
NORMAL HEMATOLOGICAL VALUES IN THE and the hemoglobin level falls (Table 15.3.1).
NEWBORN This factor coupled with a reduced life span of fetal
RBCs results in anemia that is not a functional one as
The mean cord blood hemoglobin of healthy term infants oxygen delivery to the tissue is adequate as the levels of
ranges between 14 and 20 g/dl with a mean of Hb A and 2,3DPG increase.
16.8 gm/dl. At 8-12 weeks, hemoglobin levels reach their nadir
Shortly after birth the Hb concentration increases by (Table 15.3.2), oxygen delivery to the tissues is impaired,
as much as 6 gm/dl depending on the amount of erythropoietin production is stimulated and hemoglobin
placental transfusion. The redistribution of body fluids starts increasing.
with decrease in plasma volume after birth also accounts The hemoglobin and RBC count fall earlier and to a
for this rise. Failure of hemoglobin to rise during this
greater extent in preterm infants leading to anemia of
period is a marker of blood loss.
prematurity.
Hemoglobin levels return to cord blood values by the
end of the first week. A significant Hb decrease during TABLE 15.3.1: RBC Values in term and preterm
this time even if absolute values of Hb are within the infants during the first week of life
normal range is also suggestive of hemorrhage or Hb (gms/ dl) Hct % Reticulocyte (%)
hemolysis. Term Infants
Beyond the first week of life, Hb concentrations Cord blood 17.0 (14-20) 53 (45-61) <7
decrease in both term and preterm infants. To reach Day 1 18.4 58 <7
minimal levels of 9.4 – 14.5 gm/dl in term infants by 7 to Day 3 17.8 55 <3
9 weeks of age. This “physiological” anemia occurs Day 7 17.0 54 <1
because of a decline in erythrocyte mass due to the Preterms
following reasons: <1500 grams
In utero the fetal oxygen saturation is low at around Cord blood 16.0 (13-18.5) 49 <10
45%, erythropoietin levels are high and RBC production Day 7 14.8 45 <3
776 IAP Textbook of Pediatrics

TABLE 15.3.2: Hemoglobin nadir in babies in the • Hemorrhagic disease of newborn now called vitamin
first year of life K deficiency bleeding (VKDB) resulting in bleeding
Maturity of baby at birth Hemoglobin level Time of nadir from gastrointestinal tract, umbilicus, intracranial
at nadir bleed.
Term babies 9.2-11.0 6-12 wks • Sepsis with DIC.
Premature babies 8.0-10.0 5-10 wks • Intrauterine TORCH infections.
(1200-2500gm) • Iatrogenic anemia due to excessive blood sampling.
Small premature babies 6.5-9.0 4-8 wks
(<1200gm) Shortened Red Blood Cell Life Span or Hemolysis
The average life span of a neonatal RBC is only one half
CAUSES OF PATHOLOGIC ANEMIA IN THE
to two thirds that of the RBC life span in an adult. Cells
NEWBORN
of the most immature infants may survive only 35-70
The 3 basic mechanisms for the development of anemia days. Hemolytic anemia which further shortens RBC
in any patient are survival can occur in the newborn for a variety of reasons:
1. Blood loss. Immune hemolytic anemia: Placental transfer of
2. Shortened RBC life span or hemolysis maternal antibodies directed against fetal red cell
3. Inadequate red blood cell (RBC) production. antigens is the most common cause of neonatal
hemolysis. This occurs as a consequence of maternal
Blood Loss sensitization to fetal antigens that have leaked into the
Blood loss can occur in the fetus, at birth or in the post- maternal circulation. Immune hemolysis may be due to
natal period. Rh, ABO or minor blood group incompatibility. When
The bleeding may be acute or chronic. an Rh negative mother conceives an Rh positive baby,
fetal red cells may cross the placenta and sensitize the
A. Obstetric causes of blood loss include: maternal immune system. On subsequent exposure to
• Abruptio placentae. Rh positive cells across the placenta, the antibodies
• Placenta previa. produced by the maternal immune system may cross the
• Incision of placenta at cesarean section. placenta and cause hemolysis of fetal red cells. Similar
• Rupture of a normal umbilical cord. situation may arise with mothers with blood group O
• Malformations of placenta and cord –velamentous and babies with blood group A or B.
insertion, vasa praevia. Maternal auto immune hemolytic disease: Antibodies
• Rupture of anomalous insertion of cord and from the mother cross the placenta and result in fetal
hematoma of cord. red cell hemolysis.
B. Occult blood loss before birth or during delivery Non-immune Hemolytic Anemia in the Newborn may
could be due to: occur due to–
RBC membrane defect–Hereditary spherocytosis,
• Feto-maternal bleeding
metabolic defects, hemoglobinopathies, infection or
• Feto–fetal bleeding as occurs in: Twin-to-twin
disseminated intravascular coagulation.
transfusion
• Feto-placental bleeding. If the neonate is accidentally
held above the placenta for a time after delivery, a Inadequate Red Blood Cell Production
fetal-placental transfusion may result in blood loss.
Diminished RBC production could be due to:
• Diamond-Blackfan syndrome,
C. Bleeding in the neonatal period may be due to:
• Fanconi’s anemia,
• Birth trauma resulting in intracranial bleeding, • Congenital leukemia,
cephalhematoma, sub galeal hemorrhage, retro- • Congenital infections with parvovirus, etc.
peritoneal bleeding. • Osteopetrosis
 Pediatric Hematology 777

Infections that cause anemia due to reduced red cell Apnea: severe, anemia may result in respiratory
production include parvovirus B19, CMV, toxoplasmosis, depression, manifested by increased periodic breathing
congenital syphilis, rubella and herpes simplex. Maternal and apnea.
infection with parvovirus B19 causes fetal anemia which Tachypnea, tachycardia decreased activity and
is severe enough to lead to intrauterine death, due to lethargy are frequently attributed to anemia, with
hydrops. In addition to anemia, parvovirus infections subjective improvement subsequent to transfusion. Poor
cause marked reticulocytopenia. Thrombocytopenia may
growth, inadequate weight gain despite adequate caloric
also occur.
intake often is attributed to AOP.
Diamond Blackfan Syndrome also called pure red cell
• Tachycardia may occur.
aplasia, occurs either due to a lack of erythroid stem cells
or immune suppression of stem cell differentiation. • Flow murmurs may occur.
Inheritance seems to follow an autosomal ressessive • Metabolic acidosis may be detected.
inheritance. The disorder should be suspected in any
newborn with anemia and reticulocytopenia, normal APPROACH TO DIAGNOSIS
platelets and leucocytes. Musculo-skeletal abnormalities,
Feature Inference
triphalyngeal thumbs may occur in a third of patients.
The diagnosis is confirmed by examination of bone Obstetric APH Fetal blood loss
marrow aspirate which reveals a virtual absence of History Procedures like Feto maternal
erythroid precursors. Amniocentesis Hemorrhage
Traumatic delivery Concealed hemorrhage,
ANEMIA OF PREMATURITY subgaleal hemorrhage,
Anemia of prematurity (AOP) is an exaggeration of the ICH
physiologic anemia of infancy. The Hb nadir is therefore Birth History Twin Delivery Twin to twin
reached earlier and is lower than in term babies and can transfusion syndrome
be as low as 7.8 to 9.6 gm/dl. Shortened survival of RBCs Precipitate delivery Ruptured cord, ICH
to an average of 60 days (120 days life span in adult RBCs) Maternal Drug ingestion like Early onset
and rapid body growth with relative hemodilution are History aspirin, warfarin, hemorrhagic disease
the contributory factors. Besides, iatrogenic blood losses anticonvulsants
may be higher, vitamin E deficiency is more common in
Family History Anemia in other G6PD Deficiency
small preterm infants. male children
CLINICAL PRESENTATION OF H/O attacks of Hereditary
BABIES WITH ANEMIA jaundice with spherocytosis
gallstones
Acute hemorrhage before, during or after delivery is
Clinical GI bleed on day Vitamin K deficiency
poorly tolerated by the neonate and results in a neonate
Presentation 2-3 in a well baby bleeding (VKDB)
who is pale, shocked, has acute distress, shallow, rapid
and often irregular respiration, tachycardia, weak or Bleeding in a sick Sepsis with DIC
absent peripheral pulses, low blood pressure and no baby
Repeated blood
hepatosplenomegaly. Such babies may have normal
collections especially
hemoglobin level initially but can fall rapidly in the first
in small preterms Iatrogenic anemia
6-8 hours.
asphyxia and shock Acute blood loss
Infants, who have suffered chronic blood loss in utero, pallor with CHF Chronic severe blood
vary in their clinical state at delivery from a hydropic loss, immune hydrops
infant with severe anemia to an asymptomatic infant. Anemia, jaundice, Iso immune
Often the pallor is marked and disproportionate to the hepato-splenomegaly hemolysis
evidence of distress.
Few symptoms are universally accepted as attri- SGA with anemia,
butable to anemia; however, the following are among hepato splenomegaly, Intrauterine infection
the symptoms attributable to AOP: jaundice
778 IAP Textbook of Pediatrics

LABORATORY INVESTIGATIONS IN A CASE OF In infants with severe anemia or hypoxia, O Rh

NEONATAL ANEMIA (TABLE 15.3.3)
Investigations should be tailored to requirements of the
patient based on history and examination. These include:
• Hemogram with peripheral smear for RBC
morphology.
Reticulocyte count (normal 3-7%) and RBC indices
to differentiate anemia due to hemorrhage and
hemolysis (elevated reticulocyte count) from anemia
due to bone marrow suppression (low reticulocyte
count).
• Blood group and Coombs’ test, to detect blood group
incompatibility.
• Serum bilirubin (indirect or unconjugated) elevated
levels suggest hemolysis.
• G6PD estimation.
• Kleihauer–Betke test on mother’s blood to detect the
presence of fetal RBCs in maternal circulation.
• Urine and stool examination for occult blood.
• Hemoglobin electrophoresis if alpha thalassemia
suspected.
• Bone marrow examination to confirm diagnosis of
hypoplastic anemia.
negative RBCs are an acceptable alternative.
Anemia with Congestive Heart Failure
Transfusion is required in infants in whom anemia may
be contributing to congestive heart failure. Furosemide
1mg/kg followed by a packed cell transfusion of 10-15
cc/kg may be given 3 ml/kg of packed cells or 6 ml/kg
of whole blood raises the hemoglobin by 1gm/dl. In
severely anemic babies with CHF, where large volume
of packed cells are required, a partial exchange
transfusion with packed red cells may be carried out to
reduce circulatory overload.
Anemia due to Hemolysis
Double volume exchange transfusion for hyper-
bilirubinemia followed by a top up packed cell
transfusion if required.
Other Indications for Packed Cell Transfusion

MANAGEMENT OF NEONATAL ANEMIA Besides transfusion for hemorrhagic shock, adoption of

Anemia with Shock
Therapy of acute hemorrhagic anemia is directed at
rapid expansion of the vascular space with 20 ml/kg of
isotonic saline or Ringer’s lactate, followed by either type
specific crossmatched whole blood or packed red cells
resuspended with saline.
transfusion protocols takes a variety of factors into
account, including hemoglobin levels, degree of
cardiorespiratory disease, and traditional signs and
symptoms of pathologic anemia.
Transfusion for phlebotomy losses is not routinely
required.

TABLE 15.3.3: Differential diagnosis based on findings of lab. studies

Reticulocytes Bilirubin Coombs’ test RBC morphology Diagnostic possibilities
Normal or Normal Negative Normal Physiologic anemia of infancy or prematurity;
decreased congenital hypoplastic anemia; other causes of
decreased production
Normal or Normal Negative Normal Acute hemorrhage (fetomaternal, placental,
Increased umbilical cord, or internal hemorrhage)
Hypochromic microcytes Chronic fetomaternal hemorrhage
Increased Increased Positive microspherocytes Immune hemolysis (blood group incompatibility
or maternal autoantibody)
Normal or Increased Negative Spherocytes Hereditary spherocytosis
Increased Elliptocytes Hereditary elliptocytosis
Hypochromic microcytes Alpha-or gamma-thalassemia syndrome
Spiculated RBCs Pyruvate-kinase deficiency
Schistocytes and RBC Disseminated intravascular coagulation;
fragments other microangiopathic processes
Bite cells (Heinz bodies Glucose –6 –phosphate
with supravital stain) dehydrogenase deficiencyInfections;
Normal Enclosed hemorrhage
(Cephalhematoma)

RBC Transfusion for Premature
Central Hematocrit Hemoglobin
For infants requiring significant < 40%, < 12 g/dl
ventilation (FiO2 > 40%,
pressor support)
For infants requiring minimal < 35%, < 10 g/dl
ventilation (FiO2 > 35%)
Infant requiring supplemental O2
• 24 Hrs tachycardia >180 ;
tachypnea >80
• Increased O2 requirement from
previous 48 Hrs
• Weight gain < 10 g/kg/d for 4 days
on 100 calories/kg/d
Increase in apnea >10; >3 requiring
bagging undergoing surgery < 25%, < 8g/ dl
Recombinant Erythropoietin Treatment
Multiple investigations have established that premature
infants respond to exogenously administered
recombinant human EPO with a brisk reticulocytosis and
that the drug appears to be safe. Modest decreases in the
frequency of PRBC transfusions have been documented
primarily in premature infants who are relatively large.
No agreement regarding timing, dosing, route, or
duration of therapy exists. In short, the cost-benefit ratio
for EPO has yet to be clearly established, and this
medication is not accepted universally as a standard
therapy for the individual with AOP. Babies on
erythropoietin therapy should receive oral iron therapy.
Provision of adequate amounts of vitamin E, vitamin B12,
folate, and iron are important to avoid exacerbating the
expected decline in hemoglobin levels in the premature
infant.
PREVENTION OF ANEMIA
Reducing the amount of blood taken from the premature
infant diminishes the need to replace blood. Hospitals
Pediatric Hematology 779
that care for premature infants should have the ability
to determine laboratory values using very small volumes
of serum.
The use of non-invasive monitoring devices, such as
transcutaneous hemoglobin oxygen saturation, partial
pressure of oxygen, and partial pressure of carbon
dioxide, may allow decreased blood drawing. Oral iron
therapy 2-6 mg/kg /day in preterm babies, starting by
4-6 weeks and continued till weaning has been
adequately achieved is an important preventive measure.
BIBLIOGRAPHY
1. Al-Kharfy T, Smyth JA, Wadsworth L, et al. Erythro-
poietin therapy in neonates at risk of having
bronchopulmonary dysplasia and requiring multiple
transfusions. J Pediatr 1996;129:89-96.
2. Bowden RA, Slichter SJ, Sayers M, et al. A comparison
of filtered leukocyte-reduced and cytomegalovirus
(CMV) seronegative blood products for the prevention
of transfusion- associated CMV infection after marrow
transplant. Blood 1995;86:3598-603.
3. DeMaio JG, Harris MC, Deuber C, Spitzer AR: Effect of
blood transfusion on apnea frequency in growing
premature infants. J Pediatr 1989;114:1039-41.
4. Lachance C, Chessex P, Fouron JC, et al: Myocardial,
erythropoietic, and metabolic adaptations to anemia of
prematurity. J Pediatr 1994;125:278-82.
5. Ohls RK: A multicenter randomized double-masked
placebo-controlled trial of early erythropoietin and iron
administration to preterm infants. Ped Res 1999;45:1268.
6. Roberts IAG, Murray NA. Haematology in Rennie JM.
Roberton’s Textbook of Neonatology 4th edition.Elsevir
Churchill Livingstone 2005;739-772.
7. Ringer SA, Richardson DK, Sacher RA, et al. Variations
in transfusion practice in neonatal intensive care.
Pediatrics 1998;101:194-200.
8. Strauss RG: Erythropoietin in the pathogenesis and
treatment of neonatal anemia. Transfusion 1995;35:
68-73.
9. Strauss RG: Practical issues in neonatal transfusion
practice. Am J Clin Pathol 1997;107:S57-63.
10. Widness JA, Seward VJ, Kromer IJ, et al. Changing
patterns of red blood cell transfusion in very low birth
weight infants. J Pediatr 1996;129:680-87.
780 IAP Textbook of Pediatrics
15.4 Nutritional Anemias in
Infancy and Childhood
Niranjan Shendurnikar, Omprakash Shukla, Sushil Madan
Nutritional anemias are a condition in which hemoglobin
concentration of a given individual is below the normal
level due to deficiency of one or more nutrients needed
for hemopoiesis and the hemoglobin can be increased
by the supplementation of the deficient nutrients. These
main nutrients are iron, folate, vitamin B12, proteins and
vitamin E.
IRON DEFICIENCY ANEMIA
Iron deficiency anemia is currently the most widespread
micronutrient deficiency and affects nearly 1.5 billion
people globally. Infants, preschool children, adolescents
and women of child bearing age are at greatest risk of
developing iron deficiency and its resultant anemia.
Presently available data have shown that about one-third
of world’s population suffers from iron deficiency
anemia, and of which 90 percent lives in “third world
countries”. Seventy-four percent of children between the
age of 6 to 35 months are anemic. In developing countries,
52 percent of pregnant women and about 35 to 40 percent
of non-pregnant women suffer from iron deficiency
anemia. The high prevalence of iron deficiency anemia
is accounted for by the combination of limited iron stores
at birth, timing of umbilical cord clamping, timing and
type of complementary food introduction and frequency
of infections. If not corrected it leads to increasing severity
of anemia, reduced work capacity, increased suscepti-
bility to infection and greater risk of death associated
with pregnancy and child birth.
Iron Requirements During Childhood
Understanding of iron requirements, intakes and
bioavailability is essential to explain the vulnerability of
some individuals to develop iron deficiency anemia. The
iron released from the senescent red cells during the first
8 to 12 weeks of life (a period of quiescent erythropoiesis)
is stored in the body and helps to maintain erythropoiesis
up to 4 to 6 months in a normal term infant and up to 2
to 3 months in the low birth weight infant. Normal infants
at birth have about 75 mg of iron per kg body weight,
two-thirds of which is present in red blood cells. Infants
and children should continue to absorb 0.8 to 1.0 mg of
iron daily to reach the adult body stores of 4 to 5 grams.
Iron requirements are highest in infancy during period
of rapid growth. Iron is also required more in first few
years of life, during adolescence, menstruation,
pregnancy and lactation.
Normal body losses of iron are about 20 μg/kg/day
and most of these losses occur by the shedding of cells
from intestinal mucosa. These losses are small and are
relatively constant but may increase many folds in the
presence of diarrhea, dysentery and parasitic infestations.
Certain factors protect infants from becoming iron
deficient in first few months of life. These include
(i) preferential delivery of iron to the fetus during the
pregnancy particularly during last 3 months of gestation,
(ii) placental transfusion to the newborn immediately
after the birth when the cord is allowed to pulsate before
being clamped, (iii) exclusive breast-feeding for first six
months of life, due to the better bioavailability of iron
from the breast milk. Adolescence is a period of rapid
growth, weight gain and blood volume expansion. The
overall iron requirement increases from a preadolescent
level of approximately 0.7 to 0.9 mg iron per day to as
much as 2.2 mg iron per day or perhaps more in heavily
menstruating young women. A much larger amount of
iron is actually needed to meet the growth requirements
of adolescence and even a marginal iron deficiency
during this period of growth can precipitate anemia.
Malnutrition, chronic infections and worm infestations
also contribute to a high prevalence of anemia. The causes
of iron deficiency anemia are shown in Table 15.4.1.
Dietary Iron
The dietary iron comes from two sources: Heme and non-
heme, the later being the major source of iron in diet and
is found in varying degrees in all foods of plant origin.
Heme iron is present in meat, fish and poultry, but the
intake of these products is generally low. Heme iron is
better absorbed than non-heme iron and is not influenced
by dietary factors.

TABLE 15.4.1: Causes of iron deficiency
Decreased Iron Stores
• Preterms, small-for-dates, twins
Decreased Intake/Assimilation
• Delayed weaning, malnutrition
• Iron poor diet
• Malabsorption syndromes, chronic diarrhea
• Chronic infection
• GI surgery
Increased Losses
• GI bleeding
• Malaria
• Hookworm infestation
• Peptic ulcer, diverticulitis
• Bleeding diathesis
• Fetomaternal hemorrhage
• Repeated venous sampling
Increased Demands
• Prematurity, LBW
• Recovery from PEM
• Adolescence
Additional sources of iron in the diet include the
exogenous sources originating from soil dust, water and
cooking of foods in iron pots but the bioavailability of
iron is less and the contribution insignificant. Breast milk
even in spite of low levels of iron (0.5 mg/liter) has a
better absorption and bioavailability as compared to
cow’s milk. Good sources of iron in the diet include
pulses, dals, green leafy vegetable, bajra, dates, nuts,
jaggery, meat and fish. Administration of 50 mg of
vitamin C increases iron absorption by two- fold (Table
15.4.2).
Clinical Features
Iron deficiency is a systemic disorder involving multiple
systems rather than a purely hematological condition
associated with anemia. The peak incidence of iron
deficiency in children occurs between 6 months to 3 years
and in adolescents 11 to 17 years.
TABLE 15.4.2: Sources and contents of iron
Milk (liter) Human milk (0.5 mg), Cow’s milk
0.02–0.3 mg
Foods a) Pulses (9-11 mg), Cereals (4–11 mg)
80–100 grams Green-leafy vegetables (10–18 mg)
b) Ripe banana (0.9 mg), Mango (1.3 mg)
Melon (7.5 mg)
c) Meat, fish, poultry (10–25 mg)
Additional sources- Cooking in iron pots, water, soil, dust
Pediatric Hematology 781
Symptomatology depends upon the rate of fall in
hemoglobin and hemostatic adjustment of various
systems. As the fall of hemoglobin is gradual, the onset
of symptoms is insidious. Initially pallor, anorexia and
irritability may be noticed. Later, hyperdynamic
circulation leads to palpitation, shortness of breath,
fatigue, reduced exercise tolerance and congestive heart
failure. Gradual onset of pallor may escape notice even
when the hemoglobin falls to 4 to 5 gm percent.
Platynychia, koilionychia, glossitis, stomatitis, angular
cheilosis may be observed, especially with long-standing
anemia. The triad of dysphagia due to esophageal webs,
koilonychia and splenomegaly in a patient with IDA is
known as Plummer- Vinson or Paterson-Kelly syndrome
and are not common in children. Mild degree of
hepatosplenomegaly is also not uncommon in IDA.
Pica is a well documented feature of anemia in
children and is manifested as craving for unedible things
such as dirt, clay (geophagia), ice (phagophagia), laundry
starch (amylophagia), salt, cardboard, etc. and are seen
in almost 70 to 80 percent of patients and are usually
cured by prompt iron therapy. Growth retardation and
altered host immune responses are other associated
features of IDA in children. Blue sclerae are also
occasionally observed in iron deficiency in children and
adolescents.
Iron deficiency anemia is associated with impaired
performance on a range of mental and physical functions
in children including physical coordination and capacity,
mental development, cognitive abilities, social and
emotional development. Other health consequences
include reduced immunity, increased morbidity,
increased susceptibility to heavy metal (including lead)
poisoning. Such changes may be related to functional
changes in iron containing enzymes at cellular level.
Recent observations have indicated that IDA, at a time
of crucial brain growth and development may produce
permanent and irreversible abnormalities in these
functions.
Tests for Iron Deficiency
Iron deficiency anemia develops sequentially from the
depletion of stored iron, iron deficient erythropoiesis to
iron deficiency anemia (Table 15.4.3). Laboratory tests
are needed to establish the diagnosis of IDA and to
determine its cause.
Hemoglobin, red cell count and hematocrit are
decreased in IDA. MCV, MCH and MCHC are also
reduced. Peripheral blood film shows hypochromia,
microcytosis, poikilocytosis and target cells. Reticulocyte
782 IAP Textbook of Pediatrics

TABLE 15.4.3: Laboratory tests in iron deficiency anemia Management

• Depletion of stainable iron from bone marrow
• Reduction of serum ferritin levels (less than 15 mg/ml)
• Elevation of RDW (more than 14.5%)
• Low serum iron (less than 75 mg/dl) and
• Increased total iron binding capacity (TIBC) (more than 470
mg/dl)
• Low transferrin saturation (cut off values for infants and
children, 12% and 14% respectively)
• Increased red cell protoporphyrin concentration
count is usually normal unless the child has had an acute,
recent blood loss or has received hematinics. Occasionally
platelet counts may be increased. These tests may be less
reliable in cases of mild iron deficiency anemia. Some of
these tests may be altered due to the presence of
inflammation, liver disease, diurnal variations and recent
iron intake. A low MCV with and elevated RDW is
strongly suggestive of iron deficiency anemia.
Hemoglobin levels and assay of hematocrit are
commonly used screening tests to detect IDA.
Differential diagnosis of microcytic hypochronic
anemia is iron deficiency anemia, anemia of chronic
infection, thalassemias, sideroblastic anemia and lead
poisoning. An algorythm for child with microcytic
hypochromic anemia is shown in Figure 15.4.1.
The basic principle of management of IDA needs
correction of anemia and the eradication of underlying
cause. Oral iron therapy is the ideal mode of treatment
for IDA. The treatment is safe, economical and as effective
as the parenteral therapy. Various iron salts available
include ferrous sulfate, ferrous fumarate, ferrous
gluconate, ferric salts, ferrous glycine sulfate and iron
polymaltose complexes. Ferrous compounds are 4 to 10
times better absorbed than ferric compounds. Iron salts
of carbonate, citrate, choline citrate and pyrophosphates
are not efficiently absorbed. Hemoglobin containing
preparations do not offer additional advantage over
simple ferrous salts. The currently recommended dosage
is for infants and children 3 mg/kg/day of elemental
iron, as higher doses are unnecessary, may increase side
effects and reduce the patient compliance (Table 15.4.4).
The iron requirements for different ages are often
defined in terms of body weight. However, in a commu-
nity setting, it is not feasible to use this approach. It is
recommended that one dose should be used for all
children 6 to 36 months of age. With due consideration
to the safety issues, it is recommended that 20 mg iron
be used for anemia prophylaxis for all the children in
this age-group. The daily dosage of Iron Folic Acid (IFA)
supplement (20 mg elemental iron + 100 mcg folic acid)
is recommended for children in the current NNACP
(National Nutritional Anemia Control Program).
Adolescents require 60 mg of elemental iron per day
in case of mild anemia, and 120 mg/day, (60 × 2) for
moderate and severe anemia. Therapy should continue
for eight weeks after the blood values have returned to

TABLE 15.4.4: Iron amount and percentage

iron absorption

Preparation Iron Elemental Percent iron

compound iron (mg) absorption
per tablet (mg) per tablet

Ferrous fumerate 200 66 33

Ferrous gluconate 300 36 12
Ferrous sulfate 300 60 20
(7H2O)
Ferrous sulfate, 200 74 37
anhydrous
Ferrous sulfate, 200 60 30
(1H2) (exsiccated)
Figure 15.4.1: Approach to microcytic hypochromic anemia

normal. Addition of ascorbic acid (50 mg/day) and iron
administration in divided doses between the meals help
to promote iron absorption. Suboptimal response to oral
iron therapy may be due to poor compliance, inadequate
dosage, associated infection, occult blood loss or other
causes of hypochromic microcytic anemia such as
thalassemia minor, lead poisoning or anemia of chronic
infection.
Assessment of response to treatment is made by
reticulocyte count, which rises after 2 to 4 days of therapy.
Approximately two months are required to achieve a
normal hemoglobin level (Table 15.4.5). Recent studies
have demonstrated the efficiency of weekly/twice
weekly oral iron supplementation. Human beings have
gut mucosal turnover between five and six days and
greater iron absorption may be achieved by iron
administration to new gut cells.
Parenteral iron therapy is indicated only when there
is intolerance to oral iron, persistent non-compliance or
gastrointestinal bleeding aggravated by oral iron therapy.
Iron dextran is a complex of ferric hydrochloride and
high molecular weight dextran. Intravenous injections
cause severe reactions and hence are rarely used in
children. Iron dextran can be administered by the
intravenous route either by infusion methods to bolus
(single total) dose. The dose can be calculated as:
Iron (mg) = Wt. in kg. × Hb deficit (gm/dl) × 4
Life threatening anaphylactic reactions may occur
and thus these infusions should be given in hospital
settings only. Other side effects may include fever,
abdominal cramps, pain, skin rash, arthralgia and serum
sickness like picture.
Transfusion Therapy
Blood transfusion may be needed in most severe cases
of IDA when the hemoglobin concentration is below 3
TABLE 15.4.5: Response to iron therapy in
iron deficiency anemia
12–24 h Replacement of iron enzymes; subjective
improvement; decreased irritability; increased
appetite
36–48 h Initial bone marrow response; erythroid
hyperplasia
48–72 h Reticulocytosis, peaking at 5–7 days
4–30 days Increase in Hb level
1–3 mo Repletion of stores
Pediatric Hematology 783
to 4 gm/dl, or when superimposed infection may
interfere with the therapeutic response. Careful
precautions must be taken to avoid overloading the
circulation and precipitating cardiac failure. Packed red
cells may be slowly administered, preferably 2 to 3
ml/kg at one time.
Prevention of IDA
Appropriate nutritional strategies are an important factor
in prevention of IDA. The basic approaches to the
prevention of IDA include:
1. Protection and promotion of breastfeeding, for as long
as possible, along with timely weaning is effective in
preventing IDA. Low birth weight infants need iron
supplementation from the age of 2 months.
2. Dietary modification and consumption of larger
amounts of habitual foods increases total iron
consumption by 25 to 30 percent. Processes like germi-
nation (sprouting of green gram) and consumption
of green leafy vegetables would be additional long-
term methods for prevention of IDA.
3. Periodic deworming with anti-helminthic drugs for
hookworm infestation and schistosoma should be
considered in endemic areas.
4. Supplementation with medicinal iron is considered
necessary to reduce the extent of anemia in develop-
ing countries. Administration of one pediatric (small)
tablet containing 20 mg iron and 100 μg folic acid
daily for 100 days every year has been recommended
by National Nutritional Anemia Control Program.
School-based intervention consisting of once or twice
weekly distribution of iron and folic acid tablets
through school or welfare centers can be recom-
mended as an appropriate strategy to combat IDA in
the adolescent girls.
5. Food and salt fortification with iron are evolving
rapidly and would be one of the most effective
ways to control IDA. Salt fortification gives an iron
content of 1 mg per gram of salt in the preparation.
6. Iron deficiency is prevented by increasing the use of
iron-rich foods, targeted fortification of foods for
children and the use of iron drops. In the future,
microencapsulated iron – sprinkles may be useful
strategy for treating and preventing iron deficiency
in infants and this can be supplemented with other
micronutrients such as vitamins A, C, D and folic acid
and zinc.
784 IAP Textbook of Pediatrics
7. Various contact points like measles immunization (9
months), DPT booster (16–18 months) and take home
ratios in ICDS scheme (wherever followed) should
be utilized for distribution of IFA.
Nutritional Megaloblastic Anemias
Megaloblastic anemia is caused by the deficiency of either
folate or vitamin B12 or both. These deficiencies could
arise due to:
1. Decreased intake: Vitamin B12 deficiency is observed
with strict vegetarian diets, malnutrition and in
breast-fed infants of mothers with low serum B12
levels. Folate content of goat’s milk is extremely low.
Cooking vegetables for long time in boiling water
would also reduce the folate content of diet.
2. Impaired absorption: Failure to secrete intrinsic
factor, intestinal diseases such as celiac disease,
regional ileitis and ileal resection lead to vitamin B12
malabsorption.
3. Defective utilization: Drugs such as phenytoin and
pyrimethamine interfere with folic acid metabolism.
4. Increased demands: Needs for folate and vitamin B12
are increased during infancy, especially in premature
babies due to rapid growth. The requirements also
increase during recovery from PEM, and chronic
hemolytic anemias.
Clinical Features
The commonest age is 3 to 18 months with maximum
number of cases being in 9 to 12 months. These children
appear sicker than the degree of anemia warrants.
Anorexia, mental apathy and fatiguability are early
symptoms. Sore tongue, papillary atrophy, glossitis and
diarrhea can occur. Hyperpigmentation of the dorsum
of hand and knuckles is an important finding. Tremors,
failure to thrive and developmental regression are also
observed.
Vitamin B12 deficiency is an important cause of
neurological abnormality characterized by degeneration
of some peripheral nerves, selected columns in spinal
cord and defective cerebral function. Symptoms of
megaloblastic anemia due to folate/vitamin B 12
deficiency are similar but folate deficiency does not cause
neuropathy.
Laboratory Diagnosis
Peripheral blood smear is one of the best indicator of
megaloblastic anemia. This shows presence of
macroovalocytosis of RBCs, hypersegmented neutrophils
(3% neutrophils with more than 5 lobes) and raised MCV.
There may be evidence of leukopenia and thrombocyto-
penia in severely deficient states.
Treatment
Treatment of folate deficiency needs 100 to 200 μg of
folate daily. However, it is given in dose of 1 to 5 mg of
folate per day for 14 to 21 days for therapeutic response
and for replenishment of stores. Good sources of folate
in diet are fresh leafy vegetables, legumes, nuts and meat.
Goat’s milk is a poor source of folate. Vitamin B12
deficiency in infant is suitably treated with 100 to 200
μg of vitamin B12 given intramuscularly, on alternate
days for 2 to 3 weeks, or oral dose of 100 μg/day.
Treatment with folate alone can produce hematologic
response in vitamin B12 deficiency, but does not correct,
the neurological damage caused by vitamin B 12
deficiency, thus all megaloblastic anemias should be
treated with adequate doses of both folate and vitamin
B12. Anemia unresponsive to folate or B12 may be caused
by certain metabolic disorders or antimetabolic drugs.
BIBLIOGRAPHY
1. Choudhary P: Management of iron deficiency anemia in
clinical practice. In: Sachdev HPS, Choudhary P (Eds).
Nutrition in children – Developing country concern. New
Delhi, 1994;236-44.
2. Demeyer EM: Prevention and control of iron deficiency
anemia through primary health care. Geneva, WHO,
1989;8-33.
3. Desai N, Choudhary VP: Nutritional anemia in protein
energy malnutrition. Indian Pediatr 1993;30:1471-83.
4. Dubey AP: Megaloblastic anemia. PHO Review, IAP
1995;8:5-7.
5. Lokeshwar MR, Manglani M, Rao S, Patel S, Kulkarni
M: Iron deficiency anemia – Clinical manifestations and
management. In: Mehta MN, Kulkarni M (Eds). Child
nutrition–the Indian Scene. Mumbai, 1990;269-95.
6. Madan S: Recommendations on Prevention and Control
of Iron Deficiency Anemia. In: Madan S, Mukherjee KL,
Khatua SP (Eds). Nutritional Anemia in Infancy and
Childhood. Publication of Indian Academy of Pediatrics–
Subchapter on Nutrition, Calcutta, 1990.
7. Oski FA: Iron deficiency in infancy and childhood.
N Eng J Med 1993;329:190-93.
 Pediatric Hematology 785

8. Preventing iron deficiency in woman and children
technical consensus on key issues 7–9 October 1998.
UNICEF, UNU, WHO, MI. Technical Group International
Nutrition Foundation, USA 1998.
9. Sharma S, Prasad K, Rao KV. Identification of an
appropriate strategy to control anemia in adolescent girls
of poor communities. Indian Pediatr 2000;37:261-67.
10. Technical consultation on “Strategies for prevention and
control of iron deficiency anemia amongst under three
children in India”. Indian Pediatr 2002;39:640-47.
11. Zlotkin S: Current issues for the prevention and treatment
of iron deficiency anemia. Indian Pediatr 2002;39:
125-29.

15.5 Nutritional Anemias in Adolescence

Sushil Madan

INTRODUCTION in school age children. The average prevalence rates

are: Asia (58.4%), Africa and Asia (>40%), Indonesia
Anemia is the most common form of malnutrition mostly
due to iron deficiency amongst adolescents today. It is (24-25%) and Bangladesh (98/94% for boys and girls
of public health significance in our country, anemia respectively). It primarily affects women, yet among
prevalence being > 30 percent. It is a pathological adolescents prevalence rates of anemia are closer for
condition where hemoglobin or hematocrit becomes males and females in some parts of the world (Table
abnormally low because of low essential nutrients (like 15.5.2).
iron, folic acid, protein, vitamin B12, C, and trace elements Recent regional surveys among adolescent girls of
like zinc) regardless of the cuase of these deficiencies. urban, semi-urban and rural schools in India have found
Adolescents (10-19 years) constitute more than 20 anemia prevalence rate to be between 61.9-85.4 percent,
percent of our population in India and > 50 percent suffer being highest among rural girls of low socioeconomic
from Iron Deficiency Anemia (IDA). status in the northern states of the country.3 Anemia and
iron deficiency was of higher order among rural as
IRON DEFICIENCY ANEMIA IN ADOLESCENTS compared to urban poor girls irrespective of their age
Adolescence is the most vulnerable phase of life and menarchal status. This could be due to differences
associated with high iron requirements for growth and in dietary habits, worm infestations, poor hygiene,
development accompanied by expansion of blood environmental sanitation and disposal of waste.4 Anemia
volume, muscle mass, natural loss of menstrual blood in prevalence was more among girls of low weight, height
girls and increased demands with the onset of pregnancy. and BMI as compared to those who were heavier, tall
WHO criterion is used for defining anemia by and having higher BMI.
hemoglobin (Hb) estimation in different age and sex
groups (Table 15.5.1).
Adolescents having Hb less than 12g percent are said
TABLE 15.5.1: WHO criterion for diagnosis of anemia
to be anemic and adolescent pregnant women (15-19 yrs)
should be having minimum Hb of 11g percent at the Age/Sex group Hb (g/dI)
onset of pregnancy, to prevent mental functions from • Children 6 months–6 yrs <11
being affected due to irreversible brain damage to the • Children 6–14 yrs <12
growing fetus. • Adult males <13
• Adult females (Non-pregnant) <12
• Adult females (Pregnant) <11
Epidemiology
Global data-base by WHO (2000) on child growth and • Mild anemia <11–10
malnutrition and National Family Health Survey-2 (2000) • Moderate anemia <10–7
• Severe anemia <7
in India, have suggested high prevalence of IDA (56%)
786 IAP Textbook of Pediatrics

TABLE 15.5.2: Recent surveys – prevalence of IDA-adolescent children

Country/Year Profile of children Sex (M/F) Prevalence of anemia

Asia (Global data-base by WHO on child Rural school children Both 58.4%
Growth and Malnutrition 2000)
India (NFHS-2) 2000 Urban and rural (15-19 years) F 56%
Bangladesh (Shahbuddin et at 2000) Rural community M/F (17-100%) 98/94%
East Java, Indonesia (Soitarjo DD 2001) 6486 students (12-15 years) Prepubertal boys/girls, 24/>25%
Postpubertal boys
Africa and Asia (Partnership for 14000 Rural school children Both >40%
Child Development)

Pathophysiology during growth spurt both in boys and girls wherein

additional 0.8 mg would be required per day. Girls who
Iron balance in the body is achieved mainly by control
have attained menarche, the median blood loss during
of absorption of iron rather than its excretion. Iron
menstruation has been estimated to be between 25–30
absorption is physiologically regulated by—1. Iron status
ml per month corresponding to an iron loss of 12.5–15
of subjects, more with decreased iron stores 2. Chemical
mg per month or 0.4–0.5 mg per day. With addition of
form of iron and balance between +/– factors of dietary
basal losses, the total iron requirement for menstruating
iron absorption. Fermentation, germination and malting
of food also increase iron absorption (Table 15.5.3). women is about (0.8 + 0.8 + 0.5) 2.3 mg per day. During
A dietary intake of iron needed to replace basic losses pregnancy, menstrual losses are reduced to nil, and
in stool, urine and skin, amount to 0.8 mg of iron per additional 1000 mg is required for the fetus, placenta and
day for and adolescent child. Iron needs peak sharply increased maternal blood volume. Requirements during
first trimester are small, i.e. 0.8 mg per day but rise to 6.3
TABLE 15.5.3 mg per day during second and third trimester of
pregnancy (Fig. 15.5.1).
Factors influencing dietary iron absorption
• Heme Iron Absorption
– Amount of heme iron, especially as meat
ETIOLOGY
– Content of calcium in meal Adolescent child girl in particular is more vulnerable to
– Food preparation (time, temperature) becoming anemic due to disturbed iron balance between
• Non-Heme Iron Absorption
iron requirements and iron absorbed from diet.
– Iron status of subjects
– Amount of potentially available non-heme iron
Main causal factors are increasing physiological
(adjustment for fortification iron and contamination iron) demands by second spurt of growth, menstrual loss, and
– Balance between ± factors early onset of pregnancy in absence of adequate iron
Plus-factors Minus-factors stores at birth and inadequate intakes of habitual diet
Ascorbic acid Phytate with green leafy vegetables and fruits containing iron
Meat/fish Iron-binding polyphenols and vitamin C, eating junk food and skipping meals due
The “Sauerkraut factor” Calcium rising eostrogen levels cause fall in erythropoietin and
(fermented foods) Soy protein
decreased bio availability of iron. Total calorie intake may
Fermentation Malting
Germination
be as little as 1000 calories per day and iron intake in
• Iron absorption is Physiologically girls 10-17 years is estimated to be 46 percent to 64 percent
Regulated by of recommeded daily allowance. Total calorie intake may
1. Iron status of subjects more with be as little as 1000 calories per day as seen in rural areas
– Erythropoiesis of Andhra Pradesh by National Institute of Nutrition
– Iron stores Surveys. Several dietary factors influence absorption and
2. Chemical form of iron bioavailability of dietary iron (refer to Table 15.5.3). Good
3. Balance between ± factors
sources of heme iron (meat, fish, poultry), which help in

Figure 15.5.1: Iron needs peak sharply, during growth spurt
iron absorption as well, are often missing from Indian
diets. Anemia caused by iron losses due to malaria and
hookworm infection is quite common in our country due
to adolescents working in the fields. Malabsorption of
iron in cases with giardiasis, milk allergy and celiac
disease could lead to iron deficiency accompanied by that
of B12 and folic acid deficiency (Table 15.5.4).
Clinical Features
Iron deficiency is a systemic disorder involving multiple
systems rather than purely hematological condition
associated with anemia.
The peak incidence of iron deficiency occurs in
adolescents of 11 to 17 year age group. Occurrence of
various symptoms and signs and their severity depends
upon degree and severity of anemia, which are due to
diminished supply of oxygen to different tissues and
organs. Initial symptoms are fatigue and lassitude,
TABLE 15.5.4: Causal factors—IDA
• Decreased iron stores at birth
• Inadequate iron supply from inadequate diet
• Poor bioavailability of iron
• Increased physiological requirements
• Abnormal iron losses
• Malabsorption of iron
Pediatric Hematology 787
breathlessness on exertion, pallor of bulbar conjunctiva,
mucous membrane of tongue and palmar creases,
dizziness, giddiness, dimness of vision, headache and
anorexia. Nails show flatness, softness to feel and later
become spoon shaped. Findings of congestive heart
failure indicate severe anemia, Hb < 5 g percent.
Besides being a hemopoietic factor, iron deficiency
per se, without obvious anemia causes morphological and
biochemical changes at tissue level affecting:
1. Mental and Psychomotor Functions: Iron deficient
children are restless, disruptive, irritable, having poor
attention span, memory, concentration and academic
performance due to changes in brain iron content and
distribution. Cognition in particular is adversely affected
by anemia in both nourished and undernourished subject
due to poor synthesis and catabolism of neuro trans-
mitters (dopamine, norepinephrine, serotonin) caused by
reduction in activity of monoaminooxidase and aldehyde
oxidase enzymes. A recent report on Rural Indian
children documented lower concentration and retention
even after the nutritional status was improved.
2. Growth Retardation: Apart from associated nutrient
deficiencies it can be attributed to anorexia, reduced
synthesis of nucleic acids and altered intestinal functions.
Rapid weight gain following iron therapy has been
reported.
788 IAP Textbook of Pediatrics
3. Physical Work Capacity: There is linear relationship
between work capacity and iron deficiency. Heart rates
increase even with less level of work. Aerobic capacity
diminishes, anaerobic metabolism increases with
accumulation of lactic acid leading to fatigue. The adverse
effects of anemia are compounded due to overall under
nutrition. A significantly lower Rapid Fitness Index (RFI)
calculated from total exercise time and pulse rate 1 to 1.5
minutes after the exercise was observed among anemic
subjects against non anemics.
4. Immune Response: Iron deficiency state affects the
immmune system even before causing anemia. Defects
in cell mediated immunity and reduced capacity of
leucocytes to kill bacteria have been well documented.
Hence there is increased susceptibility to infections.
5. Gastro Intestinal Tract: Iron deficiency may lead to
stomatitis and atrophic gastritis with decreased gastric
acid production causing dyspepsia. There is greater
susceptibility to mucocutaneous candidiasis and
intestinal infections.
6. Heavy Metal Absorption: Iron deficient children have
an increased absorption of iron and other divalent metals
such as lead and cadmium. There is an increased risk of
lead poisoning on exposure to lead paints from toys and
environment.
7. Iron Deficiency and Pregnancy Outcome: There is
increased maternal mortality due to severe anemia
causing hemorrhage in last trimester of pregnancy/
during labor and also due to unwanted pregnancy and
abortions. Iron deficiency along with deficiencies of folate
and vitamin B12 result in poor fetal growth, higher
percent of still births and lower birth weight babies. There
is also increased neonatal, infant and under 5 mortality
as compared to those for mothers between 20-29 years
as shown by NFHS 2.
TABLE 15.5.5: Stages in the development of iron deficiency and available confirmatory tests
Investigations Normal Pre-latent
Bone marrow iron Normal Reduced
Serum ferritin (SF) do < 15 ng
Transferrin saturation (TF) do Normal
Free erythrocyte prophyrin (EP) do do
Haemoglobin do do
Mean corpuscular volume do do
A recent report on Rural Indian Children documented
lower concentration and retention even after the nutritional
status was improved.
Diagnosis
IDA develops sequentially as observed by:
1. First Stage—depletion of stored iron, i.e. fall in serum
ferritin < 15 μg/ml, absence of stainable iron in bone
marrow during spurt of growth and increase in red
cell diameter width (RDW > 15%) (Table 15.5.5).
2. Second Stage—preanemic or latent iron deficiency →
decrease in serum iron <75 mg/dl, increase TIBC >350
ug/dl and decrease in transferrin saturation within
14 percent.
3. Third Stage— Significant fall in serum iron <30 mg/
dl, increase in erythrocyte protoporphyrin, fall in
MCV, MCH, MCHC, hypochromic, microcytic
anemia accompanied by fall in Hb, Hct, red cell count.
SCREENING TESTS
Red cell count, Hb, Hct, are all decreased in IDA. MCV,
MCH and MCHC are also decreased. The peripheral
blood film shows hypochromic microcytic anemia with
poikilocytosis and target cells. There may be a dimorphic
picture with hypochromic, microcytic red cells along with
macrocytosis in children with iron deficiency associated
with Vitamin B12 or folate deficiency.
Reticulocyte count is normal unless child has had
recent blood loss or received hematinics in which case it
may be increased. Leucoyte count is usually normal.
Hypersegmented neutrophils may be seen due to
concomitant B12 or folate deficiency or due to interference
with folate utilization.
Low MCV and MCH with anemia favor the diagnosis
of IDA however specific reference standard may be used
for comparison. MCV is much more sensitive than MCH
Latent Iron deficiency anaemia
Absent Absent
< 15 < 12
< 16% < 16%
Increased Markedly increased
Normal Progressive reduction
do Reduced

in iron deficiency, however, microcytosis may also be
seen in conditions like abnormal hemoglobinopathies,
anemia of chronic infection and inflammation, lead
poisoning and rarely sideroblastic anemia and chronic
renal diseases.
Red cell size distribution width (RDW) reveals
elevated levels in IDA as compared to normal levels in
anemia of chronic diseases or beta thalessemia trait.
Free erythrocyte protoporhyrin accumulates in the
red blood cells when it does not get sufficient iron to
combine with to form Hb. More than 70 microgram/dl
of RBC protoporphyrin above the age of 4 years is of
significant value to detect IDA. FEP over Hb ratio
increases when iron reserve is exhausted and returns to
normal only after majority of cells containing FEP are
formed during iron therapy.
Confirmatory Tests for IDA
Serum iron is reduced (N=50-180 mg/dl), TIBC is
increased (N=250-450 mg/dl). Transferrin saturation is
low (less than 16 percent suggestive and less than
7 percent diagnostic of severe iron deficiency anemia).
Serum ferritin is less than 10-12 ng/ml but it is usually
higher (however less than 50-60 ng/ml), with infection
or inflammatory diseases like rheumatoid arthritis,
collagen disorders, liver disorders, chronic renal disease
or malignancy. The test still lacks sensitivity and normal
value does not reliably exclude iron deficiency. In
addition serum transferrin receptor (sTfR) can be done
in places where infection is common for individual
screening (Table 15.5.5).
More often iron deficiency as a steady state develops
very gradually and is almost in equilibrium due to
conditions like chronic energy deficiency lasting for
months or years. The laboratory values for serum ferritin
and transferrin saturation are in normal limits but
patients respond to iron therapy by showing rise in
reticulocyte count by more than 2 percent, Hb and Hct
(by 1.0 gm/dl or by 3%) in 4-8 weeks time indicating
IDA. In such a situation with high prevalence of anemia
a. Clinical assessment
b. Hb estimation
c. Peripheral smear for microcytic hypochromic anemia
and malaria parasites
d. Stool examination for helminths, and
e. Response to iron supplementation may suffice.
Pediatric Hematology 789
Management
It involves (1) Treatment of underlyling cause and
correction of anemia in an individual patient.
(2) Prevention and control of IDA as Public Health
Program. The therapeutic approach must rely on
medicinal iron especially when anemia is moderate to
severe (Hb < 7 gm%) and treatment of cause. Ferrous
compounds are better absorbed than ferric iron, of these
ferrous sulphate, gluconate and fumerate are the
compounds most commonly used. Though somewhat
expensive, it is better to use slow release preparations,
which give higher absorption rates and minimal
gastrointestinal side effects with higher compliance. It is
better to use preparation containing folic acid like IFA
tablet because inadequate dietary intake may give rise
to folic acid deficiency for the demands of increased red
cell formation and also cause neural tube defects to fetus
with onset of pregnancy. Although iron absorption is
proportional to degree of anemia, the dose recommended
is 100 mg of elemental iron with 500 μg of folic acid once
daily for mild anemia (Hb < 10–12 g) and twice daily for
moderately severe anemia (Hb < 7–10 g) along with 25–
50 mg of vitamin C which helps in iron absorption. The
desired Hb is usually reached in 2 months, but therapy
should continue for another 2 months to build up iron
stores showing ferritin level of 30 μg/L.
Adolescent girls (15–19 years) with Hb between
5 to 8 g/dl form 10 to 20 percent of all pregnant women.
They should be first screened for systemic or obstetric
problems and infections. In the absence of any
complications, IFA tablets can be administered at the
maximum tolerated dose and Hb can be repeated a
month later. Those who do not show any improvement
may be put on parenteral medication.
Failure to oral iron therapy may be due to
(1) Inadequate doses (2) Noncompliance (3) Continued/
Intermittent occult blood loss (4) Hypochromic
microcytic anemia due to thalassemia minor/lead
poisoning/chronic infections and (5) nutritional mega-
loblastic anemia. All should be appropriately ruled out.
Noncompliance is probably due to poor counselling and
lack of motivation and not due to side effects, once
considered a major reason for failure of iron therapy. The
tablets may be given with meals and in divided doses to
improve compliance. The adolescent must be given
proper nutritional counselling diet should contain fruits
and GLV (green leafy vegetables). Absorption inhibitors
790 IAP Textbook of Pediatrics

should be avoided with principal meals. In cases with

hookworm infection, deworming is essential otherwise
anemia is likely to return once iron therapy is stopped.
Consistent improvement of hematological status is also
dependent on the treatment and improvement of the
underlying infection such as pulmonary tuberculosis and
urinary tract infection.
Parenteral iron therapy—it is indicated in cases having
severe side effects with oral iron therapy, noncompliance
or gastrointestinal bleeding, which is aggravated by oral
iron therapy. Patients must be hospitalized for total dose
infusion by intravenous route, as severe anaphylactic Figure 15.5.2: Urgent sustained effort to control IDA
reaction can take place. Usually 100 mg of elemental iron
(iron dextran complex 50 mg/ml in 2 ml of saline) is given
intramuscularly every day till calculated dose [Iron (mg)= anemia where prevalence rate is more than 30 percent
wt in kg × Hb deficit (g/dl) × 4] is administered. It has and facilities for Hb estimation are lacking. It is the most
been found to be safe and effective method of treatment rapid method of improving the iron status of an
of anemia in pregnancy and may result in better fetal adolescent child. This is a captive audience and can be
iron stores in comparison to oral route. reached by health workers in schools, clubs, textile
industry besides pediatric clinics in hospitals, PHC and
Blood transfusion—may be needed in most severe cases
MCH centers. Since diet alone cannot meet requirement
of IDA with Hb within 3 to 4 g/dl. Packed or sedimented
of iron during pregnancy in girls, dietary iron absorption
red cells should be slowly administered, preferably 2 to
is also reduced during first trimester of pregnancy, hence
3 ml/kg at one time. A modified exchange transfusion
it is better to start oral iron supplementation from early
may be considered in presence of congestive heart failure
adolescence. It will also prevent irreversible abnor-
along with diuretic, digitalis and antiallergic drugs.
malities in cognitive functions and neural tube defects
Prevention and control of IDA—Adolescence is a crucial due to iron and folic acid deficiency early in fetal life.
stage for intervention because of high prevalence of Dose recommended by National Nutritional Anemia
anemia and fact that 29 percent of urban and 45 percent Control Program as NNACP is 1 IFA tablet (100 mg
of rural girls get married before the age of 19. Adolescent elemental iron + 500 μg of folic acid) for 100 days in a
pregnancies contribute to 19 percent of total fertility year. Intervention studies have shown that intermittent
causing highest maternal mortality rates in our country oral iron administration once or twice weekly of same
upto 4 times as likely as in women older than 20 years of dosage has shown equally good results. Pregnant
age from pregnancy related causes. Besides, both boys
adolescent girls should be given same dose after the first
and girls suffer from basic morbidity such as
trimester of pregnancy for a minimum period of 100 days.
malnutrition, communicable diseases, accidents, etc.
Severely anemic children (Hb < 7 g/dl) should be given
Girls also experience discrimination at home from before
two IFA tablets daily for a minimum period of 100 days.
and after birth leading to malnutrition with anemia and
Further they should be referred to the Primary Health
vicious cycle of being small girl → adolescent pregnancy
Center for diagnosis of the causative factors and
→ low birth weight baby → small girl (Fig. 15.5.2).
treatment. Adolescent girls during lactation should be
Basic approaches for prevention and control of IDA
are: (1) Oral supplementation with medicinal iron (2) given same dose all through lactation and this is being
Dietary modifications (3) Fortification of staple food with carried through ICDS and CSSM Family Welfare
iron. This should be accompanied with (4) control of Program of the country (Table 15.5.6).
infections and improvement of socioeconomic status of Dietary modification/diversification—this seeks to change
community and sanitary measures (especially proper adolescents’ consumption behavior and their nutritional
disposal of excreta and construction of latrines). status by comprehensive nutritional education as part
Oral iron Supplementation WHO has recommended of family life education in schools. Horticultural
oral iron supplementation even in absence of overt intervention, improved public distribution system and
 Pediatric Hematology 791

TABLE 15.5.6: Basic Approach: Oral iron supplementation dosage

Risk Group Tablet strength Dosage Period

Adolescent 100 mg elemental iron I daily/once or twice weekly 100 days in a year/short
+ 500 mg folate + 25 mg Vit C courses
Adolescent with -do- Twice a day 100 days
clinical anemia
Pregnant -do- One a day From 2nd trimester of
adolescent girls Pregnancy till end
Adolescent girls -do- One a day All through lactation
with lactation

kitchen gardens could help in procurement of fruits and

vegetables. The idea is to (1) increase dietary iron intake
by increased intake of habitual foods (2) to increase iron
intake by promotion of iron rich foods (palak, sarson,
methi, cholai saag) (3) enhance bioavailability of ingested
iron with consumption of vitamin C rich foods like
lemons, tomatoes, amla, guava, sprouted dals, citrus
fruits (4) discourage intake of tea, milk, egg yolk soon
after meals (5) encourage cooking in iron utensils and
(6) promote intake of germinated and fermented foods.
With diet modification the relative bioavailability of iron
can be increased from as low as (5%) to intermediate
(10%) and as high as (>15%). Intervention studies by
Nutrition Education and Dietary Modification have
shown marked improvement by rise in Hb and/or
ferritin levels without iron supplementation (Fig. 15.5.3).
Fortification of foods with iron—It is the most effective Figure 15.5.3: The effects of dietary composition of the rela-
way of preventing IDA as iron being part of food; tive bioavailability of iron. Diets of low (5%), intermediate (10%),
compliance of population is not involved. Once and high (> 15%) are shown.
established, it is cost effective and long-term sustainable • India mixed cereal diet
Women, children (adolescent girls) 5%, Adultmen adoles-
measure. Fortification technology is already available. cent boys 3%, Pregnant women 8%.
Common salt fortified with Iron Orthophosphate and
Sodium Hydrogen Sulphate with Ascorbic acid has had has been on young children and women of reproductive
field trials in India and is found to be stable. Double age. National Nutritional Anemia Prophylaxis Program
fortified salt has been available containing iron 1 mg/ (NNAPP) was started in 1970 for pregnant women and
g+ iodine 40 μg/g. Daily intake of 15 g of salt can provide children of 1 to 11 years of age. IFA tablet containing 60
15 mg of iron and will suffice as a supplement. mg of elemental iron +500 μg folic acid was administered
Home fortification with iron and zinc sprinkless or to pregnant women during last trimester of pregnancy
iron alone successfully treats anemia in infants and for minimum period of 100 days through the rural-based
children. Fortified food with iron is still not available for ICDS and CSSM program. But after 20 years of
public health program by Government of India. Hence, implementation, 20 to 38 percent of pregnant women were
it is essential that NNACP is implemented more still anemic at the end of pregnancy in spite of having had
effectively. IFA tablets for 100 days. Following this, in 1991, focus was
Strategies for prevention of IDA—Despite the magnitude made on control of anemia by treating existing anemic
of the problem, hardly any strategies exist in Indian Public women and children in addition to prophylaxis dose as
Health program to tackle IDA among adolescents recommended under NNAPP and the new program was
especially girls. The main focus of IDA reduction programs called National Nutritional Anemia Control Program
792 IAP Textbook of Pediatrics
(NNACP). This aims at significantly decreasing the
prevalence and significance of anemia amongst women
of reproductive age and pre-school children. However,
we still remain far behind our goals in achieving reduction
of IDA as desired.
India became a signatory to World Summit for
Children in 1990. Following this, India developed
National Plan of Action for Children—a Commitment
to the child in 1993. National Nutrition Policy was revised
to see reduction of IDA in women by 1/3rd by year 2000
by oral iron supplementation, dietary diversification and
food fortification. Since these programs run vertically,
independent of each other, we are far behind achieving
our goals. At this stage (1993) it was planned to introduce
additional scheme for adolescent girls, Kishore Shakti
Yojna, as a part of ICDS Program. Herein, economically
disadvantaged girls would be given oral iron
supplementation by Anganwadi workers by home visits.
In addition, nutrition education sessions for promotion
of regular consumption of iron and vitamin C rich food
during pregnancy and adolescence would be provided
through ICDS, UBS, DWCRA, NLP and School Health
programs. This Program has neither been implemented
in all the districts and states of the country nor has it
Flow Chart 15.5.1: Reduction of IDA
shown significant impact by reduction in IDA till date
(Flow Chart 15.5.1).
Issues before us—(1) High magnitude of problem in
adolescent children as shown by NFHS 2, (2) present
focus is narrow through rural-based ICDS, CSSMP and
RCH, who view adolescents as future parents only,
(3) Adolescent scheme is not being implemented in many
districts of the country, (4) very little impact among urban
poor due to lack of infrastructure, i.e. urban health
planning (5) Health care and support services for the
development (education, life skill programs) are lacking
both in urban and rural areas of the country.
Existing strategy (NNACP) and proposed improvements—
National Nutrition Mission under the Chairmanship of
the Prime Minister desires to reduce severe anemia and
malnutrition in children by 50 percent by year 2010 as
per 10th National Plan. Hence emphasis should be on
Nationwide and Statewide implementation of the
following: (1) Intersectoral approach is the first
requirement for National Nutritional Policy by
coordination between Ministry of Health Family welfare,
DWCD, Education, Food, Social and Human Resources.
(2) Focus on adolescents (community/ household/

Individual level) in urban slums, rural and tribal areas
and at their schools and working places. (3) Integrate
Health and Social Sector Investment (4) Enforce Child
Marriage Restraint Act with community and adolescent
participation to prevent marriage before the age of 18
for girls and 21 years for boys. (5) Salt fortification
program to be hastened (6) Medical colleges to include
curriculum on adolescent’s health, nutritional status,
anemia, development at undergraduate and post-
graduate level. (7) Involve a trained Pediatrician for (a)
Sarva Shiksha Abhiyan (6-14 years group) (b) RCH 2
Programme 2005 (c) Adolescent Friendly Health Services
at Hospitals, Primary Health Centers, Schools and
Welfare Centers. (8) School curriculum to include
Nutrition Health Education (NHF) for primary level and
NHE and FLE from secondary level. (9) Ensure access to
Quality Health Care System and improve utilization and
impact by working closely with NGOs (10) Provide good
working conditions and remuneration to working staff
(11) Streamline activities for ANM, AWW, CDBMO to
see convergence of 3 basic approaches and update them
with refresher courses/CME. (12) Holistic approach as
shown by MAMTA, CDC and CDCPO will improve their
nutrition iron status, development and prevent
unwanted pregnancy, maternal deaths and low birth
weight outcome (Flow Chart 15.5.2).
Flow Chart 15.5.2: IAP state task force for adolescent care
Pediatric Hematology 793
NUTRITIONAL MEGALOBLASTIC ANEMIAS
Megaloblastic anemia is caused by deficiency of either
folate or vitamin B12 or both. Folic Acid in its active
tetrahydrofolate form is involved in the synthesis of
purines, pyrimidines and amino acids especially serine
and methionine. Vitamin B 12 acts as coenzyme and
transfers methyl group from homocysteine to form
methionine. Vitamin B12 deficiency results in decreased
utilization of tetrahydrofolate, decreasing synthesis of
thymine leading to defective DNA synthesis. High folic
acid dependency for DNA synthesis and lower folic acid
dependency for RNA synthesis lead to prolonged protein
synthesis, decreased mitosis and consequently large cells.
These are reflected as megaloblasts in bone marrow,
macrocytes and giant hypersegmented polymorph
nuclear cells in peripheral blood smears. Decreased
mitosis leads to anemia, leukopenia, thrombocytopenia,
glossitis, and cervical dysplasia.
Unlike iron deficiency, hardly any epidemiological
studies are available on the incidence of folic acid or
vitamin B deficiency in the populations. However,
despite normal Hb about 60 percent of Indian women
are folate deficient due to increased demands, decreased
absorption, accelerated breakdown of folate to
paraminobenzoylglutamate, increased urinary loss and
fetal transfer during adolescent pregnancy as indicated
by low serum and RBC folic acid levels. In moderately
severe anemia (Hb 8.5 g%) 60 percent of bone marrow
shows megaloblastic reaction and RBC folate levels are
below 80 ng per ml (normal). No stainable iron is seen in
bone marrow in such subjects. Folate is given in dose of
5 mg per day for 2 to 3 weeks and then continued as
prophylaxis dose as IFA tablets. However, some studies
recommend use of multivitamin tablet (MRC vitamin
study) including 0.4 to 0.8 mg of folic acid in
periconceptual period to prevent neural tube defects.
Vitamin C present in multivitamin would prevent
oxidation of tetrahydrofolate and help to keep the folate
metabolic pool optimal. Low status of zinc in women of
childbearing age especially poor adolescents would also
improve, since folic acid conjugase is a zinc-
metalloenzyme which would help in the absorption of
folic acid by the intestine.
794 IAP Textbook of Pediatrics
Nutritional vitamin B12 deficiency is not common in
adolescence. Rarely, it occurs as juvenile pernicious
anemia due to genetic absence of intrinsic factor. Vitamin
B12 deficiency may result in neurological manifestations
as peripheral neuritis, mental apathy and psychosis.
Infants solely breastfed for long time develop anemia.
The clinical picture gets improved by administering
single oral dose of 100 μg of vitamin B12 to the mother or
to the infant.
BIBLIOGRAPHY
1. Agarwal KN. Iron and the Brain. Neurotransmitter
Receptors and Magnetic Resonance Spectroscopy. British
J Nutr 2001;85,2:147-50.
2. Agarwal R Bharat; Approach to a child with Anemia.
The Child and Newborn, 2004;8:84-95.
3. Dwivedi Archana and Schultink Werner; Reducing
Anemia among Indian Adolescent Girls thru Once
Weekly Supplementation with Iron and Folic Acid. Dr
Panna Choudhury, Dr A P Dubey (Eds); Nutri Search,
Buletin of IAP Sub Speciality Chapter of Nutrition
2006;13,No.2.
4. Hota P. National Rural Health Mission. Indian J Pediatr
2006;73:193-95.
15.6 Thalassemia
Thalassemia is an autosomal recessive, heterogynous
group of single gene disorder, seen in certain parts of
the world and represents a major health burden world -
wide. It is caused by defect in the globin chain synthesis
of hemoglobin (Hb) due to various mutations of genes
which code for globin chain of hemoglobin, leading to
reduced or absent synthesis of globin chain.
The thalassemia refers to group of blood diseases
characterized by decreased synthesis of one of the
polypeptide chains (α or β) that form normal adult
hemoglobin molecule (Hb.A-α2β2). In α Thalassemia,
α chain synthesis is affected. In β Thalassemia, β chain is
involved.
If β chain is absent, it is termed as β0 Thalassemia, if
partially produced then β+ Thalassemia.
Clinically Important Hemoglobinopathies prevalent
in India include–
• α Thalassemia,
5.
Indian Council of Medical Research, National Workshop
on Micronutrients. Background documents Toteja GS,
Singh P. Micronutrient Profile of Indian Population. New
Delhi, Nov. 2003.
6. International Institute for Population Sciences (IIPS) and
ORC Macro, 2000. National Family Health Survey
(NFHS-2), 1998-99; India. Mumbai:IIPS.
7. Kanani S, Poojara R Supplementation with Iron Folic
Acid enhance Growth in Adolescent Indian Girls. J Nutr
2000;130:452-555.
8. Kaur S, Deshmukh PR and Garg B S. Epidemiological
Correlates of Nutritional Anemia in Adolescent Girls of
Rural Wardha. Indian Journal of Community Medicine
2006;4:Vol 31.
9. NMMB, Diet and Nutritional Status of Rural Population.
National Institute of Nutrition, 2002.
10. Park K. Park’s Textbook of Preventive and Social
Medicine, Jabalpur: Banarsidas Bhanot Publishers,
2002;381.
11. Sen A and Kamani SJ. Deleterious Functional Impact of
Anemia on Young Adolescent School Girls. Indian
Pediatr 2006;43:219-26.
12. Zlotkin S, Arthur P, Shaver C, Antwi KY, et al. Home
fortification with Iron and Zinc Sprinkles or Iron
Sprinkles Alone Successfully Treats Anemia in Infants
and Young Children. J Nutr 2003;133:1075-80.
MR Lokeshwar, Nitin Shah,
Swati Kanakia, Mamta Manglani
• β Thalassemia,
• Hemoglobin S,
• Hemoglobin D,
• Hemoglobin E,
• Double Heterozygous Disorders.
• Several other hemoglobin (Hb) variants have been
reported from India but their frequency is relatively
low.
Classification of α-Thalassemia Syndromes
The α-Thalassemias are classified into 4 different
categories depending upon the number of genes affected.
Since the gene of α-globin is duplicated on chromosome
16, each diploid human cell contains four copies of the
α-globin gene. The four α-Thalassemia syndromes with
increasing clinical severity include
• Silent carrier,
• α-Thalassemia trait,
• Hb. H disease and
• Hydrops fetalis
 Pediatric Hematology 795

TABLE 15.6.1: The β-globin genes are represented one on each chromosome 11
Syndrome Clinical Features Hemoglobin pattern Genes affected
α-globin
Silent carrier No anemia, normal 1-2% Hb Bart’s (γ4) 1
red cells at birth
Thalassemia trait Mild anemia,
Hypochromic 5-10% Hb. Bart’s (γ4) 2
Microcytic red cells
at birth
HbH disease Moderate anemia, 5-30% HbH (β4) 3
Hypochromic,
microcytic red cells
Hydrops fetalis Death in utero caused Mainly Hb. Bart’s, small 4
By severe anemia amounts of Hb Hs

and are, due to 1, 2, 3 and 4 gene defects respectively.

The β-thalassemia genes are represented one on each
chromosome 11.
The β-Thalassemias also include four clinical
syndromes of increasing severity (Table 15.6.1).
• Silent carrier,
• Thalassemia trait,
• Thalassemia intermedia,
• Thalassemia major.

Epidemiology
Although reliable data are still lacking for many regions
of the world, recent data indicate that about 7% of the
world population is carrier of hemoglobin disorder and
that 300,000-500,000 children are born each year with
severe homozygous state of these diseases.
Though first described in 1925 by Thomas Cooley Figure 15.6.1: Prevalence of thalassemia
and Lee, now world over, there are more than 250 million
carriers (Heterozygous)of β-Thalassemia gene (1.5% of thalassemia minor is around 3-17 %, whereas region
world population), and in South East Asia –40 million below the line the incidence is around 1-3% or less.
(50% in India alone i.e. 20 million). A higher frequency is noted in certain communities such
First case reported in India is by Dr. Mukherjee from as in
Calcutta (India) in 1938. • North India- Sindhis, Punjabis,
About 100,000 children are born every year world • Migrants from Pakistan- Khatris and Khukrajas,
over with the homozygous state for thalassemia. With • Gujarat- Bhanushalis, Lohanas,
the birth rate of 22.8 per 1000, it is estimated that, 8-10,000 Baniyas, and Kuchies,
children born in India. There are around 65,000 - 67,000 • Maharashtra - Neo-Buddhists, Mahars,
thalassemia patients in our country. Kolis, Agri’s,
β-gene represented on chromosome no. 11 and 16. • Karnataka – Goudas and Lingayats,
In India prevalence of this gene varies, 1-17 % (3.3%). etc.
If you draw a line between Mumbai and Kolkata on map • Goa- Goud Saraswats also
of India, region above the line the incidence of • From Certain Muslim and Christian communities
796 IAP Textbook of Pediatrics

Pathophysiology of teeth, and complications that include-distortion of ribs,

vertebrae, and pathological fracture of long bones,
Hb. consists of two pairs of amino acid chains α and β.
splenomegaly, and its complications-hypersplenism,
↓
hepatomegaly, gallstones, and chronic leg ulcers.
Imbalance in the production of these peptide chains of
globin (α and β) leads to abnormal hemoglobinopathies.
↓ PATHOPHYSIOLOGY OF β -THALASSEMIA
Excessive unpaired peptide chain in hemoglobin is (SEE FIG 15.6.2)
precipitated on red cell membrane and damages it
leading to premature destruction of RBC (Hemolysis) in Molecular Genetics
bone-marrow and in peripheral circulation particularly More than 200 mutations are described all over the world.
in reticulo-endothelial system of spleen. (Ineffective Common mutations responsible for more than 90% of
Erythropoiesis) thalassemia mutations in our country include-
↓ • 619 bp deletion,
Gamma chain synthesis persists after fetal life
• IVS 1 - 5 (G - C),
↓
• IVS 1 - 1 (G - T),
Increased fetal hemoglobin with its high affinity for
• FS 8/9 (+ G),
oxygen, leads to tissue hypoxia, which, in turn, stimulates
• FS 41/42 (- CTTT)
erythropoietin secretion, leading to both medullary and
extramedullary Erythropoiesis Recently, some rarer mutations have been described
↓ include Codon 4/5 and 6 (ACT CCT GAG - ACA TCT
This resulting in expansion of bone marrow space- with TAG), Codon 47/48 (+ ATCT), Codon 55 (+ A), IVS
characteristic hemolytic faces with frontal, parietal and 2 - 837 (T - G), Codon 88 (+ T), Codon 5 (- CT)
occipital bossing, malar prominence and mal-occlusion IVS 1 – 110 (G - A), Codon 15 (TGG - TAG).

Figure 15.6.2: Pathophysiology of β-Thalassemia


Classification
Homozygous states – Two types
• Thalassemia Major
• Thalassemia Intermedia
Thalassemia Major– Children are clinically severe type
and are dependent on regular blood transfusion for their
survival (Fig. 15.6.3).
Thalassemia Intermedia– Symptoms are milder and are
not dependent on blood transfusion for their survival.
Usually symptoms appear after the age of 2 years or more
(Fig. 15.6.4).
Heterozygous States
Two types
• Thalassemia Minor
• Silent carriers
Thalassemia Minor–Heterozygous state and is
characterized by elevated HbA2 more than 3.4% and have
microcytic hypochromic red cells.
Silent Carriers
They are asymptomatic and have no hematological
findings and are diagnosed by chain synthesis. Suspected
when one of the parents of thalassemia major does not
have increased HbA2.
Figure 15.6.3: Thalassemia Major
Pediatric Hematology 797
Figure 15.6.4: Thalassemia Intermedia
Clinical Manifestation and Diagnosis of
Thalassemia
When to suspect?
The spectrum of clinical manifestation of Beta
Thalassemia varies widely.
• One end of the spectrum is the:
– Serious homozygous form (Thalassemia Major)
that presents in early infancy (6-18 months) with
pallor, failure to thrive, irritability, intercurrent
infections and hepatosplenomegaly.
– If undiagnosed and untreated, more than 90% do
not survive beyond 3 to 4 years of age.
Untreated or irregularly treated children develop
significant hemolytic faces including fronto-parietal
bossing with a hot-cross-bun appearance of the skull
(caput quadratum), depressed bridge of nose, malar
prominences and malocclusion of teeth with protrusion
of maxillary teeth (Fig. 15.6.5).
Usually these children are apparently born normal
and do not have any symptoms till the age of 2 to 6
months. Affected children initially grow well for initial
few months. The child becomes irritable with gradually
increasing pallor, not taking feeds well, recurrent
infection and develops mild hepato-splenomegaly. Often
798 IAP Textbook of Pediatrics

of PBF and a reticulocyte count can help in suspecting

and identification of hemoglobinopathies.
• Reticulocyte count ranges from 2 to 4%.

Red Cell Indices- Hb, RBC, MCV, MCH and

MCHC, RDW

The CBC in Thalassemia Trait

• Marked reduction in mean cell volume (MCV) and
mean cell hemoglobin (MCH).
• RDW is the coefficient of variation of red cell volume
distribution. RDW is the objective documentation of
subjective anisocytosis. (Normal range- 11.5% to
14.5%.). High red cell count, relative to hemoglobin
Concentration and hematocrit.
• The red cell distribution width (RDW) is within
normal range.
Iron deficiency anemia (IDA) is associated with—
Figure 15.6.5: Thalassemia major: hot cross-bun appear- • Low red cell count relative to hemoglobin
ance of the skull (caput quadratum) concentration and hematocrit.
• With low mean corpuscular volume (MCV) and mean
these children are treated initially with oral irontherapy cell hemoglobin (MCH).
with the mistaken diagnosis of iron deficiency anemia. • The red cell distribution width (RDW) is markedly
• Other end of the spectrum is the heterozygous form increased.
(thalassemia minor) who can lead practically normal The following Table gives the differences in
life except for mild persistent anemia not responding laboratory values between β-thalassemia trait and mild
hematenics, and have normal life span and they can iron deficiency anemia (IDA).
pass on their genes to their siblings.
• In between these two extremes, are forms with Low MCV Normal MCV High MCV
varying degree of clinical manifestations of anemia, RDW Normal Thalassemia Normal Aplastic anemia
spleno-heptomegaly, and bony changes, who, trait
maintain their life fairly comfortably and are not RDW High IDA Chronic liver Megaloblastic
dependent on blood transfusion for their survival and disease anemia
malignancies, Hemolytic
are called as Thalassemia Intermedia and are
myelofibrosis anemia
homozygous. myelotoxic drugs

LABORATORY TECHNIQUES
Methods for investigation of Thalassemia
For, reliable detection of hemoglobinopathies and
thalassemia, it is advisable to correlate clinical profile and
ethnicity of the individuals, with the blood count, blood
film, and do further investigations to confirm the
diagnosis.
Complete Blood Count (CBC) with red cell indices and
Peripheral Blood Film (PBF) Examination and
reticulocyte count.
CBC is frequently sufficient to postulate the diagnosis
of thalassemia. A primary screen with CBC, examination
PS of Thalassemia Child
Peripheral blood smear is diagnostic with characteristic
bizarre picture of red cells, which are microcytic,
hypochromic, with poikilocytosis, polychromasia,
moderate basophilic stippling, and fragmented
erythrocytes, target cells, and large number of
normoblasts (Figs 15.6.6A to D).
Reticulocyte count ranges from 2-4%. Some abnormal
hemoglobin, like HbS; and HbC can be detected or
suspected on CBC values and PBF examination.
Normoblasts are increased on peripheral smear.

Figures 15.6.6A to D: (A) Basophilic stippling, (B) Normoblasts, (C) Reticulocytes, (D) PS of sickle cell disease
Naked-eye single-tube red-cell osmotic fragility test
(NESTROFT) (Fig. 15.6.7)
Many investigators have studied naked-eye single-
tube red-cell osmotic fragility test (NESTROFT) as a
screening modality in β-Thalassemia trait.
The test has a high sensitivity of 95 percent and high
negative predictive value of around 98 % but its poor
precision, inter technician variability and low specificity
has precluded it from becoming a routine procedure,
particularly after the availability of better parameter on
cell counters.
Iron Status
In Thalassemia Major
• Serum iron (SI) level increased depending upon iron
overload.
• Total iron binding capacity (TIBC) decreased.
• Transferrin saturation (T.S.) increased
• S Ferritin increased in thalassemia and is
proportionate to iron overload.
Figure 15.6.7: Thalassemia minor Nestrof test
Pediatric Hematology 799
In Iron Deficiency Anemia (IDA)
• Serum iron (SI) level decreased.
• Transferrin saturation (TS) decreased.
• Total iron binding capacity (TIBC) increased.
• S Ferritine–Decreased.
• Osmotic Fragility–Reveals Reduced Fragility.
• Bone marrow examination though not required for
diagnoses, shows normoblastic erythroid hyperplasia
and iron staining of bone marrow shows increased
store of iron in the form of hemosiderin.
HbA2 meassurement by:
• Demonstration of red cell inclusion bodies
• DNA analysis
• Hb Electrophoresis– HbF, Hb A2 and other
abnormal Hb-Fetal hemoglobin increased in the
patient (Thalassemia major) and Hb A2 is > 3.4
percent in both parents (Thalassemia Minor).
• Estimation of hemoglobin A2 by electrophoresis.
Quantitation of Hb A2 remains the Gold standard for
the diagnosis of thalassemia trait.
Till recently electrophoresis was considered the gold
standard for measurement of Hb A2. The technique is
however, laborious, time consuming and unsuitable for
mass screening.
• Cellulose acetate electrophoresis pH 8.5 with elution
• Citrate agar or acid agarose gel electrophoresis pH
6.2
• Isoelectric focusing
• Micro column chromatography
• Automated high performance liquid chroma-
tography. (HPLC)
• Quantitation of HbF
• Assessment of distribution of HbF
• Tests for Hb S
• Test for unstable Hb.
800 IAP Textbook of Pediatrics

Measurement of Hb A2 by elution from electophoresis

on cellulose acetate
• Hemoglobin Electrophoresis at 8.4-8.6
Hemolysate is separated into its components fraction,
on cellulose acetate membrane. The relative
proportion of separated fractions are quantitated by
spectrometry of the elute of the separated fraction
Satisfactory separation of Hbs C,S,F,A,J, is obtained.
In general Hbs, S, D and G migrate closely together
as do Hbs C, E and O Arab. Differentiation between
these Hb, can be obtained by using acid agarose gel,
citrate agar electrophoresis, HPLC, or IEF.
• Isoelectric Focusing (IEF)
Hemoglobin is separated on a gel according to their
isoelectric point (PI), the point at which the molecule
has no net charge. Hb molecule migrates through the
gel until they reach the point at which their individual
PIs equal the corresponding pH on the gel. At this
point, the charge on the Hb is neutral, and migration Figure 15.6.8: Bio-Rad variant machine
ceases. The pH gradient counteracts diffusion, and
Hb variant forms a discrete narrow band. The
advantage of IEF is that the bands are sharper than
cellulose acetate and Hb D\G are separated from S.
Its disadvantages include precision of quantifying
hemoglobin at low concentration and needs expertise
to interpret. Only reference laboratories use the test.
• Micro column Chromatography
Micro column chromatography and HPLC are
becoming popular. Hb A2 value of > 9 percent
indicated the presence of a co-eluting abnormal Hb
such as Hb E, Hb D iron and Hb lepore. Micro column
chromatography is an ion exchange chromato-
graphy.
The hemolysate is poured into a column containing
ion exchange resin. The added buffer elutes the
hemoglobin The technique is accurate but suffers
from the disadvantage that other Hb variants cannot
Figure 15.6.9: Graphical representation of various types of
be identified and their presence interferes with
hemoglobin
accurate measurement of Hb A2.
• High Performance Liquid Chromatography
separated graphically and quantified by spectro-
Both anion- and cation- exchange HPLC has been
photometer utilizing sophisticated computer software
applied to identify Hb variants. Cation- exchange has (Fig. 15.6.9). Prior to sample application, the
become far more popular for routine use. Dedicated instrument has to be primed and calibrated followed
instruments have been developed to identify and by use of controls to check reproducibility, HPLC has
quantify HbS by their retention times (the times at great advantage over other techniques of accurately
which they elute) and computing the area under the quantifying all normal and abnormal HbS seen in the
peak. BioRad “Variant” (Fig. 15.6.8) α Hemoglobins are chromatogram.

Other Investigations that Help in Diagnosis of Thalassemia
Radiological Findings
X- ray skull and long bones – Radiological findings include
widening of medulla due to bone marrow hyperplasia,
thinning of cortex and trabeculation in the long bone and
metacarpal and metatarsals.
Skull X-ray shows “hair-on-end” appearance, thinning
of cortex and trabeculation in the long bones and
metacarpal and metatarsal bones (Figs 15.6.10A to D).
Various other tests are indicated as and and when the
disease progresses and involves other organs. Such as
• Liver Function Tests (LFT)—Serum Billirubin, SGOT,
SGPT, GGT.
• Glucose tolerance curve to rule out diabetes.
• Endocrinal studies such as pituitary glands -Growth
hormone, and thyroid gland functions such as T3, T4,
and TSH, Parathyroid- Serum calcium, phosphorus,
paratharmone, and panaceas-fasting blood sugar and
glucose tollerance test and other endocrinal studies
as required.
Clinical Consequences of Iron Overload
Most of the complications of β-thalassemia are attributable
to iron overload. Excess iron is toxic to the heart, liver,
and various endocrine glands.
The commonly affected endocrine glands include
• Pituitary gland, thyroid gland, parathyroid gland,
pancreas, gonads
• Clinically they may not be evident initially, and hence,
investigations are required for early detection, and
should be done in all thalassemia children from time
to time and treat them appropriately.
• Diabetes may be seen as early as five years of age
and particularly seen in adolescent children, whereas
short stature is commonly noted after 10-11 years of
age.
• Dysfunction of thyroid and parathyroid gland may
be sub-clinical initially. Hence a glucose tolerance test,
thyroid functions particularly T3, T4 and TSH, Sr.
calcium, phosphorus should be done frequently if
possible every year, beginning at the age of 5 years.
A B C D
Figures 15.6.10A to D: (A and B) "Hir-on-end"appearance , (C and D) Osteopenia and thinning of cortext
Pediatric Hematology 801
• Affection of the liver is seen in thalassemia children
due to various causes including
– Repeated plasma borne infection,
– Iron overload,
Hence it is necessary to do the liver function test like
serum bilirubin, SGPT, SGOT, GGT, alkaline phospha-
tase and hepatitis markers particularly HBSAg and HCV
antibodies every six months to a year and so also look
for HIV infection by doing HIV test.
It is required to evaluate and monitor the organ
functions regularly particularly- heart, endocrine glands,
growth failure, and complications due to repeated blood
transfusions. Evaluation of weight and height velocity
should be done 10 years age onwards.
Growth failure is seen in 30% of patients in the
western world and nearly all patients in our country,
with few exceptions, these children grow normally in
the first decade particularly when treated efficiently and
growth failure usually becomes evident in the second
decade of life and later.
The mean age of attainment of different stages of
sexual maturity in thalassemic subject is delayed. The
cause of short stature in the iron overloaded patient is
not fully understood.
Various causes attributed for Growth retardation
• Poor compliance to regular transfusion therapy and
poor maintenance of Hb level above 10-11 gm%
• Inadequate chelation therapy.
• Growth hormone deficiency secondary to pituitary
hemosiderosis.
• Defective hepatic biosynthesis of somatomedins
(Insulin like growth factor I-IGF1) and sex steroid
deficiency.
• Chronic hypoxia secondary to anemia is a
contributory factor for growth retardation. Patients
receiving frequent transfusions to maintain Hb level
above 10-11 gm% along with adequate iron chelation
therapy are physically indistinguishable from their
nonthalassemic peers.
• Toxic effect of high doses of deferioxamine on skeletal
growth.
802 IAP Textbook of Pediatrics
• Chronic hypoxia secondary to anemia is a
contributory factor for growth retardation. Patients
receiving frequent transfusions to maintain Hb level
above 10-11 gm% along with adequate iron chelation
therapy are physically indistinguishable from their
non-thalassemic peers.
Evaluation of Cardiac Complications
In β-thalassemia, 70% of deaths are due to cardiac
complications.
• Cardiac failure, and arrhythmias are the main cause
of mortality in thalassemic children.
• Iron overload leads to deposition of iron in various
parts of the heart including ventricular walls and the
conduction system. When iron accumulates in the
cardiac tissue, free iron damages the cells of the layers
of the heart, due to lipid peroxidation and lysosomal
rupture.
• Early detection of cardiac involvement can be done
by evaluation of ferritine level regularly and then
doing the various tests to evaluate the cardiac
functions like ECG, 2D Echocardiogram, stress test,
Holter monitoring. Ejection fraction is decreased and
abnormality in ECG may be present. Cardiac
complication seen in thalassemic children are
evidence of overt cardiomyopathy, abnormalities
such as left atrial dilatation, aortic root dilatation,
reduced left ventricular internal dimension in systole
and diastole. All these assist in evaluation, but do not
quantitate cardiac function. T2 weighted Cardiac MRI
is the only method of assessing severity of cardiac
iron overload.
Bone Disease in Thalassemia Major-Osteopenia
and Osteoporosis
• Osteopenia and osteoporosis are major causes of
morbidity in aging thalassemic population, more in
women.
• Osteoporosis as defined by WHO, a progressive
systemic skeletal disease is characterized by low bone
mass and micro architectural deterioration of bone
tissue, with consequent increase in bone fragility and
susceptibility for bone fracture osteopenia.
• Hence monitoring for bone disease in thalassemia
children is essential particularly in adolescents and
older children.
This can be done by:
• Estimation of Serum Ca/ P/Alk. PO4ase is a poor
indicator.
• DEXA Scan for bone density is ideal.
• A simple, cheap, reliable screening test may be the
estimation of Urine Ca/Cr ratio (> 0.2) and Urine
P/Cr ratio (> 0.6).
This will help in early detection and prompt
management of bone diseases in thalassemic children.
WHO Criteria for Osteoporosis
CATEGORY Z– SCORE
Normal at or below - one SD
Osteopenia between -1 and -2.5 SD
Osteoporosis at or below -2.5 SD (without
fractures)
Established at or below -2.5 SD (with
osteoporosis fragility
fractures)
Bone Mineral Density Study – DEXA Scan
(See Figs 15.6.11 and 15.6.12).
TREATMENT OF OSTEOPENIA/OSTEOPOROSIS
• Hormone replacement therapy- In females – estrogen,
in males-HCG
• Calcitonin-inhibitor of osteoclasts
• Hydroxyurea, biphosphonates and IV pamidronate-
other modalitiess
• Moderate and high impact activities—walking, ballet
dancing, aerobics jogging, etc.
• Diet, rich in calcium and vitamin D
• Hormone replacement therapy for endocrine
abnormalities.
In Summary
During the approach of a case with thalassemia, it is not
only necessary to suspect thalassemia by doing simpler
tests like, evaluation of hematological parameter like CBC
along with various “Red Cell Indices”, “NESTROF test”
and confirm the diagnosis by estimating HbF and HbA2
and other abnormal hemoglobin by doing various test
like hemoglobin electrophoresis, column chromato-
graphy, isoelectric focusing or micro-column
chromatography or high performance liquid chromato-
graphy using various instruments like Bio-Rad Variant
 Pediatric Hematology 803

Figure 15.6.11: DEXA Scan for bone dentistry over the vertebra

Figure 15.6.12: DEXA scan for bone dentistry over the vertebra
804 IAP Textbook of Pediatrics
but also it is important to anticipate complication due to
iron overload involving various organs and due to
transfusion complications and hence it is necessary to
evaluate time to time organ functions for early detection
and complications.
MANAGEMENT OF THALASSEMIA MAJOR
Comprehensive management includes the following:
• Confirmation of the diagnosis
• Correction of anemia– Packed red cell transfusions
• Removal of excess iron– Chelation Therapy
• Management of complications – Endocrine and
Cardiac complications
• Pharmacological methods to increase gamma chain
synthesis
• Curative Treatment– Stem Cell Transplantation
• Future treatment– Gene replacement therapy.
• Prevention of disease by antenatal diagnosis and
genetic counseling
Management of thalassemia major should be
preferably done at a comprehensive thalassemia care
center with outdoor transfusion facilities.
A team approach includes:
• Pediatric hematologist,
• Pediatrician,
• Blood transfusion specialist
• Endocrinologist,
• Psychologist and
• Social worker, etc
This not only helps patients and the family to face
various medical and psychological problems but also
helps in early detection and management of complica-
tions.
TRANSFUSION THERAPY IN THALASSEMIA
Transfusion therapy in thalassemia has two goals:
• To prevent anemia
• To suppress endogenous erythropoiesis to avoid
ineffective erythropoisis
Regular Blood Transfusions are Presently
the Mainstay of Treatment of Thalassemia Major
• Palliative– Pretransfusion - Hb level is around
< 7 gm% and mean Hb maintained is < 8.5 gm/dl.
• Hyper Transfusion– Pretransfusion Hb level is
around > 10gm% and mean Hb. Maintained is
> 12 gm%.
• Super Transfusion– Pretransfusion Hb level is
around > 12gm% and mean Hb. Maintained is
>14gm%.
• Moderate– Transfusion-Pretransfusion- Hb level is
around 9-10.5 gm% and mean Hb. Maintained is
>12gm %
• Current recommendation is to maintain the mean
post transfusion Hb. level of 12 gm/dl and transfuse
the child at level of 9 to 10.5 gm/L (Moderate
Transfusion). Post–Transfusion level of Hb should
not rise above 15 to 16 gm/dl.
Type of Transfusion
Leukoreduced packed red cell transfusion is desired
type of blood for thalassemic children.
Reduction of leukocytes to 5 × 106 is considered
adequate. Leukoreduction helps in reducing unwanted
reactions associated with leukocytes. It helps in
prevention of transfusion reactions and is achieved by
centrifugation;/saline washing/filtration.
It is ideal to use leukodepleted red cells done in the
blood bank. However, wherever, this is not feasible.
Methods for leukodepletion
• Centrifugation– Packed red cell transfusions— can
remove 70% of leukocytes from 1 unit of blood.
• Saline-cell washing (Triple Saline Washed)
(Fig. 15.6.13) or Deglycerolized–red cells can remove
90-95% of contaminated white cells. Saline washed
packed cells (triple saline washed) reduces blood
transfusion complications.
• Deglycerolized–red cells. (Frozen cells) are useful to
patients with rare RBC antigens for whom it is
difficult to crossmatch the donor’s blood. Very
expensive and advanced technology is involved and
is useful for rare blood groups. Frozen blood with
absence of these antibodies, can be stored as long as
7 years or more.
• Third generation leucocyte filters can remove 99.9%
of white cells. However, filters do not remove
cytokines. Bedside, filters are available commercially
which are highly expensive (Rs. 650 at discounted
rate). They are meant for single use only, and are

Figure 15.6.13: Cold centrifuse
disposable and hence are not affordable to most of
our patients (Fig. 15.6.14).
• Irradiated blood cells– should be given to patients
who have received BMT or candidates waiting for
bone marrow transplantation.
Thalassemic Children Live on Borrowed Blood
• This obviates anemia
• Improves tissue oxygenation, and prevents chronic
hypoxia
• Improves normal growth and development
• Prevents erythropoiesis thus avoiding expansion of
the bone marrow and extra medullarys erythropoiesis
• Reduces hemolytic facies
• Reduces hepatosplenomegalyand cardiomyopathy
• Reduces gastro-intestinal absorption of iron.
Blood Transfusion is Mandatory for
• All children with thalassemia major
• Children with thalassemia intermedia who cannot
maintain Hb above 7g/dl, or
• Those who show evidence of growth retardation and
severe bony changes
• Post-transfusion level of Hb should not rise above 15
to 16 g/dl.
Pediatric Hematology 805
Figure 15.6.14: Leucocyte filter
WHEN TO START THE TRANSFUSION
• Blood transfusion is started as soon as diagnosis
firmly established (Except in children > 18 months of
age).
• If age is > 18 months, these children are observed to
r/o Thalassemia Intermedia and if Hb drops < 7
gms%, regular transfusion started.
• If facilities are available it is worthwhile having DNA
analysis done prior to transfusion therapy. This will
help in prenatal diagnosis of future children.
• It is equally important to know complete Genotype
of RBC to prevent red cell alloimmunization
following repeated blood transfusion. As this facility
is not available in our country, Comb’s crossmatching
is strongly recommended. To avoid alloimmuni-
zation, patients’ red cell antigen particularly ABO,
Rhesus, Kell, Kidd, Duffy system should be typed
before institution of trasfusion therapy which is not
done in our country due to lack of facilities.
WHAT TYPE OF TRANSFUSIONS
Ideal transfusion therapy includes:
• The most ideal way to transfuse thalassemics is using
group and type specific saline washed packed red
cells (HCT - 65 to 75%) that are compatible by direct
antiglobulin test (Coomb’s crossmatched).
806 IAP Textbook of Pediatrics
RATE AND FREQUENCY OF TRANSFUSIONS
• 10-15 ml/kg of saline washed packed red cells every
3 to 4 weeks.
• Rate not more than 5 ml/kg/hr, however, in patients
with cardiac dysfunction not more than 2-3
ml/kg/hr should be given.
• Shorter intervals of 2 to 3 weeks are more physio-
logical.
• 10 ml /kg rises Hb level by about 3.5 gm /dl this is
adequate to maintain pretransfusion desired base line
Hb level of 10-11 gm /dl. when given 10 ml/kg every
third week.
• Average time taken is 3-4 hours.
• These red cells should be transfused at the rate of 3
to 4 ml/kg/hour.
Advances in Transfusion Therapy
Neocyte transfusions and Neocyte-Geriocyte exchange
transfusions.
Neocyte transfusions, to improve the survival of red
cells after transfusion, have been tried but with limited
success. In a unit of blood, red cells have a survival of
60 days. Proper et al in 1980 introduced the concept of
transfusing thalassemic children with young red cells,
the mean age being around 12 days. IBM 2991 Cold
centrifuge is used for both washing the red cells as well
as for dividing them into population of different age
group by differential centrifugation techniques. They
survive in the recipient for about 90 days, thus reducing
the amount of blood required and prolonging the interval
between two transfusions. They are experimental and
are not of practical use as there are greater risks of
alloimmunization, greater risk of viral infections and as
its high cost/sophisticated technique involved.
Amount and Rate of Transfusions
• Approximately 180 ml/kg of red cells are required
to be transfused per year in non-splenectomized, non-
sensitized patients to maintain the hemoglobin above
10 gms%, whereas splenectomized patients require
133 ml/kg per year.
• Even without hypersplenism, the requirement is 30%
higher in non-splenectomized patients.
Efficacy of Transfusion Regimen
Rate of fall of Hb. should not exceed 1gm/dl/week in
splenectomised patients, and not more than 1.5 gm/dl/
week in non splenectomised patients. If Hb fall is greater
then investigate further for.
• Alloimmunization of RBC’s.
• Hypersplenism (Blood transfusion requirement
increase more than 200c.c/kg./Yr.).
• Drug induced, like aspirin, ribaverin, bleeding,
infection like malaria.
If transfusion requirement is >200c.c/kg/yr, explore
the cause of high transfusion requirement.
OUTDOOR CENTRE FOR THALASSEMIA
(PROGRESS IN TRANSFUSION THERAPY)
In the past, thalassemic children had to be admitted for
blood transfusion alongside other sick children of the
ward.
• Prolonged hospital stay, cross infections, increased
cost, both to the parents and the institution as well as
psychological trauma was the brunt of such therapy.
• With the advent of outdoor transfusion centers
(Figs 15.6.15 and 15.6.16), transfusion can be well
planned causing minimal psychological trauma to the
child and parents as transfusion is given in a cordial
compliant surrounding with other thalassemic
children.
There are fewout door transfusion centers in our
countries.
• Blood bank support crucial to sustain regular
transfusion. Organizing camps possible with the help
of NGOs support.
• There are more than 25 outdoor transfusion centers
all over the country. Outdoor center LTMG hospital
Bombay started in 1988.
Advantages of Outdoor Thalassemia Centers
• Transfusions are given on OPD basis and hence no
hospitalization required.
• Children are more comfortable.
• It has made the therapy more convenient and
compliant as it can be planned on school holidays
and on the day convenient. There is less school
absenteeism and Parents lose less workday.
• When child is admitted in the ward of the Hospital,
expenditure-indoor is around – Rs.790/pt/day and
when treated on outdoor basis the expenditure is
around - 180/pt/day. This has reduced cost to parents
as well as to the institution.
• Group therapy as a part of the intervention program
has an important role and direct beneficial impact on
outcomes.
• It can be used as a platform to spread information,
current knowledge and for genetic counseling.

Figure 15.6.15: Outdoor transfusion center
Figure 15.6.16: Outdoor transfusion center services at
LTMG Hospital Sion, Mumbai
• There is no threat of contacting infections from other
patients in the wards.
• There is great psychological support.
• Identification with the staff helps better compliance.
• Parents exchange and share their experiences and
feelings.
• Trained nurse/doctor in charge plans the transfusion
therapy well in advance giving sufficient time for
proper testing.
• Trained nurse is responsible for maintaining the vein
- the lifeline of thalassemic children, for the proper
Pediatric Hematology 807
use of filters and for training parents about the use of
desferal pumps, etc.
• This change in environment has made transfusion
therapy a great success.
Adequacy of Transfusions
It is important to check the adequacy of transfusions to
achieve best results and manage thalassemics ideally.
• In the first decade of life, normal growth confirms
adequate transfusions.
• Also the number of normoblasts should be <5/100
WBCs in well-transfused children. This may be an
indicator in older children (However, this is not
applicable to those children who have not been
initiated on therapy early and adequately in early
life).
COMPLICATIONS OF TRANSFUSION
• NHFTR (Non hemolytic febrile transfusion reaction)–
• Alloimmunizaton.
• Plasma borne infections -Transfusion transmitted
infections
• Iron overload.
PREVENTION OF INFECTIONS
• Other major problems encountered due to repeated
blood transfusion are transfusion transmitted
infections
• Hepatitis B-5 - 30.6% of cases, and Hepatitis C-30-
39% of cases.
• HIV infection can be tested for p24 antigen and DNA
PCR to detect HIV infection in the window period
and are expensive and impractical for our nation at
present. Incidence of HIV ranges from 0%
Chaudhary, et al to 70%-by Currymbhoy et al (1997)
and 10% by Manglani et al. Therefore it is mandatory
to screen blood for HIV, HBV, HCV by sensitive tests.
• Other infections seen are CMV, Yersinia spp, and
malaria, etc.
Steps to Prevent These Infections Include
• Stringent Donor Selection,
• All thalassemic children who are negative for the
hepatitis B surface antigen and antibody, should
receive hepatitis B vaccine in 4 doses at 0, 1,2 and 12
months intramuscularly, Booster dose may be given
after 5 years.
808 IAP Textbook of Pediatrics
• Other infections include malaria–It is not possible to
screen the donors or blood bag in endemic countries
like ours for malaria, and hence the policy is to treat
the child whenever indicated.
• Leukodepletion can minimize CMV infection.
• Now screening for HbC antibodies are made
compulsory thus reducing the incidence. Interferon,
Pegylated interferon, Ribaverin are commonly used
in treatment of these children is highly expensive.
• Yersinia Spp. Infection is more common in
thalassemic children receiving Inj desferal. Stop
desferal and initiate co-trimoxazole or amino-
glycoside.
Iron Overload and Chelation Therapy
One of the other major problems encountered in the
management of thalassemia is iron overload.
Iron Overload Occurs in Thalassemic
Patients due to
• Treatment with multiple transfusions–One bottle of
blood transfusion given adds 200-250mg of iron to
the body store
• Ineffective erythropoiesis
• Excessive dietary absorption of iron from gut, to
compensate the large turnover of red cell mass
(especially in inadequately transfused children) [2-5
gm/year in thalassemic children compared to 0.0015
g/year in normal individuals]
• Lack of physiologic excretory mechanism for the
excess iron.
The goal of iron chelation is to reduce the iron store
and subsequently maintain at low level (less than 1000
ng/ml).
Drugs Used Presently
• Desferrioxamine (Injectable)
• Deferiprone (Oral)
• Deferasirox (Oral)
A major problem encountered in the management of
thalassemia is iron overload.
Regular red cell transfusions to maintain hemoglobin,
as well as increased iron absorption from GI tract due to
ineffective erythropoiesis, and consequent low
hemoglobin in irregularly transfused children is
responsible for iron overload.
• As a general rule, patients with Thalassemia Major
should begin chelation therapy once they have had
10-20 transfusions or when ferritin leval rises above
1000/ug/liter.
• Though several hundred compounds have been
developed and tried desferrioxamine (DFO) is gold
standard therapy and found to be most effective and
safe iron chelator.
• It is reported that 2000 to 4000 patients die due to
iron overload every year.
Desferrioxamine (Desferal) (DFO)
The dose is 30 to 40 mg/kg/day given subcutaneously
over 8 to 10 hrs for 6 nights a week with the help of
subcutaneous desferal infusion pump (Fig. 15.6.17). The
dose is adjusted according to body wt. and extent of iron
over-load.
In recent times, methods of administration have
improved with better, more convenient smaller, lighter
infusion pumps with LCD display.
Figure 15.6.17: Subcutaneous deferral infusion pump
• Balloon pumps, pre-filled syringes of desferal are
available though they are prohibitively costly.
• Intravenous desferal can be given particularly in those
with very high iron overload through port-a-caths
(central line). It is not easy to maintain the central
catheter and infections are common.
• However, high dose desferal (3 to 9 g/day) can be
given intravenously in severe hemosiderosis to
prevent/reverse cardiac toxicity of iron overload.
• It is useful adjunct to subcutaneous infusion.
• However, close monitoring for adverse reaction is
required.
• Depot Desferal (desferrioxamine) (DFO) is the
newer modification in chelation therapy. With depot

preparation of desferal there is slow release of
desferrioxamine leading to substantial plasma level
of desferrioxamine in the blood for longer period and
hence urinary iron excretion is sustained for longer
period. This is more effective than the conventional
subcutaneous infusion.
Though, desferrioxamine is the gold standard in the
management of iron overload in thalassemia major, it
has not become popular particularly in the developing
countries and is being used in only 10 to 15% of
thalassemics in our country. This is mainly due to its high
cost and the need for continuous subcutaneous injection
over 6 to 8 hours. Poor compliance particularly seen in
the adolescent groups who often revolt against the use
of this pump. This has resulted in delay and irregularity
of its use. Hence, many of the thalassemic children
develop complications related to iron overload and may
require to be given high dose intravenous desferal
through the port or central line. This again is beyond the
reach of many children in developing countries.
Toxicity of Desferal (desferrioxamine) (DFO)
• Minimal
• No tachyphylaxis has been observed
• When given parenterally there may be liberation of
histamine leading to bradycardia, hypo/hyper-
tension, rigors, headache, photophobia, feeling cold
and hot, etc.
• When given subcutaneously local pain, indurations,
irritability and redness may occur.
• Visual abnormality may occur in 4 to 10 percent of
patients and includes decreased acuity of vision,
peripheral field vision defects, defective dark
adaptation, thinning of retinal vessels, retinal
stippling and abnormal visual evoked responses and
cataract.
• High frequency sensory-neural hearing loss has been
reported in 4 to 38 percent of patients.
• As the auditory and visual toxicities are reversible,
yearly slit-lamp examination and audiometry are
mandatory to detect them early and if found, desferal
should be stopped.
• Delayed linear growth has also been reported in
children below three years of age with desferal. These
may be accompanied by mild skeletal abnormalities
such as short trunk, sternal protrusion and genu
valgum
Pediatric Hematology 809
Role of Vitamin C
Ascorbic acid deficiency increases insoluble iron
(hemosiderin). Vitamin C helps in conversion of
hemosiderin into ferritin, from which iron can be
chelated. High doses of vitamin C can lead to increased
free radical liberation and lipid peroxidation, resulting
in tissue damage and rapid cardiac decompensation and
even death. Addition of 100 mg of vitamin C daily, prior
to DFO therapy increases iron excretion.
Sixty percent of DFO chelated iron is excreted in urine
and 40 percent in stool.
Other Chelating Agents
Over the last 20 years, more than 500 oral chelating
compounds have been tried all over the world in search
of an ideal chelating agent which can be effective, cheap,
safe and can be given orally. Among the various drugs
under trial, few have completed animals studies, a few
are being tried in human volunteers and very few have
been marketed.
Deferiprone
One of the drugs which has been approved in some
countries across the world is dimethyl-hydroxy pyridone
(1,2 dimethyl-3-hydroxy pyrid-4-one (L1), developed in
Hider’s laboratory-London, now generically named as
Deferiprone and available in India under the brand
name of Kelfer.
• It mobilizes iron from transferrin, ferritin, and hemo-
siderin.
• It has undergone extensive trials in USA, UK, Canada,
India and various other centers.
• Dose: 75 to 100 mg/kg body weight/day in three to
four divided doses.
• Results show that it is 70 to 100 percent as effective
as desferrioxamine and leads to effective reduction
in both serum ferritin and tissue iron overload.
• Twenty to thirty percent children develop arthro-
pathy, which is reversible after reducing the dose or
on stopping it. However, if the drug is not
discontinued in time or its dosage not reduced, it may
lead to swelling of the joint, synovial thickening,
synovial effusion, chondromalacia, mild flexion
deformity of the knee, painful external rotation of the
hip and vague generalized backache,destruction of
joint cartilage and irreversible damage to the joint.
810 IAP Textbook of Pediatrics
• Physical examination of the joints and complete blood
count including platelet count must be done regularly
when child is on deferiprone (L1) therapy.
• ANA, anti ds-DNA, antihistone antibodies have been
reported positive in a few cases, suggesting a drug-
induced lupus.
• Absolute neutropena and thrombocytopenia also
have been reported in occasional cases.
• There has been no evidence of ear or eye toxicity.
• Urinary excretion of Ca, Cu, Mn, Mg does not get
affected.
• Kidney and liver parameters did not show any
alteration.
• Some children can have GI symptoms like nausea,
vomiting, pain in abdomen and diarrhea.
To bring down the cost, to improve the compliance
and efficacy of the chelation therapy and reduce the side
effects, combination therapies have been tried.
Oral Deferiprone (L1) 75 mg/kg/day for 4 to 5 days in
a week and DFO 30 to 40 mg/kg day subcutaneously
with the help of subcutaneous infusion pump over 6-8
hours on weekends (2 days) have been shown to be more
efficacious in reducing both liver and heart iron. This is
based on the principle of shuttle hypothesis of one
chelator mobilizing the iron from stores in tissues and
the other helping in excretion from the blood stream.
With recent advances in chelation therapy especially
with the availability of oral chelating drugs like
deferiprone (L1) compliance has remarkably improved.
The cost of therapy has reduced considerably and hence
even in the developing countries many children are able
to get chelation therapy.
Deferasirox (Oral)- ICL 670 (Exzade)
• A novel chelating agent belongs to tridentate tiazole,
with high affinity to iron as Fe+++ and chelates at a
ratio of 2:1 (Deferasirox: Iron).
• Deferasirox-is a new, oral iron chelator for treatment
of iron overload associated with chronic blood
transfusion. As half-life of the drug is 11-16 hrs and
hence can be given once a day.
• Given orally in the dose of 20 mg to 40 mg once daily.
• It should be given approximately same time each day
on an empty stomach 30 minutes prior to food. Tablet
should be dispersed in water/orange /apple juice.
• It is available as 250/500 mg tablet for oral suspension
dispersible tablets.
• Dosage adjustment should depend upon patient’s
response, S. Ferritin, serum creatinine levels.
• Five times as effective as subcutaneous DFO and 10
times more potent than deriprone in animal study.
• Iron excretion is predominantly fecal. It excretes iron
from both reticuloendothelial cells as well as
paranchymal cells of various organs and chelated iron
excreted by liver through the bile.
• Only side effects reported include mild abdominal
pain, gastrointestinal discomfort, constipation,
diarrhea, skin rash. No changes in auditory, visual
(ocular) or cardiac functions were observed.
• It also has the ability to prevent myocardial cell iron
uptake, remove the iron directly from myocardial
cells and exchange the iron with DFO.
• RFT/LFT/CBC should be monitored particularly in
patients who are increased risk of complications, have
pre-existing renal conditions, have associated co-
morbid conditions.
• Co-administration of ICL 670 (Deferasirox) with Inj
DFO has synergic effect and helps in reducing dose
of both the drugs thus improving the compliance and
cost of the treatment as is done with oral chelation
therapy with deriprone and inj. desferal. Shuttle effect
also seen with this combination, as ICL 670-
Deferasirox acts as intracellular chelator and DFO as
extracellular. Other advantage is, it does not chelate
zinc or copper.
• Bidentate (L1) chelator –mobilizes tissue iron into
blood stream.
• Hexadentate (DFO) – binds irreversibly and excretes
iron.
• Combination therapy is more effective.
• HBED and L1 and ICL670A and DFO also have been
successfully tried.
Future Perspectives
• Newer drugs like PIH (pyridoxal-isonicotynoyl
hydrozone) HBED- and diamethyl HBED though
looked promising, as they were relatively non-toxic
and effective. However, as they are non-patentable,
industry has none or limited interest
• Pharmacologic manipulation of HbF–drugs like
hydroxyurea, butyrate’s, 5-azacytidine,
• Erythropoietin has been tried to induce HbF
production with varying success.
• Pharmacologic gene manipulations have been tried
in order to increase the production of HbF and to
 Pediatric Hematology 811

prevent the precipitation of unpaired Hb chains.

Drugs used are 5-azacytidine, hydroxyurea, butyrate
derivatives. Though some of the studies have shown
Hb increment following butyrate therapy, majority
of workers have not found it to be useful. Hydroxy-
urea has been found useful particularly in thalassemia
Intermedia and double heterozygotes and Sickle cell
disease.

Management of Complications
• Gallstones–More commonly seen in children not
receiving regular treatment. If asymptomatic may not
need any specific treatment.
• Prophylactic cholecystectomy, may be done along
with spleenectomy
• Leg Ulcers– Seen more commonly in Thalassemia
intermedia and in Thalassemia Minor. Bed rest,
regular transfusion, wound care, local tissue factors - Figure 15.6.18: Splenectomized thalassemic child
G-CSF (1 vial diluted in normal saline) have been
found to be useful. If the child has already developed splenomegaly
and signs of hyper-splenism are present, and is above
HYPERSPLENISM AND SPLENECTOMY 5 years of age, splenectomy should be considered
Causes of Hypersplenism (Fig. 15.6.18).

• Inadequate transfusions STEM CELL TRANSPLANTATION

• Alloimmunization
• Chronic liver disease
• Auto immune hemolytic disease
Splenectomy
Indications for Splenectomy In Thalassemia:
and Post Splenectomy Care
• An increase in the yearly requirement of packed cells
more than double the basal requirement, i.e. packed
cell 230 to 250 cc per kg.
• Decreased platelet counts are a relatively late
manifestation of hypersplenism.
• With the advent of hyper and super-transfusion
therapy, splenomegaly and hypersplenism have
become a rarity. Hence splenectomy is usually not
needed in these patients.
• All children needing splenectomy should receive
pneumococcal vaccine, H. influenza type b vaccine,
and meningococcal vaccine 6 to 8 weeks prior to
surgery. In endemic areas, prophylactic antimalarial
treatment may be given to prevent malaria
• Avoid Spleenectomy before the age of 5 yr.
This is only the curative therapy available today.
Sources
• Bone Marrow,
• Peripheral Blood,
• Cord Blood,
• Fetal Liver.
Though expensive, it is cost effective as compared to
yearly cost of regular blood transfusion and chelation
therapy.
Bone Marrow Transplantation
A ray of hope for permanent cure and better future for
children with genetic disorders has emerged with the
rapid advancement in the techniques and the success of
bone marrow transplantation.
The credit of first bone marrow transplantation in
thalassemia major goes to E. Donald Thomas who
performed this procedure in an 18 months old
thalassemic child in 1982, using HLA matched older
sister as donor. This child was cured of thalassemia. The
first BMT in india in thalassemia was successfully done
by Dr M Chandy and his group at Christian Medical
College, Vellore.
812 IAP Textbook of Pediatrics
The Principles of Bone Marrow
Transplantation in Thalassemia
• To destroy and prevent regeneration of defective stem
cells.
• Sufficient immune suppression for good engraftment
of normal marrow.
• To infuse stem cells with normal gene for β-globin
chains.
• To prevent GVHD with high dose therapy of
busulphan, cyclophosphamide, total body irradiation
and other modalities.
All over the world, more than 1000 transplantations
for thalassemia major have been done, with a 70 to 80
percent cure rate.
Figure 15.6.19: Bone marrow transplantation donor is
elder brother
The Three Most Important Adverse Prognostic
Factors for Survival and Event-free Survival are
(Lucarelli et al)
• Presence of hepatomegaly (liver more than 2 cm
below costal margin)
• Portal fibrosis
• Irregular chelation.
Patients are Classified as Different Classes as
Below to Prognosticate the Outcome of Bone
Marrow Transplantation
• Class I : None of the above factors
• Class II : One or two factors
• Class III :All of the above
For those in Class I, the success rate is around 93 %
and with all three factors present, the success rate drops
to as low as 60%.
Bone marrow transplantation is most successful in
patients who are young, properly transfused, and well-
chelated and in clinically well preserved without
hepatomegaly. The cost of BMT in India is around
Rs. 5-8 lacks and is being done at Christian Medical
College, Vellore, Tata Memorial Hospital, Parel, Mumbai,
Jaslok Hospital, Mumbai, and AIIMS in Delhi and many
other centers in the country (Fig. 15.6.19).
STEM CELLS
Also can be obtained from the cord of unaffected fetus
at delivery. Umbilical cord stem cells have good results
in most centers even with 0-2 HLA mismatched stem
cells. Lower GVHD and longer engraftment have been
reported. However, some have found higher early
morbidity.
BMT in-utero at 16 to 18 weeks of gestation is
underway. There would be no rejection as immune
system is not developed at that time. Mother’s purified
stem cells can be used. Success and practical application
is awaited.
Endocrine Evaluation and Growth Monitoring
Iron overload is responsible for dysfunction of many of
endocrine glands like thyroid, parathyroid pituitary
gland, gonads and pancreas leading to hypothyroidism,
altered calcium metabolism, stunted growth, delayed
puberty and diabetes. Clinically they may not manifest
initially and hence, regular evaluation is necessary.
• Glucose tolerance test, thyroid function tests, serum
calcium and phosphorus should be evaluated from 5
years age onwards annually.
• Ten years onwards, one must monitor the height and
weight velocity, perform the investigations for cardiac
complications (2D-ECHO), consider pertinent
hormone assays and do a DEXA scan for bone
density.
• This helps in early detection and better management.
PREVENTION OF BIRTH OF THALASSEMIC CHILD
The treatment of thalassemia-major is very expensive,
painful and psychologically disturbing. Emphasis must
therefore, shift from treatment to prevention.
Fortunately, thalassemia major is a preventable disease.

As we know, thalassemia minor or carrier state can
be easily detected in a person by doing simple blood test
HbA2 by hemoglobin electro-phoresis or variant machine
or column chromatography.
Prevention includes population education, mass
screening, genetic counseling and antenatal diagnosis
and therapeutic abortion of affected pregnancy.
• Not even 5-10% of thalassemic children born in India
receive optimal treatment.
• Cost of treatment of 4-year-old thalassemic child is
around Rs.90-100,000 annually.
• Bone marrow transplantation as a curative treatment
is out of reach for majority of children.
• Need of the day
• Population education.
• Mass screening of target population.
• Genetic counseling of “minor” couples.
• Prenatal diagnosis.
Population Education
Population education is done through various mass
media, awareness campaigns in colleges and com-
munities, posters, banners, etc. In a large population such
as in India, it may be more cost-effective to involve high-
risk communities to begin with.
Mass Screening
Various methods of screening blood for thalassemia
minor are available which include peripheral smear
examination, RBC indices, Meintzer’s fraction,
Discriminant functions, NESTROFT (Naked Eye Single
Tube Red cell Osmotic Fragility Test), etc. However, none
of them are confirmatory. The only confirmatory test is
HbA2 estimation. To conduct an effective mass screening
program, the targeted population should belong to the
premarital and newly married groups, i.e. before they
have begun their families.
Genetic Counseling
If a person is a thalassemia minor, he/she should avoid
marrying another minor, but it is not a must. Because if
two minors marry, they can be given the option of
prenatal diagnosis. Genetic counseling is offered to all
who test minor. If only one of the partners is a minor,
there is no chance of them having a thalassemia major
child, but 50 percent chance during each pregnancy of
Pediatric Hematology 813
having a thalassemia minor child. But if both partners
are carriers or thalassemia minor, there is a 25 percent
chance of having a thalassemia major child, 50 percent
chance of having a thalassemia minor child and 25
percent chance of a normal child, during each pregnancy.
These are the people who should be convinced to
undergo prenatal/antenatal diagnosis.
Prenatal/Antenatal Diagnosis
When both partners, who are thalassemia minors, plan
to have their baby, they are told to report to their
hematologist as soon as possible after pregnancy is
confirmed. There are many centers for prenatal diagnosis
in Mumbai, Delhi, Chennai, Hyderabad, etc. The couple
is referred to one of them before 8th week of pregnancy
so as to enable the center to give an appointment for the
test between 9th and 11th week of pregnancy. This is the
ideal time for testing. This test is known as chorionic
villous sampling (CVS) and is done generally without
anesthesia.
The risk of fetal losses is below 1 percent in expert
hands, the risk of misdiagnosis also being below 1
percent.
Reasons for Misdiagnosis
• Failure to amplify target DNA fragment
• Maternal contamination
• Sample exchange
• Mispaternity.
The diagnosis is available within a week of test and is
given as:
i. ‘Affected’ which means the fetus has thalassemia
major, or
ii. ‘Unaffected’ meaning that the fetus is either
thalassemia minor or normal.
Affected fetuses are advised to be terminated and
unaffected fetuses to be continued.
If the couple misses to report before 8 weeks of
pregnancy, there is still a possibility for prenatal
diagnosis by 16 to 18 weeks of pregnancy. The tests done
include amniocentesis or cordocentesis. The results are
given as ‘affected’ or ‘unaffected’ with this test too.
Medical termination of affected fetuses is advised.
Since, couple with thalassemia minor has a 75 percent
chance of having an ‘unaffected’ fetus during each
814 IAP Textbook of Pediatrics
pregnancy, they can have children. But if they do not
wish to terminate the affected fetuses, they can opt for
adoption or no children or artificial methods using donor
sperms/ova.
Genetic Engineering
Aim is addition of a normal copy of the gene along with
key regulatory sequences. Insertion of normal gene in
the stem cells of recipient remains known challenging
goal of future therapy. There are two main approaches
to gene therapy:
• Somatic gene therapy in which non-germ line cells
are involved.
• Transgenic approach in which transfused gene can
be expressed in subsequent generations. This therapy
is still in experimental stage and likely to be therapy
of future in management of thalassemia. This
approach, however, has been impeded by difficulty
of attaining high-titer vectors for sustained
expression. Lenti Viral vector derived from Human
Immunodeficiency Virus, where a large fragment of
human beta gene and its locus control region, have
been introduced, though experimental, more effective
therapies will become available near future to cure
the disease.
PRE-IMPLANTATION DIAGNOSIS
• Biopsy of blastula: By washing uterine cavity after in
– vivo fertilization.
• Analysis of a single blastomere from an eight cell
embryo after in-vitro fertilization.
PRE-CONCEPTION DIAGNOSIS
• Analysis of the first polar body of an unfertilized egg
• Distinguish between eggs which carry the defective/
normal gene.
• In-vitro fertilization of normal egg.
• Replace in mother’s uterus-successful pregnancies are
reported.
• Useful for couples against MTP.
• Technically demanding, difficult to organize, high
cost.
CONCLUSION
Until last few decades thalassemia was regarded as
uniformly fatal disease and death was expected during
the second decade of life before adulthood. Till 1960s
and1970s particularly in developing countries like
INDIA—many children died even before diagnosis.1980s
and 1990s-regular transfusion-hyper transfusion therapy,
desferal therapy in western world and not in developing
world, markedly improved growth and development.
However. in future with progress in the understanding
molecular biology and pathophysiology of thalassemia,
advances in the transfusion therapy, organized quality
care and effective chelation therapy, thalassemics can
become fully active members of the society with proper
physical, mental and sexual growth without any disfigu-
ration and are able to profit from their opportunities and
enjoy positions they are entitled to in the society. With
the free availability of oral chelators in near future, and
establishment of more and more outdoor transfusion
centers and thalassemia societies, the management of
thalassemia major will become easier and economically
feasible. With the advent of BMT, cure is possible and
gene therapy still remains hope for the future. In
developed countries where all these facilities are already
available, more and more thalassemic children are
leading a normal healthy life and even achieving
parenthood. Prenatal screening and antenatal diagnosis
as well as modern management of thalassemia are
technologically complex and expensive, and thus their
benefits remain limited only to the industrialized
developed world and in certain centers in India.
Unfortunately, developing countries like ours still have
a long way to go. Management of the disease has brought
brighter prospects of survival extending in to 3rd and
4th decades of life provided they receive the latest
treatment with good compliance, and have
metamorphosed thalassemia major from a fatal to a
preventable, manageable as well as a curable disease.
Thalassemia hence should no longer be seen as a
disease of childhood since patients now have prospects
of survival beyond adolescence particularly in countries
where health services are able to supply adequate
treatment. Hence today’s expectations of thalassemic
adolescents are:
• To reach the age of puberty, with normal growth and
development.
• Expect same attainments as those of their healthy
peers–in education, employment and a well–adjusted
social and sexual life.

• Growth failure and pubertal delay and fertility
represent major obstacles to the fulfillment of these
hopes.
This has opened a new chapter in the management
of thalassemia beyond blood transfusion and chelation
therapy. Problems of adolescence, growth and puberty,
bone mineralization, proper sexual development,
sexuality, ability to have proper education, to find
suitable employment, marriage and parenthood are
concerns that today require attention.
BIBLIOGRAPHY
1. Agarwal MB. Thyroid function in multi-transfused iron
loaded thalassemic patients. Ind Pediatr 1992;29:997-
1002.
2. Ashraf T, Saliman, et al. Thyroid function in thalassemia
major. J Tropical Pediatr Dec. 1999.
3. Borgna – Pignatti C, DeStefan OP, Zonta L, et al. Growth
and sexual maturation in thalassemia major. J Pediatr
1985;106:150-55.
4. Colah RB, Mohanty D, Beeta Thalassemia: Expression,
Molecular mechanism and mutation in Indians.
Ind.J.Pediatr.1998;65:815-23.
5. Costin G, Kogurt MD, Hymen CG, Orleger JA. Endocrine
abnormalities in thalassemia major. Am J Dis Child
1979;133:497-502.
6. De Sanctis V, Katz M, Vullo C, et al. Effect of different
treatment regimes on linear growth and final height in
B-thalassemia major. Clin Endocrinol 1994;40:791-98.
7. De Virgillis S, Congia M, Frau F, et al. Desferrioxamine
induced growth retardation in patient with thalassemia
major. J Pediatr 1988;113:661-69.
8. DM Flynn, Angela F, et al. Hormonal changes in
thalassemia major. Arch Dis Child 1976;51:828-34.
9. F deluca, R Melluso, G Sobor, et al. Thyroid function in
thalassemia major. Arch Dis child 1980;55:389-92.
10. Gulati R, Bhatia V, Agarwal SS. Early onset of endocrine
abnormalities in B-thalassemia major in developing
country. J Ped Endocrinol Metabol 2000, 13: 651-656. Dr.
Rakesh Malhotra. Thesis submitted to University of
Bombay for D.M. (Endocrinology) Exam. July 2002, Dept.
of Endocrinology, KEM Hospital and GS Medical
College, Mumbai.
11. Kattamis C, Liakopoulou T, Kattamis A. Growth and
development in children with thalassemia major. Acta
Pediatr Scand 1990, (suppl) 366: 111-17.
Pediatric Hematology 815
12. Kattamis F, Touliatos N, Haidas S, et al. Growth of
children with thalassemia – effect of different transfusion
regimes. Arch Dis Child 1970;450:502-09.
13. Lokeshwar MR, Manglani M, Rao S, et al. Current trends
in Thalassemia therapy. Proceedings of international
symposium cum workshop on “Anemia in children”
1991;14-21.
14. Nadkarni A, Goraskar AC, Krishnamoorthy R, et al.
Molecular pathogenesis and clinical variability of Beeta
thalassemia syndrome among Indians. Am. J. Hematol
2001;68(2):75-80.
15. Neil Mcintosh. Endocrinopathy in thalassemia major.
Arch Dis Child 1976;51:185-200.
16. Pintor C, Cella SG, Mansol. Impaired growth hormone
(GH) response to GH releasing hormone in thalassemia
major. J Clin Endocrinol – Metab 1986;62:263-67.
17. Rodda CP, Reid ED, Johnson S, et al. Short stature in
homozygous B-thalassemia is due to disproportionate
trunk shortening. Clin Endocrinol 1995;42:587-92.
18. Theodoridis C, Ladis V, Papatheodoron A, et al. Growth
and management of short stature in thalassemia major. J
Pediatr Endocrinol Metab. 1998;11:835-46.
19. Vanna Saeng S, Fucharoen S, Pootrakful P, et al. Pituitary
function in thalassemic patients and the effect of chelation
therapy. Acta Endocrinol 1991;124:23-30.
20. Verma IC, Bijarnia S. The burden of genetic disorder in
India and a frame work for community controle. Commu.
Genet. 200ask 2;5:192-96.
21. Verma IC, Choudhury VP, Jain PK. Prevention of
thalassemia a necessity in India. Ind J Pediatr 1982;59:
649-54.
22. Vishwas Khajanchi. Thesis on ‘Endocrine Dysfunctions
in Thalassemic Children’, dissertation submitted at the
D.M. (Endocrinology) Examination, University of
Mumbai, July 2002, for FCPS (Pediatrics) Examination,
held by College of Physicians and Surgeons, Bombay,
Dr. E. Moses Road, Parel, Mumbai.
23. Weatherall DJ, Clegg JB, The Thalassemia Syndromes
4th Ed. Oxford, Blackwell Scientific Publications 2001.
24. Wolman TJ. Tranfsusion therapy in Cooley’s anemia
growth and health as related to long range hemoglobin
level: A progress report. Am NY Acad Sci 1964;119:
736-47.
25. World Bank 2006, report of a joint WHO –March of dime
meeting 2006-Quoted, Guidelines for the clinical
management of thalassemia. 2nd edition Thalassemia
International Federation –Nicosia Cyprus. 2007;9.
26. Zamboni G, Marrati P, Talgiaro F, et al. Parathyroid
hormone, calcitonin and Vit. D metabolism in β-
thalassemia major. Eur J Pediatr 1986;145:133-36.
816 IAP Textbook of Pediatrics
15.7 Sickle Cell Disease
Sickle cell disease is a term used for a group of genetic
disorders characterised by production of hemoglobin
(Hb) ‘S’. It is the result of single base pair change, thymine
for adenine, at 6th position on β-globin gene on
chromosome number 11 replacing valine for glutamic
acid. The substitution of single amino acid is responsible
for profound change in molecular stability and solubility
of hemoglobin ‘S’. Minor variations in non-coding
nucleotide sequence of gene are also seen. The
polymorphic variations are called haplotypes. Four such
haplotype have been found. Arab-Indian haplotype (No.
31) is found in Eastern Saudi Arabia and Indian
subcontinent. Benin haplotype (No. 19), Bantu haplotype
(No. 20) is prevalent in Africa, Mediterranean countries,
Northern and Southern American countries. Senegal
haplotype Africa. The term SCD includes several distinct
genotypes. More commonly seen are homozygous sickle
cell anemia (SS), heterozygous form (AS), sickle thala-
ssemia (Sβ0), less commonly seen forms are SD Punjab
disease, SO Arab disease.
Epidemiology
Sickle cell anemia is particularly common among people
whose ancestors came from sub-Saharan Africa, India,
Saudi Arabia and Mediterranean countries. Nearly 20
million people are affected in India. In broad term, the
prevalence of the sickle cell trait (healthy carrier who
have inherited the mutant gene from one person only)
ranges between 10-40% across equatorial Africa, in west
African countries such as Ghana and Nigeria the
frequency of trait is 15-20%.
Prevalence rate in India north east India 0-18%,
central India 22-44%, west India 0-33% and south India
0-40%.
Pathophysiology
Hemoglobin is normally present in the soluble form in
the red blood corpuscle. The ‘Sol’ form of Hb changes to
gel” form when Hb ‘S’ is polymerized on deoxygenation.
In gel form Hb is crystallized to small rigid boat shaped
object known as tactoids. These tactoids polymerise
forming insoluble fiber like structures, deforming RBC
VS Dani
to sickle shape. The polymerization is facilitated by
hypoxia, hyperthermia, decreased pH, 2-3 DPG
concentration and carbon monoxide concentration.
On reoxygenation the red cell initially resume normal
configuration, but membrane damage is pronounced
with repeated cycle of sickling and unsickling resulting
in the fixation of membrane in sickle configuration
leading to irreversible sickle cell formation and
hemolysis. The hemolysis is responsible for anemia in
sickle cell disease.
In SCD the red cells have increased adherence to
endothelium. The red cells assume sickle shape after
deoxygenation and damage the endothelial cells leading
to sub-endothelial infiltration and narrowing of vessels.
Platelets aggregate over the adherent red cell damaged
endothelium causing blockage ischemia of tissue.
Clinical Manifestation
Clinical manifestations of sickle cell disease are extremely
varied. Some patients are entirely asymptomatic whereas
other patients are constantly troubled by painful
episodes. The clinical picture in most patients falls
between these two extremes.
Sickle Cell Crisis
The term sickle cell crisis was defined by Diggs as “any
new syndrome that develops rapidly in patients with
sickle disease due to inherited abnormality.” There are
three categories of sickle crisis—painful crisis,
sequestration crisis, vaso occlusive crisis and aplastic
crisis.
Vaso-occlusive Sickle Cell Crisis
Vaso–occlusive crises are acute painful episodes due to
intravascular sickling and tissue infarction. Vaso-
occlusive episodes are major clinical manifestation of
sickle cell disease and occur most commonly in bones,
lungs, liver, spleen, brain, and penis.
Acute Painful Event
The most common vaso occlusive crisis. There are
typically rapid onset deep throbbing pain, usually

without any abnormal physical or laboratory finding but
sometimes accompanied by local tenderness, erythema,
warmth and swelling. The underlying pathologic cause
is bone marrow ischemia, sometimes leading to frank
infarction with acute inflammatory infiltrate.
Lumbosacral spine, knee, shoulder, elbow and femur are
most commonly involved. In children younger than 5
years of age small bones of hands and feet are often
affected. This painful ‘Hand foot syndrome’ is typically
the first clinical manifestation of sickle cell disease. Hand
and foot syndrome disappears when bone marrow from
small bones of hands and feet stops erythropoetic activity.
The age at which a child experiences the hand foot
syndrome is strong predictor of overall severity by 10
years of age. Avascular necrosis of bone occurs secondary
to vaso occlusion of nutrient artery. Femoral head,
humerus, upper part of tibia can be affected but weight
bearing makes femoral head necrosis more likely to cause
severe disability. Painful abdominal crisis occurs due to
localized areas of bowel dysfunction due to vaso
occlusion. Its exact cause is unknown, although
mesenteric sickling and vertebral diseases with nerve root
compression have been suggested. There is severe
abdominal pain and signs of peritonitis. The manage-
ment includes bowel rest and maintenance of hydration.
If patient’s condition deteriorates despites these
measures, surgical exploration may be necessary.
Acute right upper quadrant pain with liver enlarge-
ment, tenderness, hyperbilirubinemia and abnormal liver
enzymes concentration may be as a result of intrahepatic
sickling.
Acute Splenic Sequestration Crisis
The event is characterised by sudden trapping of large
amount of blood in spleen or less commonly liver and
sudden, rapid, massive, enlargement of spleen with
trapping of considerable portion of red cell mass patients
suddenly become weak, dyspneic with rapidly enlarging
spleen, anemia and shock. The hematocrit becomes half
the patient’s usual value and associated with brisk
reticulocytosis with increased nucleated RBCs and
moderate to severe thrombocytopenia.
Splenic dysfunction occurs due to obstruction of
sinusoidal blood flow, causing diversion of blood
through intrasplenic shunts, bypassing phagocytic
reticuloendothelial element of the spleen. Sequestration
may recur within 4 months of initial episode. To eliminate
Pediatric Hematology 817
recurrence, elective spleenectomy after first episode is
recommended.
Aplastic Crisis
This event associated with temporary cessation of bone
marrow activity due to suppression by intercurrent viral
or bacterial infection parvovirus B19 is most commonly
associated organism. The child present with anemia
without compensatory reticulocytosis. Any child of sickle
cell disease with reticulocytopenia should be considered
as having parvovirus B-19 infection until proven
otherwise. Treatment requires packed red blood cell
transfusion.
Infection
Infection is the most common cause of morbidity and
mortality in children with sickle cell disease. The major
risk factor for increased vulnerability to infection is
splenic dysfunction. This leads to appearance of RBCs
with “Howell Jolly bodies” and irregular surface
characteristics (pits). When percentage of pitted RBCs
exceed 3.5%, the spleen is generally non-functional. Other
risk factors are defective alternative pathway for
complement mediated lysis due to deficient levels of
serum opsonin and abnormal production of antibodies.
In young children, risk of pneumococcal sepsis is
approximately 400 times that of normal children and
H. influenzae sepsis appears to be 2-4 times as commonly.
Capsulated organisms most commonly involved are,
streptococcus pneumonae H. Influenza. Osteomyelitis is
most often caused by salmonella.
Acute Central Nervous System Event
Among children with sickle cell anemia approximately
11% and 20% will have either overt or silent stroke
respectively before 18 yrs of age. Incidence is estimated
to be 0.7% per year during first 20 yrs of life, with highest
rate in children 5-10 yrs of age. This complication may
occur in isolated but also appears in setting of
pneumonia, aplastic crisis viral illness, painful crisis,
priapism or dehydration. The most common underlying
lesion is internal carotid stenosis or obstruction but
proximal MCA and ACA are also involved.
Pathologically acute sickling may simply be the “last
straw” causing acute infarction in chronically damaged
due to endothelium, already injured by sickle cells.
Symptoms and signs are hemiparesis, speech defect,
seizures, gait dysfunction.
818 IAP Textbook of Pediatrics
Diagnosis: Best initial diagnostic test is CT scan. But it is
limited by not able to pick up in first 4 to 6 hours where
MRI can be the investigation of choice.
Treatment: Oxygen to maintain SPO2 above 96%. Simple
blood transfusion within 1 hr of presentation with goal
of increasing Hb to maximum of 11 gm/dl. Standard
approach in exchange transfusion reduces at least<50%
if not 30%. The maintenance of blood transfusion
programme for secondary prevention of stroke should
be considered. This results in 85% reduction in the rate
of overt strokes.
Intracranial hemorrhage is also category of sickle cell
related events. Many of these episodes are subarachnoid
hemorrhage from small bleeding aneurysm that probably
arises from internal damage.
Acute Chest Syndrome
These are episodes of acute lung injury with radiographic
evidence of infiltrate and usually accompanied by chest
pain, fever, cough tachypnea and hypoxia. This is leading
cause of morbidity and mortality in children and occurs
more commonly in children than adults.
Management: All patients with ACS must be treated in
hospital. PO2 of <75 mm Hg indicates poor prognosis.
Oxygen therapy is important in hypoxic patient.
Transfusion is critical for patient with persistent hypoxia.
Exchange transfusion is indicated if hematocrit is high.
Preliminary evidence inhaled nitric oxide may be of
benefit in severe hypoxia.
Priapism
Priapism is persistent painful penile erection. Highest
incidence is in children between 2-4 yrs. Recurrent
priapism manifests with episode lasting for few minutes
to several hours. It most commonly occurs around 4 am
during sleep or soon after waking. It usually subsides
spontaneously. If pain, engorgement persists for 24-48
hours, blood transfusion is indicated. Impotency may be
a sequelae.
Cardiovascular System
Abnormal cardiac findings in most patients with sickle
cell anemia are primarily due to chronic anemia and
compensatory increased cardiac output. Cardiomegaly
is found in most of the patient. Pulmonary hypertension
is the most severe cardio-vascular complication.
Renal System
Sickle cell nephropathy includes gross hematuria,
papillary necrosis, nephritic syndrome, renal infarction,
hyposthenuria, pyelonephritis and renal medullary
carcinoma. Hepatobiliary complication includes
cholelithiasis, hepatic infarction and transfusion related
hepatitis.
Eyes
Tortuosity and loculation of conjunctival vessel are seen.
Sickle cell retinopathy includes proliferative and non-
proliferative retinopathy which can lead to vitreous
hemorrhage and retinal detachment.
Others
Gallstones are common complication. Only symptomatic
gallstones should be subjected to surgery.
Somatic and sexual growth is delayed in SCD. Age
of menarch is delayed by 2.5 years. Zinc deficiency has
been suggested as a cause for poor growth in our study.
We have observed that zinc supplementation augments
sexual growth but does not affect somatic growth.
Diagnosis
All newborns from high risk population should be
screened for SCD. Blood obtained from umbilical cord
or heel prick. Dried samples on filter paper may be sent
to central laboratory. The diagnosis can be done by Hb
electrophoresis, isoelectric focusing, high performance
liquid chromatography, globin DNA analysis, etc.
Diagnosis should be confirmed after 3 months.
Intrauterine diagnosis can be made by detection of
alteration of a site of specific restriction enzyme by
hemoglobin synthetic oligoneucleotides which detect
single base substitution and polymerase chain reaction
(PCR) amplification of DNA. Chorionic villous biopsy
or amniocentesis can be carried out for obtaining fetal
cells at 8-10 weeks and 14-16 week respectively.
In older children diagnosis is usually done on Hb
electrophoresis on cellulose acetate agar at pH 8.6.

Management
Patient with sickle cell disease should be followed on
routine basis. Patient and his family should be educated
about the nature, course, treatment and its complications
of the disease. Genetic counseling should be done of all
parents with disease and trait preferably in first 1-2
months of pregnancy. All patient of sickle cell disease
should receive pneumococcal, H. influenza, typhoid and
hepatitis B vaccines, in addition to routine immunization.
Protein conjugated pneumococcal vaccine to children less
than 2 yrs is given which should be followed by
polysaccharide (23 valent) vaccines after years.
Prophylactic penicillin should be given to all children
younger than 5 years. (125 mg BD until the age of 3 years
and after 3 years, 250 mg BD). Folic acid 1 mg/day can
be given to prevent megaloblastic anemia.
Transcranial Doppler ultrasonography is used to
screen children for risk of strokes. Children with ICA
flow of 200 cm/sec or higher should receive prophylactic
maintenance transfusion.
Painful events are usually treated with adequate
hydration and analgesics mostly NSAIDS Ibuprofen,
Diclofenac and rarely-opiate drugs can be used.
Blood Transfusion
Patients with SCD tolerate chronic anemia well and
require transfusion under following circumstances:
Sequestration crisis, CNS infarction, Aplastic Crisis,
preoperative, and hypoxia with acute chest syndrome.
In sequestration crisis and aplastic crisis, a standard
simple transfusion is necessary while in all other
situations exchange transfusion is preferable.
Other Approaches to Anti-sickling Therapy
1. Replacement of defective gene by bone morrow
transplantation or more specific gene therapy.
Pediatric Hematology 819
2. Stimulation of HbF production by 5 Azacytidine,
sodium butyrate and hydroxyurea.
BIBLIOGRAPHY
1. AL Hajeri A, Serjeant GR, Fedorowicz Z. Inhaled nitric
oxide for acute chest syndrome in people with sickle cell
diease (Review). Cochrane Database of Systematic
Reviews 2008.
2. C Hirst, WC Wang. Blood transfusion for preventing
stroke in people with sickle cell disease. Cochrane
Database of Systematic Reviews 2008 Issue 2.
3. Drover G J and Platt OS. Sickle cell disease, in Nathan
and Oski’s Hematology of infancy and Childhood, 6th
edition Vol.12003, Sounders Company: 790-841.
4. Dayana VP Di Nuzzo, Silvana F Fonseca. Sickle cell
disease and infection. I Pediatr (Rio de J) Porto Algre
2004;80:5-15. Serjeant GR. Sickle Cell Disease, 3rd edition
2004 Oxford Medical Publication
5. Driscoll MC, Hurler A, Styles, et al. Stroke risk in sibling
with sickle cell anemia blood, 2003:101:2401-04.
6. Gladwin, MT, Sachdev V, Jison ML, et al. pulmonary
hypertension as risk factor for death in sickle cell anemia,
NEJM 04,350:886-95.
7. Jones AP, Davies SC, Olujohungbe A. Hydroxyurea for
sickle cell disease.
8. Kizito, ME, Mworozi E Nduguia C: Bacteremia in
homozygous sickle cell disease in Africa: Is
pneumococcal prophylaxis justified? Arch dis child
2007;92:21-24.
9. Paul S. Frenette and George F. Atweh. Sickle cell disease:
old discoveries, new concepts, and future promise. J Clin
Invest 2007;117(4):850-58.
10. Sickle cell anemia: Report by Secretariat, Fifty-ninth
world health assembly, Provisions Agenda item 11.4:
World Health Organization, A59/9, 24 April 2006.
11. Singh PC, Ballas SK. Drugs for preventing red blood cell
dehydration in people with sickle cell disease. Cochrane
Datatbase of systematic Reviews 2007, Issue 4.
12. The management of sickle cell disease. National Institute
of Health National Heart, Lung and Blood Institute.
Fourth edition 2002.
820 IAP Textbook of Pediatrics

15.8 Red Cell Membrane Disorders

Rashmi Dalvi, Bharat Agarwal, R Agarwal

Hereditary or acquired defects in the structural compo-

nents of the red cell membrane can result in decreased
survival or increased destruction of RBCs, giving rise to
a variable degree of anemia.

Hereditary Spherocytosis (HS)

This is the commonest of the red cell membranopathies
and is inherited mainly as an autosomal dominant trait,
resulting in a deficiency of the membrane proteins,
spectrin, ankyrin, or protein 4.2. The membranes of these
RBCs are rigid and therefore get sequestered in the
spleen. In the process they undergo various metabolic
changes, nutrient loss, and lose other membrane
components. The resultant net loss of surface area gives
the rigid spherocytic shape to the RBCs making them
susceptible to destruction by splenic macrophages.
Clinical features: A typical HS patient is relatively
asymptomatic. There may be a history of mild jaundice,
anemia may be mild or absent, but splenomegaly is
almost always present. More severe forms may present
in the newborn period with severe hyperbilirubinemia,
necessitating exchange transfusion.
As in other chronic hemolytic anemias they are prone
to aplastic crisis following parvovirus infection or
deficiency of folic acid. Some patients may develop, or
rarely even present for the first time with symptomatic
gallstones. Rarely leg ulcers and growth retardation may
complicate the course.
Laboratory features: The hemoglobin may be mildly
decreased or normal, however, there is marked reticulo-
cytosis indicating compensatory erythroid hyperplasia.
The peripheral blood smear shows characteristic
spherocytes lacking the central pallor. The MCV is
normal but the MCHC is raised. These red cells show
increased osmotic fragility when incubated with
hypotonic NaCl solutions in vitro yielding a diagnostic
osmotic fragility curve (Figure 15.8.1).
Differential diagnosis: Spherocytes are also seen in other
states such as ABO incompatibility, other immune hemo-
lytic anemias, burns and Clostridium perfringens sepsis.
Figure 15.8.1: PS showing micro-spherocytes
Management: Splenectomy is curative in typical forms of
HS, as it prolongs RBC survival to almost 80 percent of
normal and prevents the other complications. Because
of the higher risk of postsplenectomy sepsis in children,
it should be postponed at least up to 5 years of age.
Transfusions may be required during aplastic crisis or
in the first years if hemolysis is poorly compensated. For
pre- and post splenectomy care refer Page 811.
Other hereditary membrane disorders: Include hereditary
elliptocytosis, hereditary pyropoikilocytosis, hereditary
stomatocytosis and xerocytosis.
Acquired RBC membrane defects: These include acan-
thocytosis seen secondary to abetalipoproteinemia, or
vitamin E deficiency; paroxysmal nocturnal hemoglo-
binuria and membrane damage due to heavy metal
toxicity (Cu, Fe), hyperthermia and infection.
RED CELL ENZYMOPATHIES
Normal physiologic function and survival of mature
RBCs is critically dependent for their small but distinct
energy needs, on the glycolytic pathways (Embden-
Meyerhof and Hexose Monophosphate shunt) and
certain nucleotide salvage pathways. Defects in these
pathways could result in decreased survival of red cells.
 Pediatric Hematology 821

Glucose-6-Phosphate Dehydrogenase Deficiency Diagnosis: Diagnosis is based on the clinical manifes-

(G6PD) tations, of sudden pallor, jaundice, dark urine and mild
hepatosplenomegaly. The laboratory features seen
This is the commonest red cell enzyme defect, an
X-linked disorder seen in males, and very rarely in female include anemia, reticulocytosis, hyperbilirubinemia and
homozygotes. The clinically significant mutants identi- hemoglobinuria. Estimation of enzyme activity is done
fied are G-6-PD-Aminus (Afro-Americans), G-6-PD- by qualitative screening tests, or more reliably by
Bminus, (Asia, Middle-East), G-6-PD-Mediterranean, and quantitative assays. Table 15.8.1 shows common drugs
G-6-PD-Canton. causing hemolysis in G-6-PD deficient subjects.
G-6-PD is a vital enzyme in the HMP shunt pathway Therapy: Therapy is usually conservative. Exposure to
which helps generate NADPH to counter oxidative stress. offending agents should clearly be avoided. Severe
Deficient individuals manifest a reduction in enzyme hemolytic episodes may need packed red cell transfusion
activity and/or stability, and are, therefore, unable to and need to be monitored for complications such as renal
cope with increased oxidative stress and develop failure and DIC.
hemolysis.
Clinical features: Clinical manifestations vary according Pyruvate Kinase Deficiency
to the type of oxidant exposure and the G-6-PD variant. Pyruvate kinase deficiency results in a variable degree
a. Neonatal jaundice: Some cases may present in the of chronic hemolysis which can vary from the asymp-
newborn period with acute hemolysis and hyperbi-
tomatic to severe life-threatening transfusion dependent
lirubinemia necessitating exchange transfusion. Risk
anemia. The latter may be seen in the newborn when
factors for neonatal hemolysis include prematurity,
exchange transfusion may be required. Splenomegaly,
sepsis, drugs and maternal medication.
icterus, decreased heptoglobin, and reticulocytosis with
b. Acute hemolytic episodes: In these individuals
marrow erythroid hyperplasia may be seen in direct
increased oxidative stresses as that occurring in fever,
proportion to the severity of disease. In severe cases
infection, diabetic acidosis, exposure to certain drugs
especially in young children splenectomy may ameliorate
and toxins can overwhelm the red cells antioxidant
capability and precipitate hemolytic anemia. In cases the symptoms.
of severe stress, intravascular hemolysis with hemo- Other enzymes which may cause clinically signifi-
globinuria may occur. Hemolysis is usually self- cant anemia include Pyrimdine 5' nucleotidase, and
limited and the hematocrit stabilizes in 7 to 10 days. NADH and NADPH reductase.
Among many agents that provoke hemolysis in G-6-
PD deficient individuals, some commonly used ones TABLE 15.8.1: Common drugs causing hemolysis
are prominent: antimalarial drugs (pamaquine, in G6PD deficient subjects
primaquine), sulfonamides, urinary antibiotics (nali-
dixic acid, nitrofurantoin), acetanilide, phenyl- Antimalarials Nitrofurans
Chloroquine Nitrofurantoin
hydrazine, nephthalene (mothballs) and dyes. Other
Primaquine
agents which could cause hemolysis but are safe in Quinine Sulphones
usual doses are: chloroquine, aspirin, acetaminophen, Antipyretics Dapsone
vitamin C, quinidine, isoniazid, procainamide and Paracetamol
Vitamin K. Aspirin Other drugs
c. Chronic hemolytic anemia: These patients have Phenacetin Ascorbic acid
moderate to severe degree of chronic hemolysis, Sulphonamides L-Dopa
exacerbated by exposure to oxidants. The syndrome Sulphadiazine Quinidine
Sulphadimidine GTN
of favism characterized by profound hemolysis
Sulphanilamide Vitamin K
following the ingestion of fava beans is seen in
Sulphapyridine
individuals with the Mediterranean type of defect.
822 IAP Textbook of Pediatrics
15.9 Autoimmune Hemolytic Anemia
Acquired erythrocyte defects may have immune
(Coombs’ positive) or non-immune causes (Coombs’
negative). Immune hemolytic anemia can be either
isoimmune or autoimmune. The commonest immune
cause is blood group incompatibility between the fetus
and the mother, e.g. Rh or ABO causing isoimmuni-
zation. This is discussed elsewhere.
Warm Autoimmune Hemolytic Anemia (AIHA)
Red blood cell survival is shortened in AIHA due to
action of immunoglobulins (antibody) on the red cell
membrane (antigen). Antibodies of the IgG class are most
commonly responsible for AIHA in children. Rh
erythrocyte antigen is involved in more than 70 percent
of cases. Since the antibody has its maximum activity at
37°C, the resultant hemolysis is called warm antibody
induced hemolytic anemia (Tables 15.9.1 and 15.9.2 and
Fig. 15.9.1).
Clinical Features
This is a severe life-threatening condition, the clinical fea-
tures are: Sudden onset of pallor, jaundice and dark urine.
There may be splenomegaly. The laboratory findings
usually are: Very low Hb with marked reticulocytosis.
The peripheral smear may show spherocytes,
polychromasia, and autoagglutination (Fig. 15.9.2). Direct
Coombs’ test is usually positive. Other evidence of
hemolysis like hyperbilirubinemia, increased plasma Hb,
low heptaglobin level and hemoglobinuria should be
noted.
Management
Because of this being the life-threatening condition, the
Hb, reticulocyte count and spleen size should be
monitored very carefully. The modalities for treatment
of AIHA are:
1. Blood transfusion: Identification of compatible blood
may prove difficult. Since no totally compatible blood
can be found, washed packed red cells in small
volumes with high dose corticosteroid cover should
be employed.
2. Corticosteroid therapy: Hydrocortisone 8 to 40 mg/day
IV or prednisolone 2 to 10 mg/day PO is admini-
Bharat Agarwal, Rashmi Dalvi
TABLE 15.9.1: Causes of immune hemolytic anemia
A. Isoimmune
1. Hemolytic disease of the newborn
2. Incompatible blood transfusion
B. Autoimmune: IgG only; C’3 only; mixed IgG and C’3
1. Idiopathic
a. Warm antibody
b. Cold antibody
c. Cold-warm (Donath-Landsteiner antibody)
2. Secondary
a. Infection, viral
i. Infectious mononucleosis (Epstein-Barr virus
(EBV), cytomegalovirus (CMV), hepatitis, herpes
simplex, measles, varicella.
ii. Bacterial: Typhoid fever, septicemia
b. Drugs and chemicals: quinine, quinidine, phena-
cetin, p-aminosalicylic acid, sodium cephalothin
(Keflin), penicillin, tetracycline, rifampin, sulpho-
namides, chlorpromazine, pyramidon, dipyrone,
insulin, lead.
c. Hematologic disorders: leukemias, lymphomas,
lymphoproliferative syndrome, idiopathic thrombo-
cytopenic purpura (Evans syndrome), paroxysmal
cold hemoglobinuria.
d. Immunopathic disorders: systemic lupus erythe-
matosus, periarteritis nodosa, scleroderma,
dermatomyositis, rheumatoid arthritis, ulcerative
colitis.
e. Tumors: Ovarian teratomata, dermoids, thymoma,
carcinoma.
stered. Corticosteroids are given for several days and
slowly tapered off over a 3 to 4 weeks period. Lack of
response for 21 days should be considered as steroid
failure.
3. Intravenous gammaglobulin (IVIgG): In large doses may
be effective in steroid failures.
4. Plasmapheresis has been successful but the effect is
short-lived if antibody production is ongoing.
5. Splenectomy may be beneficial in some patients but
the results are unpredictable. It is indicated if the
hemolysis continues to be brisk despite above
measures for 3 to 4 weeks.
6. Cytotoxic agents, immunosuppressants (Cyclosporine-
A) and hormonal treatment (Danazol) have been used
with variable success, but their use has not been
completely evaluated.
 Pediatric Hematology 823

TABLE 15.9.2: Causes of non-immune

hemolytic anemia from RBCs

I. Membrane defects
A. Primary membrane defects with specific morphologic
abnormalities
1. Hereditary spherocytosis
2. Hereditary elliptocytosis
3. Hereditary stomatocytosis
4. Congenital hemolytic anemia with dehydrated red
cells
B. Altered phospholipid composition; increased lecithin
(phosphatidylcholine)
C. Hereditary ATPase deficiency
D. Secondary membrane defects: abetalipoproteinemia
II. Enzyme defects
A. Energy potential defects
(Embden-Meyerhof: anaerobic, ATP-producing pathway)
1. Hexokinase
2. Glucose phosphate isomerase Figure 15.9.1: Child with autoimmune hemolytic
3. Phosphofructokinase anemia on steroid therapy
4. Triosephosphate isomerase
5. Phosphoglycerate kinase
6. 2,3-Diphosphoglyceromutase
7. Pyruvate kinase
B. Reduction potential defects
(hexose monophosphate: aerobic, NADPH-producing
pathway)
1. G-6-PD
2. 6-Phosphogluconate dehydrogenase (6-P-GD)
3. Glutathione reductase
4. Glutathione peroxidase
5. Glutathione synthetase
6. 2,3-Glutamyl-cysteine synthetase
C. Other defects
1. Ribose phosphate pyrophosphokinase
2. Adrenylate kinase
3. ATPase Figure 15.9.2: Blood film: autoagglutination
III. Hemoglobin defects
A. Heme: congenital erythropoietic porphyria Cold Autoimmune Hemolytic Anemia
B. Globin
Cold hemaglutinin disease is almost always caused by
1. Qualitative: hemoglobinopathies (Hb S, C, H, M)
2. Quantitative: alpha and beta thalassemia
IgM antibody. But these are found less often in the pedia-
IV. Congenital dyserythropoietic anemias tric age group. It usually occurs during Mycoplasma
A. Type I pneumoniae infection. The hematologic features in cold
B. Type II AIHA are similar to those in warm AIHA but are less
C. Type III marked. Treatment consists of control of the underlying
D. Type IV disorder. Transfusions may be necessary.
824 IAP Textbook of Pediatrics
15.10 Bone Marrow Failure Syndrome
Bone marrow failure syndrome results from failure of
production of mature red cells, granulocytes and platelets
leading to pancytopenia. It can lead to pancytopenia, (i.e.,
aplastic anemia) or mono or bicytopenia, (e.g. agranulo-
cytosis).
Aplastic anemia is classified as acquired or inherited
in etiology. Inherited cases may or may not be present at
birth (congenital). The etiological classification of aplastic
anemia is shown in Table 15.10.1.
Acquired Aplastic Anemia
Severe aplastic anemia is defined as presence of two or
more of peripheral indicators like ANC < 500/cmm,
platelet count <20,000/cmm, corrected retic count < 1.0
percent, in addition to hypocellular bone marrow (< 30%
cellularity).
Epidemiology
Incidence is 2 to 6/million/year and is seen all over the
world. A small peak occurs at the age of 5 to 6 yrs due to
inherited causes of AA.
TABLE 15.10.1: Etiology of aplastic anemia
A. Acquired
a. Idiopathic
b. Secondary
i. Drugs, e.g. sulpha, or anticancer drugs, antiepilep-
tics, chloromycetin, gold, etc.
ii. Radiation
iii. Chemicals, e.g. benzene
iv. Viruses, e.g. Hepatitis, EBV, Parvovirus, HIV, etc.
v. Pregnancy
vi. Paroxysmal nocturnal hemoglobinuria (PNH)
vii. Miscellaneous: Thymoma, eosinophilic fascitis,
Hypogammaglobinemia, Preleukemic syndromes,
etc.
B. Inherited
a. Fanconi’s anemia
b. Dyskeratosis congenita
c. Reticular dysgenesis
d. Shwachman—Diamond syndrome
e. Miscellaneous—e.g. Familial aplastic anemias,
Monosomy 7, Down’s syndrome, Dubowitz syndrome,
Amegakaryoctic thrombocytopenic purpura, etc.
Nitin Shah, MR Lokeshwar
Clinical Presentation
Thrombocytopenia will lead to bleeding manifestations
especially skin bleeds, mucosal bleeds, hematuria and
rarely intracranial hemorrhage. Neutropenia will lead
to infection and PUO, with or without localization of
infection. Anemia appears last and if severe will lead to
fatigue, breathlessness, puffiness, edema of feet and CCF.
One should look for evidence of etiological factors like
hepatitis, history of drug. Presence of hepatomegaly,
lymphadenopathy, bone pains, etc. usually rule out
aplastic anemia and suggest more sinister disease like
leukemia.
Etiology
1. Idiopathic
2. Secondary: (a) Drugs like chloromycetin, sulphona-
mides, NSAIDs, (b) Post-hepatitis, (c) Pregnancy,
(d) PNH, (e) Radiation and cytotoxic drugs, (f) Chemical
like benzene, (g) Infections like parvovirus, EB virus,
CMV, HIV, etc.
Pathophysiology Seed and Soil Theory
a. Seed theory: It contemplates that AA is caused due
to lack of pluripotent stem cells/progenitor cells.
b. Soil therapy: Lack of surrounding microenviron-
ment/stroma of bone marrow. Success of BM
transplant favors seed theory whereas success of
immunotherapy proves that in some patients it is the
soil which is at fault. Probably there are different
mechanisms of damage in different patients.
Laboratory Diagnosis
1. Peripheral blood: There will be anemia with normal
RDW with normocytic, normochromic RBCs,
occasional macrocytosis. Iron study may show iron
overload. There is presence of leukopenia with
decreased ANC, as also a decreased platelet count
with normal MPV. Stressed erythropoiesis is evident
in form of raised HbF and i-antigen in some patients.
2. Bone marrow: It is mandatory to do bone marrow
trephine biopsy as well as aspiration to diagnose AA.

It shows hypocellular marrow with empty spicules,
increased fats spaces, and increased lymphocytes/
plasma cells, etc (Figs 15.10.1 and 15.10.2).
3. Chromosomal studies: It should be done to rule out
Fanconi’s anemia which will show chromosomal
breaks.
4. Tests to find out etiological factors like LFT HbSAg,
etc.
Treatment
Supportive Care
It is the mainstay of therapy in all the cases and includes:
(1) Blood transfusion/packed cell transfusion should be
given to maintain Hb above 8 to 10 gm percent. Avoid
blood from relatives if BMT is contemplated. Iron
chelation may be necessary after 40 to 50 transfusion so
as to keep serum ferritin level less than 1000 ng/ml.
Figure 15.10.1: Trephine biopsy in aplastic anemia
Figure 15.10.2: Bone marrow aspiration in aplastic anemia
Pediatric Hematology 825
Bleeding: Platelet packs are given if patient has acute
mucosal bleeds or severe internal bleeding especially
with platelet count < 5 to 10,000/cmm. General measures
like local pressure, dental care, avoiding use of NSAIDs,
also help prevent bleeding.
Infections
Whenever the patient of AA has fever, one must collect
blood for culture, urine culture and culture from obvious
sites of infections before starting empirical broad spec-
trum antibiotics. Modify the antibiotic after the culture
report especially if patient does not show response in 48
to 72 hrs. One may consider use of antifungals if culture
shows fungal growth or when patient does not improve
inspite of changing antibiotics in 7 to 10 days time.
Antifungals used are fluconazole or Amphotericin-B.
Androgenic Steroids
They stimulate erythropoiesis. Nandronolone enanthate
is used in a dose of 2 to 5 mg/kg/day of injectable form
once in 10 days and continued till response is evident.
Efficacy is around 20 to 30 percent and that too only in
moderate AA. Side effects are many, especially mascu-
linization, stunted growth, hepatotoxicity, cancer liver,
etc.
Immunotherapy
Some patients of AA have immune-mediated disease and
hence benefit by immunotherapy with drugs like
cyclosporine-A, ATG, ALG either used alone or in combi-
nation. Cyclosproine-A is given orally in a dose of 10 to
12 mg/kg/day for upto 6 months. Side effects like
electrolyte disturbance, renal toxicity, hirsutism, gingi-
val hypertrophy, etc. can occur. ATG/ALG are animal
sera against human lymphocytes or T cells. They are used
in the dose of 10 to 40 mg/kg/day I.V. drip form for 5 to
10 days after test dose. Side effects include anaphylaxis,
serum sickness, thrombocytopenia and severe
leukopenia. The success rate is 60 to 70 percent.
Steroids
Steroids stimulate erythropoiesis. It also stabilises
capillary membrane and decreases bleeding. They are
useful to counteract side effects of androgenic steroids
on growing epiphysis and the serum sickness of
immunotherapy. Oral prednisolone is used in the dose
826 IAP Textbook of Pediatrics

of 0.5 to 1 mg/kg/day and tapered to a minimum

effective dose. IV methylprednisolone has been used in
dose of 15 to 20 mg/kg/day IV drip form and tapered
gradually over 15 to 21 days. It has been found to be
effective in 30 to 40 percent of cases. Side effects include
hypertension, fluid electrolyte imbalance, infections,
suppression of neuroendocrinalaxis, psychosis, avascular
necrosis of head of femur, etc.

Growth Factors
Hemopoietic growth factors like G-CSF and GM-CSF
have been used to counteract neutropenia in patients of
AA especially neutropenia following BMT. It helps
control infections. Combination treatment with ALG or
ATG with methyl prednisolone cyclosporin and GCSF
also have been tried with better success.

Bone Marrow Transplantation (BMT)

Cure can occur following BMT using HLA identical
sibling donor which is possible in 30 to 40 percent of cases.
The cure rate is 70 to 80 percent in severe aplastic anemia.
It is more useful in children. The problems are high cost,
GVHD acute and chronic, infection and graft failure, etc.
Nowadays these facilities are available at many centers
in India.
FANCONI’S ANEMIA (FA) (FIG. 15.10.3)
Introduction
It is a type of inherited aplastic anemia. The basic defect
is in the poor DNA repairs leading to spontaneous or
induced breaks in chromosomes. In 1927 Fanconi
reported cases of three brothers who had pancytopenia
with typical physical changes. Since then more than 700
cases of FA have been reported worldwide. Now by
definition diagnosis of FA requires presence of
chromosomal changes, and both physical changes or
anemia need not be present. In fact, more and more FA
cases are diagnosed who do not have aplastic anemia or
typical physical changes by studying chromosomal
changes in family members of an index case of FA.
Epidemiology
Mean age at diagnosis is 7 to 8 years with 4 percent cases
< 1 year old and 10 percent cases > 16-year-old in age.
Male to female ratio is 1.06 : 1.0.
Figure 15.10.3: Fanconi's anemia with strunted growth with
mental subnormality, hyperpigmentation around the mouth and
knuckle and polydactyly
Mode of Inheritance
Family studies have shown autosomal recessive type of
inheritance with chances of FA occurring in siblings and
cousins with increased chances of parenteral
consanguinity.
Physical Changes
Patients with FA were originally identified by presence
of characteristic physical changes including generalized
or perioral hyperpigmentation, café au lait spots, short
stature, microcephaly, mental retardation, skeletal
anomalies like absent or hypoplastic thumb, bifid or
triphalangeal thumb, absent radius, hypogonadism,
spinal anomalies, renal anomalies like ectopic kidney
(Fig. 15.10.4), eye anomalies, deafness, ear malfor-
mations, GI anomalies, cardiopulmonary anomalies, etc.
15 to 30 percent of patients with FA are physically normal
or have only short stature and or skin changes.
Laboratory Diagnosis
Investigations done in a case of suspected FA include
CBC, platelet count, red cell indices, retic count, HbF

Figure 15.10.4: Ectopic kidney in Fanconi's anemia
estimation, bone marrow aspiration and biopsy,
chromosomal studies, skeleton X-rays, USG for KUB.
CBC: It will show progressive anemia, macrocytosis, low
retic count and changes of stressed erythropoiesis like
increased HbF levels and presence of ‘i’ antigen.
Gradually patient will progress to pancytopenia once
aplasia of bone marrow sets in.
Bone marrow and trephine biopsy: It will show changes
typical of aplastic anemia.
Cytogenetics: FA patients will show chromosomal
changes like breaks, gaps, rearrangements, endoredup-
lication, exchanges, etc. Peripheral blood lymphocytes
induced by PHA are studied for these changes. These
changes can be spontaneous or following clastogenic
stress like with DEB, Nitrogen mustard, Nitromycin and
cyclophosphamide. Homozygotes will show 8 to 9 breaks
per cell following lymphocytes cultures with DEB as
compared to 0.06 in non-FA persons. Some FA patients
may show clonality. Spontaneous but not DEB induced
breaks are also seen in Bloom’s syndrome whereas some
FA patients may show chromosomal changes only
following clastogenic stress. Hence, chromosomal study
is done always with DEB to correctly diagnose FA.
Pediatric Hematology 827
THERAPY
Prognosis
Without therapy 80 percent FA patients die at mean age
of 16 years and 2 years following aplasia and most by 4
years following aplasia. Twenty-five percent survive
beyond third decade.
Androgens
Mean age of survival with androgen is 17 years or 7 years
following onset of aplasia which is little better than no
therapy. Fifty to seventy-five percent of FA patients
respond to androgens and it may take 6 to 12 months for
peak response to occur. One can add prednisolone to
androgens. The doses and follow-up are same as for
acquired aplastic anemia.
Bone Marrow Transplantation (BMT)
The only hope of long-term survival is BMT for FA
patients. Due to inherent chromosomal instability, these
patients are sensitive to radiation and chemotherapy
used for conditioning. Accordingly low doses of
cyclophosphamide should be used for better outcome.
The success of BMT is 78 percent with conditioning
regimen using 20 mg/kg of cyclophosphamide over 4
days and 5 cGy of total abdominolymphoid radiation,
48 percent when cyclophosphamide is used in the dose
of 50 mg/kg over 4 days. One must screen the sibling
donor before BMT to rule out occult FA.
Other Treatment
As expected immunotherapy with ATG/ALG or IV pulse
methylprednisolone is helpful in less than 10 percent of
patients. This proves that it is the ‘seed’ which is at fault
in FA and not ‘soil’.
Other measures like supportive care, use of blood
products, prevention of HLA sensitization, treatment of
infection, monitoring of toxicities of drugs used, etc.
should be as for acquired aplastic anemia.
Complications
FA patients are prone to develop malignancies later on.
It includes 15 to 20 percent chances of leukemia mainly
AML and liver cancers mainly due to androgens. Rare
cancers include preleukemia, gynecological tumors,
Wilms’ tumor, meduloblastoma, etc.
828 IAP Textbook of Pediatrics
Pure Red Cell Aplasia
This could be either acquired or congenital.
Acquired
Acquired red cell aplasia leading to anemia associated
with reticulocytopenia have been described. The causes
in most of them are uncertain and may be associated with
thymoma and remission is followed removal of tumor of
thymus. Antibodies against erythropoietin, erythroblast
have been reported.
High doses of chloramphenicol have been reported to
inhibit erythropoiesis resulting in anemia, thrombo-
cytopenia, erythroid hypoplasia with vacuolated
normoblasts in the marrow. Viral infection may also lead
to marked reticulocytopenia (less than 0.1%) and bone
marrow aspiration shows markedly reduced number of
erythroid precursors.
Viral infection like parvovirus may lead to selective
suppression of erythroid precursors suggesting aplastic
crisis in hemolytic anemia.
The acquired pure red cell anemia may respond to
corticosteroid therapy. In some cases immunosuppres-
sive therapy with cyclophosphamide or azathioprine
have been found to be useful particularly if cortico-
steroids are ineffective.
Congenital
Diamond Blackfan syndrome or constitutional chronic
pure red cell aplasia is characterized by isolated erythroid
15.11 Physiology of Hemostasis:
Approach to a Bleeding Disorder
Blood is a fluid connective tissue in constant circulation
throughout the body. Vascular injury results in extravasa-
tion of blood. Nature has devised hemostasis system to
prevent bleeding. Hemostasis involves presence of intact
vascular component, platelet and coagulation factors.
Vascular Component
The initial response to a bleeding injury is vasocon-
striction. This is a temporary attempt to reduce/arrest
bleeding immediately.
hypoplasia occurring in early childhood. It is an inherited
disorder autosomal dominant or recessive inheritance.
A variety of congenital abnormalities may be associated
such as stribismus, webbed neck, deformed thumb, bony
abnormalities of finger and ribs. Congenital anomalies
like double ureter with hydronephrosis have been re-
ported. Investigations suggest normochromic,
macrocytic anemia with marked reticulocytopenia.
Marrow aspiration characteristically discloses cellular
marrow with profound erythroid hypoplasia with
markedly increased M. E. ratio. Serum iron level may be
high, fetal hemoglobin is elevated in most cases and also
antigen on the red cell surface. Hypogammaglobulinemia
may be associated. Erythrocytes adenosine deaminase
have been found to be elevated. Mainstay of treatment
is transfusion therapy and adrenal corticosteroid.
Hemosiderosis is unavoidable complication and may also
eventually lead to portal hypertension and hyper-
splenism and hence chelation therapy and splenectomy
may be required. Dose of steroid is 1 to 2 mg/kg of
prednisolone for 4 to 6 weeks and if unsuccessful, then
may be discontinued. Steroid therapy may have to be
maintained to the minimal required dose.
Methylprednisolone may be tried. Successful marrow
transplantation have been reported in patients with
refractory to therapy and having HLA identical sibling.
Intravenous gammaglobulin have been found to be
useful. In most of the patients carefully adjusted steroid
therapy has been found successful.
Renu Saxena
Platelets
Exposure of underlying collagen following endothelial
injury activates the platelets. Initial event is a change in
shape of platelets from discoid to appearance of multiple
pseudopod like projections on its surface leading to
adhesion and aggregation of platelets at the site of injury
(primary aggregation) forming a white plug. Activation
of platelets stimulates the arachidonic acid pathway
within the platelet releasing thrombaxane A2 and ADP
(from the dense granules of platelet). These substances
cause further aggregation of platelets (secondary

aggregation), thereby increasing the size of the white
plug. Activation of platelets also results in release of PF3
on the surface of platelets which further stimulates the
coagulation reactions. This platelet plug serves as a
temporary seal, while formation of clot is necessary to
repair the damaged vessel.
Coagulation
The most important step in coagulation is thrombin
generation. This requires presence of activated F X,
F V, PF3 and prothrombin (F II). It has been proposed
that activation of factor X to Xa is possible by two
different systems. The extrinsic system is activated by
release of tissue factor (TF), a transmembrane glyco-
protein present on the surface of many cell types. Tissue
factor forms a complex with FVII forming activated F
VIIa which activates factor X (Fig. 15.11.1).
It was earlier believed that the intrinsic system gets
activated by the activation of F XII which in turn activates
factor XI, F IX respectively. F IXa in presence of F VIIIa
Figure 15.11.1: Normal coagulation pathway
Pediatric Hematology 829
activates factor X to Xa. Currently it is believed that factor
XII and XI do not play an active role in triggering of the
coagulation cascade. It has been shown that TF-VIIa
complex also activates F IX to F IXa which in presence of
F VIIIa activates X.
Factor Xa, in the presence of F Va and phospholipid,
converts prothrombin to thrombin. Thrombin acts on
fibrinogen to produce fibrin monomers, which are acted
upon by F XIII to form Fibrin polymers. Coagulation
cascade is controlled by multiple positive and negative
controls as given below.
Positive Feedback Controls
These controls stimulate coagulation system by increas-
ing the thrombin generation.
a. Thrombin itself activates platelets to make more PF3
available for activation of the coagulation cascade.
It also potentiates activation of F VIII and V.
b. F VII is activated by factor Xa and which is further
enhanced by presence of tissue factor.
830 IAP Textbook of Pediatrics

TABLE 15.11.1: Approach to a bleeding patient: Hemostatic defects

Vessel Wall Platelet Coagulation factor

Bleed Localized Generalized Generalized

Duration Since birth Since birth : hereditary Since birth : hereditary
< 6 mos: Acute ITP Recent onset : Acquired
> 6 mos: Chronic
Specific Associated • Drug ingestion • Umbilical cord
History autoimmune • Preceding illness Stump bleeding : F-XIII
disease • Delayed wound healing
Fibrinogen def.
• Spontaneous severe trauma
Family ± + X-linked [F VIII, IX]
Autosomal recessive [XIII, X, II, I]
Onset Immediate Immediate Delayed
Size Point Petechiae Ecchymotic patches
petechiae
Mucosal bleed Common Common Less common
(epistaxis, gum,
menorrhagia)
Hemarthrosis - - Common
Deep muscle - - Common
bleed
Intra-abdominal - - Common
bleed

Negative Controls Based on the history, pattern and severity of bleeding,

Thrombin generation is regulated in vivo by presence of
naturally occurring proteins in blood. These include
antithrombin III, protein C, protein S and tissue factor
pathway inhibitor (TFPI). The first 3 are produced in the
liver and act as antithrombotics. Antithrombin III
combines with thrombin and inactivates it. Protein C
inactivates F VIIIa and Va. Protein S serves as a cofactor
to protein C. TFPI inhibits action of TF VIIa complex.
Fibrinolysis
Polymeric fibrin is degraded by plasmin (an enzyme in
blood) to monomers, releasing fibrin degradation pro-
ducts (FDP) which include D-dimers. Plasmin is formed
by activation of plasminogen by tissue plasminogen
activator (TPA). Tissue plasminogen activator inhibitor
inactivates the TPA.
Approach to a Bleeding Patient
Bleeding constitutes a prominent manifestation of
hemostatic disorders. It may be secondary to hereditary
defects in vascular wall, platelets or coagulation factors.
the cause of bleeding can be identified in many children
(Table 15.11.1). Detailed clinical history is helpful for the
diagnosis of the underlying defect.
The preliminary screening tests in patients with
bleeding disorders include platelet count, bleeding time,
activated partial thromboplastin time (APTT), plasma
prothrombin time (PPT) and clot stability tests.
A platelet count of less than 1.5 lac is considered
thrombocytopenic. However, a count less than 40,000/
cmm is often associated with spontaneous bleeding. In
acute thrombocytopenia, especially in children, a
preceding history, upper respiratory tract infection is
often available. This usually regresses spontaneously
within 6 weeks. Persistence of thrombocytopenia for
more than 6 months is suggestive of chronic thrombo-
cytopenia. Bone marrow may show increased/normal
megakaryocytes in chronic idiopathic thrombocytopenic
purpura. Such megakaryocytic thrombocytopenia also
occurs in megaloblastic anemia, myelodysplastic syn-
drome, autoimmune diseases, DIC, HUS, etc. Thrombo-
cytopenia also occurs in systemic diseases like aplastic
anemia, leukemias, myelophthistic anemia, thyrotoxi-

cosis and HIV. Bleeding time measured by Ivy’s
technique is an indicator of platelet count, function and
vascular defect. It is prolonged in cases with
thrombocytopenia platelet function disorders and
vascular defects. When platelet count is normal, a
prolonged bleeding time is suggestive of platelet function
defect and requires measurement of PF3 availability
content of platelet and agonist induced platelet
aggregation.
Plasma prothrombin time (PPT) is an indicator of
extrinsic and common pathway of coagulation. Activated
partial thromboplastin time is an indicator of intrinsic
and common pathways of coagulation. Prolongation of
PPT alone is suggestive of F-VII deficiency and needs to
be confirmed by F-VII assay. Prolongation of APTT alone
occurs in F VIII, IX, XI, or XII deficiency. Mixing tests of
APTT performed with normal serum or aluminium
hydroxide Al (OH3) adsorbed plasma further help in
differentiating these deficiencies. Normal serum contains
factors IX, X, XI, XII whereas Al(OH3) absorbed plasma
contains FV, VIII, XI, XII. Correction of an isolated
prolonged APTT with normal serum but not with
absorbed plasma suggests F-IX deficiency. Its correction
with adsorbed plasma but not with normal serum
suggests F-VIII deficiency. Correction with both, i.e.
normal serum and adsorbed plasma occurs in F-XI and
F-XII deficiency. However, specific factor assays are
confirmatory. Prolongation of both APTT and PPT along
with thrombocytopenia may occur in acute DIC and
needs to be confirmed by doing thrombin time and
fibrinogen degradation products (FDP). Thrombin time
gets prolonged in DIC due to presence of
hypofibrinogenemia (fibrinogen < 100 mg/dl) or FDP.
15.12 Platelet and Bleeding Disorders
Normal hemostasis requires an integrated vessel wall,
quantitative and qualitatively well functioning platelets
and availability of coagulation factors. Any defect in
above three can lead to bleeding. The defects can be
hereditary or acquired. Vessel wall injuries are usually
local events and platelet and coagulation abnormalities
are systemic events.
Pediatric Hematology 831
Prolongation of APTT and PPT with normal platelet
count and thrombin time may occur in hereditary
deficiency of common pathway factors of coagulation or
combined deficiency of factors. The latter occurs usually
in liver damage vit K deficiency inhibiting synthesis of
factors II, VII, IX, X. In factor XIII deficiency, however,
platelet count, APTT, PPT and bleeding time remain
normal. Abnormal clot stability tested with 5 Molar urea
is the only abnormality observed and thus this test
constitutes an important preliminary screening test.
Based on above tests most patients with hereditary
hemostatic defects can be diagnosed. However in some
patients with bleeding, the above tests may be normal.
These may have hereditary defects of fibrinolytic path-
way protein (tissue plasminogen activator, plasminogen
activator) inhibitor, vessel wall defects or mild platelet
dysfunction.
BIBLIOGRAPHY
1. Colman RW, Hirsh J, Marder VJ, Salzman EW: Hemo-
stasis and thrombosis edited by RW Colman J Hirsh, VJ
Marder, EN Salzman Lippincott Philadelphia 1994.
2. Davie EW, Ratnoff OD: Waterfall sequence for intrinsic
blood clotting science 1964;145:1310.
3. Esmon CT: The regulation of natural antocoagulant
pathways. Science 1987;235:1348.
4. Lammle B, Griffin JH. Formation & Fibrin clot: the
balance of procoagulant and inhibitory factors. Clinics
in hematology1985;14:281.
5. Loscalzo J, Schafer AI: Thrombosis and Hemorrhage
edited by J Loscalzo, AI Schafer, Williams & Wilkins,
Baltimore, 1998.
6. Mac Farlane RG: An enzyme cascade in the blood clotting
mechanism and to function as a biological amplifier.
Nature 1964;202:498.
VP Choudhry, Amit Upadhyay
Approach to a Bleeding Child
A careful history, a family pedigree and detailed history
and physical examination can give us a fair idea about
the cause of bleeding. Cephalhematoma or prolonged
bleeding from umbilical cord may be earliest indicator
of defective coagulation pathway like vitamin K
deficiency or hemophilia. Spontaneous hemarthroses
832 IAP Textbook of Pediatrics
and muscle hematomas suggest any of the hemophilias
while mucocutaneous bleeding suggests platelet
disorders. Excessive bleeding in response to circumcision
can be seen in hemophilia or in Glanzmann’s
thrombosthenia and delayed bleeding in response to
circumcision suggests factor XIII deficiency. Organ
specific bleeding like hemoptysis or hemetemesis are
very rarely the presenting symptom of any systemic
bleeding disorder except for the presence of hematuria
in hemophilia and almost always suggest local causes.
Nutritional history and details of drugs intake are helpful
for diagnosis.
Careful examination of the skin and mucous
membrane is necessary for detecting petechial spots and
Figure 15.12.1: Diagnostic approach to thrombocytopenia
purpuras. Hematomas, ecchymosis and oozing at the
venepuncture or injection site should be actively looked.
Joints should be examined for any deformities.
Hyperelasticity of skin and hyper extensibility of joints
can be seen in Ehler-Danlos Syndrome. Gum swelling
with petechial spots around the hair follicle is typical of
scurvy. Presence of significant lymphadenopathy or liver
or spleenic enlargement may point towards underlying
hematolgic malignancies.
In any child with bleeding, an initial screening of PT,
APTT, platelet count and a peripheral blood film
examination are essential and serve as basic tests for
further tests like coagulation factor assays, platelet
function tests, or bone marrow examination.

Disorder of the Platelets
Platelet disorders can be classified as either quantitative
or qualitative defects. Most common platelet disorder in
pediatric practice is thrombocytopenia.
Causes of thrombocytopenia are multiple. It may
result from decreased production (aplastic anaemia) or
due to increased destruction of platelets. Idiopathic
thrombocytopenic purpura is the major cause of
thrombocytopenia. Approaches to the differential
diagnosis of thrombocytopenia along with its causes are
given in Figure 15.12.1.
Idiopathic Thrombocytopenic Purpura (ITP)
Term is still being used conventionally while the true
term should be immune thrombocytopenic purpura. It
has an incidence of 4.0-5.3 per 1 lac children.
Pathogensis (Fig. 15.12.2): Thrombocytopenia results
from the increased destruction of antibody coated
platelets by the reticulo endothelial system predo-
Figure 15.12.2: Pathogenesis of idiopathic thrombocytopenia purpura
Pediatric Hematology 833
minantly in the spleen. The antibodies are directed
towards the platelet membrane antigens, usually
GP II b/III a, GP Ib/IX and GPIa -IIa. The antibodies are
usually IgG but may be IgM or IgA and are usually
polyclonal. The sources of the antibodies is not yet fully
clear. It is postulated that these antibodies are produced
by some fetal autoantibody clones which escape their
deletion during immune system maturation and may get
activated following any viral or unidentified immune
trigger leading to production of antibodies, which cross
reacts with the platelet membrane glycoprotein. When
these antibody—coated platelets come in contact with
cells of RE system, the Fc portion of the antibody binds
with the Fc receptor of the RE cell resulting in
phagocytosis of the platelet. Spleen is the major site of
platelet destruction. Other factors like decreased
production of platelets secondary to destruction of
megakaryocytes or intramedullary destruction of
platelets may also contribute to the thrombocytopenia
though this is much more common in adult ITP.
834 IAP Textbook of Pediatrics

Types — Based on the natural course and clinical
presentation, three distinct patterns have been identified,
viz.
Acute ITP
It is associated with severe thrombocytopenia and is
preceded by viral infection in over 50 percent of the cases.
It has self limiting course and majority (80 to 90%) of
children have a natural remission within two months.
Chronic ITP
Patients have insidious onset of symptoms with
moderate thrombocytopenia persisting for at least six
months. Children with chronic ITP have only 10-20
percent chance of natural remission.
Relapsing ITP
Onset is similar to acute ITP but children have relapses.
Relapses may get precipitated following viral infections.
Clinical Presentation (Figure 15.12.3)
Children with ITP have isolated thrombocytopenia and
often develop petechiae, ecchymosis, and easy bruising.
The peak age for acute ITP is between 3 to 5 years, while
infants below 1 year often develop chronic ITP. Boys and
girls are equally affected unlike in adults where it is 4 to
5 times more common in females. Acute ITP is often
preceded by febrile viral episodes while relapses may
occur with or without preceding viral illness. MMR
vaccine also rarely leads to ITP. Severe manifestation of
ITP includes hematuria, gastrointestinal bleeding, severe
epistaxis, menorrhagia in adolescent girls, etc.
Intracranial bleed may occur in 1 to 2 percent of children
and may prove fatal. Physical examination is essentially
normal except signs of hemorrhage in acute ITP. Spleen
may be palpable in 5 to 15 percent of children with
chronic ITP. Natural course of disease, clinical
presentation and the outcome in acute and chronic ITP
is summarized in Table 15.12.1.
Laboratory Features
Isolated thrombocytopenia is the only abnormality found
in complete blood count. Platelets are variable in size
with predominantly young large platelets and mean
platelets volume is usually high. Giant platelets can also
be seen in PBF. Platelets distribution width is increased.
Coagulation studies are normal except for increased
bleeding time in the majority. Circulating anti platelet
antibodies can be demonstrated. Current Phase III assays
for detection of these antibodies are sufficiently specific
but not sensitive.
Bone marrow examination reveals normal or
increased number of megakaryocytes but is essential to
exclude the possibility of leukemia, aplastic anemia or
tumor cell infiltration. Bone marrow examination is not
essential in a typical case of ITP. However, bone marrow
examination is essential in children with: (a) chronic ITP,
(b) abnormalities of the total or differential white cell
counts, (c) moderate or severe anemia, (d) with atypical
history (e) failure to respond to previous steroid or other
therapies, and (f) before starting steroid therapy.

TABLE 15.12.1: Acute and chronic ITP

Features Acute Chronic

Peak age 2-6 yrs 20-40 yrs

Sex predilection None F:M 3:1
Antecedent infection Common Unusual
Onset Acute Insidious
Hemorrhagic Bullae Common in Rare
(oral mucosa) acute phase
Eosinophilia/lymphocytosis Common Rare
Platelet count < 20 × 109/L 30-80 × 109/L
Duration 4-6 wks > 6 months
Natural course 80% Uncommon
Spontaneous remission
Associated immunological None 20%
states
Figure 15.12.3: Child showing petechiae, purpura and ecchymosis
 Pediatric Hematology 835

Differential Diagnosis of 10,000 or more can be observed because in 80-85% of

Diagnosis of ITP is made by exclusion of other cuases of
thrombocytopenia by history, clinical examination and
laboratory investigations. Several conditions should be
excluded before making the diagnosis of ITP. Intake of
drugs such as qunidine, heparin, prolonged use of
analgesics, anticonvulsants, cephalosporins, sulfona-
mides, etc. should be excluded. Children with aplastic
anemia and leukemia have anemia which is out of
proportion to the blood loss along with abnormal blood
counts. The presence of lymph nodes, hepatospleno-
megaly or sternal tenderness suggests the possibility of
leukemia. Abnormalities of the limb are characteristics
or TAR (Thrombocytopenia with absent radii) syndrome.
Children with Fanconi’s anemia usually have
dysmorphic physical features and isolated thrombo-
cytopenia. Rarely thrombocytopenia may precede the
development of aplastic anemia.
Supportive Care
Supportive care includes restriction of physical activities
and avoidance of aspirin and related drugs. All
immunization should be avoided during the acute phase.
Children with severe thrombocytopenia (platelet count
< 20,000/cu mm), severe mucosal bleeds, hematuria,
gastrointestinal bleeding, girls with menorrhagia should
be admitted to control the bleeding episode. Oral anti
fibrinolytic drugs can be used for mild to moderate
bleeding episodes.
Treatment
The decision whether to treat or only close monitoring
depends on platelet count and presence and severity of
bleeding. Most of the children with ITP usually do not
require drugs. A non-bleeding child with a platelet count
patients ITP resolves by itself within 4-6 weeks.
For a child with minor bleed, supportive treatment
alone is usually sufficient. For any platelet count of less
than 10,000 or patient with life threatening bleeding
treatment is required. The most commonly used drugs
are:
1. Corticosteroids
2. IV IgG
3. Anti D IgG (Table 15.12.2)
1. Corticosteroids: These are the most commonly used
drugs for ITP. The mechanism of actions is:
(a) decreased clearance of opsonised platelet
(b) decreased production of antiplatelet antibodies
(c) increased capillary stability.
There are many treatment regimes being used.
Prednisolone in doses of 0.5-2 mg/kg/day to form a
maximum of 3-4 weeks is the most commonly used
regime. Usually prednisolone is used (2mg/kg/day)
for 2-3 weeks subsequently in tapering doses for
another 2-3 weeks. For quick responses either high
dose oral prednisolone (4mg/kg/day × 4 days) or IV
Methyl prednisolone (30 mg/kg/day × 3 days) can
be used. Serious side effects of prolonged steroid
therapy include hypertension, growth retardation,
osteoporosis, pseudotumor cerebri, psychosis and
Cushing’s syndrome.
2. IV IgG: IV IgG forms the mainstay of treatment of
serious episodes. It is used in doses of 400 mg/kg/
day × 5 days or 1 gm/kg/day × 2 days with the latter
being preferred approach now a days. IV IgG block
the Fc receptors and thus prevents the platelet
phagocytosis. Majority of patients will have
prolonged remission with single dose. Headache and
vomiting are the usual side effects and can be seen
upto 1-2 days post therapy. These are very expensive
however and carry small risk of transmitting TTIs.

TABLE 15.12.2: Mechanism of action of corticosteroids IV IgG and anti-D

Effect Corticosteroids IV-IgG Anti-D

Reticulo-endothelial blockade ± + +
Platelet antibody binding + ± –
Altered FcR binding + + ±
T-helper cell suppression + + –
Improvement in capillary resistance + – –
Cytokine production Reduced Reduced Normal

Antibodies synthesis Reduced Reduced Normal/Reduced

836 IAP Textbook of Pediatrics
3. Anti D: Anti (Rh) D binds Rh positive RBCs and leads
to their destruction in spleen. Since this saturates
splenic Fc receptors, more platelets survive in the
circulation. A positive direct Coomb’s test, a
decreased haptoglobin level and mild and transient
hemolysis occur in all Rh positive patients after anti
D. Generally, anti D therapy does not require blood
transfusion, although serious hemolysis can occur
rarely. A single dose of 50-100 ug/kg is recom-
mended, as IV infusion over 3-5 minutes which
usually increases platelet counts in 70-80 percent of
patients to > 50,000/ul. This therapy is not effective
in Rh negative and in splenectomised patients.
Platelet Transfusion
Because of ongoing destruction platelet transfusion is not
used to raise platelet count in ITP. Occasionally it can be
used to transiently increase platelet count in combination
with other drugs in life threatening bleeding episodes or
prior to surgery.
Recombinant Factor VII
This agent can be used in life threatening refractory
bleeding episodes. It is also effective in assertive bleeding
episode in patient with platelet function disorders.
Splenectomy
Children with uncontrolled bleeding or children without
any response to steroids or IVIgG therapy, or with
chronic ITP should be considered for splenectomy.
Majority of the patients (65-88%) achieve remission
immediately after splenectomy. Splenectomy results in
immediate rise of platelets as the antiplatelet antibodies
are synthesized in the spleen and secondly the
reticuloendothelial system of the spleen is responsible
for clearing of antibody coated platelets. Platelet count
rises immediately after splenectomy and the maximum
level is achieved within 10-15 days. Peak platelet count
of 5,00,000 / mm3 is associated with prolonged remission.
Some patients may relapse even after splenectomy.
Children after splenectomy are more susceptible to
develop postsplenectomy sepsis secondary to infection
by encapsulated organism such as meningococcus,
pneumococcus, H. Influenzae. These children present with
fever, chills and may progress to coma, DIC and death.
All children should receive meningococcal and
pneumococcus and H. influenzae vaccination prior to
surgery. Penicillin prophylaxis should be initiated after
splenectomy and should preferably be given for life-long.
Chronic ITP
The objectives of therapy is to decrease the risk of serious
hemorrhages than to achieve normalization of platelet
counts. Platelet count does not co-relate with severity of
bleeding episodes. Treatment to children with chronic
ITP needs to be individualized depending upon the
platelet count, degree of bleeding, age of child, duration
of thrombocytopenia and child’s activity level. If platelet
remains in a hemostatically safe range (> 15-20,000/mm3)
patients are often observed and active treatment is
reserved for clear signs of bleeding like increased
bruising, menorrhagia, prolonged epistaxis, etc.
Corticosteroids, IVIg and anti D have been used on
either needed or on monthly basis either alone or in
combination with danazole or vinca alkaloids to maintain
platelet counts > 50,000/mm3. Alternatively, splenec-
tomy is successful in 78-80 percent of pediatric patients.
Recently many newer drugs like dapsone, immuno-
suppressive drugs like cyclosporin, mycophenolate
mofetil, cytotoxic drugs like cyclophosphamide,
azathioprine, monoclonal antibodies like Rituxmab,
Campath, etc. are being used in refractory cases with
variable responses.
Vinca alkaloids: Both vincristine and Vinblastine
increase the platelet count in approximately 70 percent
of ITP patients with sustained response in about 10
percent. Recommended dose of vincristine is 0.02
mg/kg and of vinblastine is 0.1 mg/kg given as bolus
injections at weekly interval for a minimum of three
courses. Peripheral neuropathy and constipation are the
main side effects.
Cyclophosphamide has been used in refractory ITP
patients. It is given in dose of 1-2 mg/kg/day P.O. daily
or 20-30 mg/kg IV every month. It increases platelet
count in more than 60 percent of patients and 30-35
percent of patients remain in long remission after 3-4
months of therapy. The mechanism of action involves
immunosuppression. Alopecia, bone marrow suppres-
sion, hemorrhagic cystitis and risk of secondary
malignancy are the potential side effects.
Azathioprine: It is a purine analogue which gets
converted into 6-MP in body and acts as an immune

modulator. Recommended dose is 1-4 mg/kg/day
for at least 4-6 months. It produces good sustainable
response in around 40 percent of refractory patients.
Danazole: It is a semi synthetic androgen and postulated
to decrease the number of Fc receptors on phagocytic
cells by antagonizing the action of estrogens. It is used
in dose of 300-400 mg/m2/day in divided doses. Virilisa-
tion and liver dysfunction are the main side effects.
Monthly LFTs are recommended.
Rituxmab: This is monoclonal antibody against CD 20.
It leads to depletion of circulating CD 20 positive Pre-B
cells in the blood leading to decreased antibody produc-
tion resulting in decreased destruction of platelets. It has
been shown to produce sustained response in more than
50 percent of refractory pediatric ITP patients. The
recommended dose is 375 mg/m2 weekly for 4 weeks.
Risk of anaphylaxis is present and it should be given
under supervision.
Immune Thrombocytopenia
Platelet isoantibodies can be acquired under three
circumstances:
1. Congential isoimmune thrombocytopenia in the
neonate may result from the placental transfer of
isoantibodies formed by the mother due to
incompatible fetal platelet antigens.
2. Placental transfer of platelet antibodies from the
meternal circulation of a mother with ITP.
3. Post-transfusion isoimmune thrombocytopenia
which transfused platelets from the blood or blood
products provoke the formation of autoantibodies.
Pathophysiology of congential isoimmune
thrombocytopenia is similar to erythroblastosis fetalis.
Immunization to the platelet isoantigens (namely
PLA-1) has been observed. Mother’s platelets are
negative for PLA-1 antigen while the baby’s platelets are
positive. Fetal platelets cross the placenta and the mother
produces the antibodies which are responsible for the
neonatal thrombocytopenia. The bleeding is usually mild
and the purpura occurs in the second week of life which
subsides within 2 to 4 weeks. If bleeding is severe,
transfusion of washed meternal platelets are effective.
Corticosteroids and exchange transfusion are also
effective.
Neonatal thrombocytopenia can result from the
placental transfer of platelet antibodies from the maternal
Pediatric Hematology 837
circulation. Nearly half of infants, born to mothers with
ITP, develop thrombocytopenia. The neonate is at higher
risk of developing thrombocytopenia when the mother
is having acitve disease or high levels of platelet
associated antibodies. Neonates often develop pupuric
or ecchymotic spots at birth and first few days are critical.
Intracranial bleed is an important cause of death.
Neonates with severe bleeding manifestation should be
treated with intravenous immunoglobulins or steroids.
Exchange transfusion removes the antibodies and may
help in controlling the bleeding.
PLATELET FUNCTION DISORDERS
Hemostatic disorders are more often secondary to the
quantitative disorders of the platelets. However, the
process of adhesion, activation and aggregation are
essential for hemostasis. Hereditary disorders in any of
these processes also result in the bleeding disorders
(Table 15.12.3). These disorders are termed as platelet
functional disorders.
Bernard–Soulier Syndrome
This is an autosomal recessive disorder characterized by
a triad of large platelets, moderate thrombocytopenia and
prolonged bleeding time. There is reduced or abnormal
expression of platelet GP Ib/IX (receptor for vWF) on
the surface of platelet. Platelet aggregation studies show
normal response to all agonists except for ristocetin.
Abnormal RIPA (ristocetin induced platelet aggregation)
can be corrected by addition of normal platelets. Platelet
flow cytometry can be used to confirm the disorder.
TABLE 15.12.3: Causes of platelet function disorders
Hereditary diseases
Associated with thrombocytosis
Glanzamann’s thrombasthenia
Thrombopathic thrombasthenia
Defects of release reaction
Storage pool disease
Cyclo-oxygenase
Gray platelet syndrome
Isolated PF3 release
Thrombopathy (Deficient PF3 content)
Von Willebrand’s disease
Associated with thrombocytopenia
Bernard-Soulier syndrome
Wiskott-Alrich syndrome
838 IAP Textbook of Pediatrics
Wiskott–Aldrich Syndrome
It is an X linked inherited disorder characterized by small
platelets, thrombocytopenia, recurrent infections and
eczema. Platelet aggregates are abnormal and bleeding
time is usually increased. Splenectomy is helpful in the
majority of patients.
Glanzmann’s Thrombasthenia
It is an autosomal recessive inherited diorder
characterized by severely reduced or absent platelet
aggregation in response to multiple physiological
agonists because of qualitative or quantitative
abnormalities in platelet glycoproteins GP IIb (CD 41)
and GP IIIa (CD-61). Patients with this disorder have a
normal platelet count, but a markedly increased bleeding
time, decreased or absent clot retraction and abnormal
platelet aggregation to physiologic agonists. Anti-
fibrinolytic agents and platelet transfusion are used to
control bleeding episodes.
Storage Pool Diseases
Platelets have two major types of granules – dense (delta)
and alpha granules. Dense granules contain ATP, ADP,
calcium and serotonin while the alpha granules contain
bigger molecules like vWF, fibronection, fibrinogen,
PDGF, PF4, etc. Bleeding disorders arise either due to
decrease in number or by decreased release or their
contents. Defects in the dense granules, alpha granules
or both can be present. Dense granules defects can also
be associated with defective biogenesis of melanosomes
leading to associated oculocutaneous albinism, e.g.
Chediak–Higashi syndrome or Hermansky–Pudlak
syndrome.
Defects in α-granules leads to Gray Platelet
Syndrome, which is characterized by abnormalities of
platelet α- granules, thrombocytopenia and fibrosis in
the bone marrow. Blood smear shows agranular platelets
that appear grey on wright’s stain because of lack of these
(azurophilis) granules. Platelet functional studies show
defective aggregation in response to ADP and epinephrin
in case of dense granule disorder, while defective
aggregation in response to thrombin and collagen is seen
in cases of alpha granule disorder. Diagnosis can be
confirmed on electron microscopy.
CLINICAL FEATURES
In all these disorders children have mild to moderate
mucosal bleeding, petechiae, ecchymosis, etc.
Menorrhagia may be the predominant feature. Bleeding
time is prolonged and thrombocytopenia may be
associated with Bernard-Soulier and Wiskott-Aldrich
syndrome. Diagnosis of platelet functional disorders is
based upon the high index of suspicion, presence of
bleeding manifestation from early childhood along with
defects of platelet adhesion, aggregation or deficient
release reactions and positive family history.
Management is supportive. Drugs such as aspirin,
NSAIDs, etc. which impair the platelet functions, should
be avoided. Hormonal therapy may be used to control
menorrhagia. Platelet transfusion is indicated in the
presence of uncontrolled bleeding. DDAVP and
antifibrolytic agents can be helpful in selected cases in
mild to moderate bleeding episodes. Recombinant factor
VIIa has also been used successfully in few patients with
platelet function disorders to control bleeding.
Hereditary Coagulation Factors Deficiency
Hereditary disorders are common in children; however,
deficiency of the coagulation factors can also result from
acquired causes (Table 15.12.4). Among these disorders
hemophilia A, hemophilia B and von Willebrand’s
disease are common. Deficiencies of these factors result
in bleeding of varying severity except for factor XII which
is associated with thrombosis.
von Willebrand’s Disease
This is the most common inherited bleeding disorder
with prevalence as high as 1 percent of the general
population. von Willebrand Factor (vWF) is a central
component of hemostasis which serves a carrier for factor
VIII and acts as a link between platelet and the vessel
wall. It binds to platelet GP Ib (vWF receptor) on
adjoining platelets and subendothelium and helps them
making clump. Its deficiency leads to von Willebrand’s
disease. Several subtypes have been identified, and of
these types 1, 2 and 3 are most common. Deficiency may
be quantitative (type 1 and 3) or qualitative (type 2). Type
1 variant is the most common and the mild form in which
vWF is 10-50 percent of the normal. In type 2 vWF is
 Pediatric Hematology 839

TABLE 15.12.4: Coagulation factor deficiency

Hereditary Disorder
Common diseases Factor deficiency Inheritance
Hemophilia-A VIII X-linked recessive
Hemophilia-B IX X-linked recessive
von-Willebrand’s disease VIII and vascular factor Autosomal dominant
Uncommon Diseases
Hemophilia-C XI Autosomal recessive
Parahemophilia V -do-
Factor X deficiency X -do-
Factors VII, V, XII, XIII — -do-
Acquired Disorders
Deficiency of vitamin K dependent factors
– Hemorrhagic disease of the newborn
_ Liver disorders
_ Malabsorption
Disseminated intravascular coagulopathy
Inhibitors to coagulation factors (Fact. VIII/IX)

abnormal in structure or function. Type 3 is the most
severe form with very low or undetectable levels of vWF.
Type 1 is usually inherited as autosomal dominant while
type 3 is usually autosomal recessive. Patients usually
present with mucocutaneous bleeding but type 3 may
present with hemarthroses and muscle hematomas
simulating hemophilia. Bleeding time is markedly
prolonged. Ristocetin co-factor assays and vWF antigen
assays are diagnostic.
Factor VIII activity is reduced and in type 3 cases, it
can be 3-10 percent of normal. Mild to moderately severe
disease (type 1) may show good therapeutic response to
DDAVP while type 2 and 3 are usually not responsive.
Severe form requires treatment with factor replacement
in the form of plasma or factor VIII concentrates
containing large quantity of intact vWF molecules.
Hemophilia
Hemophilia A and B are inherited bleeding disorders
and account for 80 to 90 percent of inherited coagulation
disorders. They are inherited as sex linked recessive
disorder. Women are carriers of hemophilia defect but
are asymptomatic while their male offsprings suffer from
the disease. Sporadic mutation of the gene is common
and accounts for 20 to 30 percent of cases.
Pathophysiology
Factor VIII and IX are essential for the generation of
thrombin. Activated factor IX forms a complex with
factor VIIa, calcium, membrane phospolipid to generate
Xa for the continuation of coagulation pathway. Factor
VIII has two components, viz. factors VIII related antigen
(VIII-Ag) and factor VIII coagulant activity (VIII-C). Ratio
of factor VIII C to factor VIII-Ag is one. In patients of
hemophilia and carriers, factor VIII-coagulant activity is
reduced while antigenic component remains normal.
Based on the factor levels, hemophilia is classified as
severe (factor level < 1% of the normal), moderate (factor
level between 1 to 5% of the normal) and mild (factor
level > 5% of the normal). Factor VIII or IX gene has been
analyzed and the common mutational defects have been
identified such as deletions, point mutation, stop condon,
etc. Point mutations are usually the underlying mutations
in 70 percent of hemophilia A and in 90 percent of
hemophilia B patients. Inversion 22 is the most common
and accounts for about 45 percent of various mutations.
Hind III and other mutations can be identified in
additional 40 percent of cases. Molecular studies are
being used as a tool for the antenatal diagnosis and
control of hemophilia.
CLINICAL PICTURE (TABLE 15.12.5)
Manifestations of hemophilia are dependent upon the
severity of hemophilia. Patients with mild disease are
usually asymptomatic and may develop prolonged
bleeding following teeth extraction, severe trauma or
following surgery. While patients with severe hemophilia
develop spontaneous bleeds in the skin, subcutaneous
tissues, and in the musculoskeletal system. Nearly
one-third of children develop bleeding following
840 IAP Textbook of Pediatrics

TABLE 15.12.5: Incidence and severity of clinical manifestation of Hemophilia

Severe Moderate Mild

Incidence
Hemophilia A 70% 15% 15%
Hemophilia B 50% 30% 20%
Bleeding Manifestation
Age of onset < 1yr 1-2 yrs 2 yrs-Adult
Neonatal Hemorrhage
- Post Circumcision Common Common None
- Intracranial Occasionally Rare Rare
Muscle/joint bleed Spontaneous Following trauma Following
trauma
CNS bleed High risk Moderate risk Rare
Post Surgical Bleeding Common Common Rare
Oral Bleeding Common Common Rare

circumcision. Excessive bleeding may result from the Prenatal Diagnosis

umbilical cord. One or two percent of neonates may
This is possible by either chorionic villous sampling
develop intracranial bleeds. Common manifestations in
(CVS) at 10-12 weeks of Gestation or by Amniocentesis
children with severe hemophilia include easy bruising,
at 16-18 weeks of gestation. Both procedures yield fetal
oral bleeds, especially from the frenulum, hemarthrosis,
cells for DNA analysis. Direct fetal blood sampling can
(Fig. 15.12.4) and intramuscular hematomas. Intra
also be performed at 18-20 weeks of gestation for assay
articular bleeding accounts for > 90 percent of all serious
of fetal factor VIII or IX. Complication rates are < 1
bleeding events in hemophiliac and mostly involved
percent for CVS and 1-2 percent of amniocentesis. Pre-
weight bearing joints such as knee, elbows and ankle.
natal diagnosis enables to prevent along with
Acute hemarthrosis is characterized by rapid joint
identification of genetic mutation in the affected sibling
swelling with pain, redness, stiffness and restriction of
is essential to look for the same mutation in the fetus.
movements. Recurrent joint bleeding in the same joint
results in progressive joint damage and the development
of hemophilic arthropathy over prolonged periods. It is
characterized by synovial hypertrophy, cartilage
damage, loss of joint space and bony changes. Decreased
use of the affected joint leads to muscle atrophy and
ankylosis of the joint. Bleeding in the muscles causes
severe pain and disability. Retroperitoneal bleed results
in severe abdominal pain, anemia, and even shock.
Intracranial bleeds though uncommon but often causes
death. Its early recognition and prompt treatment is
essential to reduce the mortality. Hematuria is often
troublesome. Gastrointestinal bleeding is severe and may
be difficult to control.

Laboratory Investigations
Partial thromboplastin time and clotting time are
prolonged while bleeding time and prothrombin time
are normal. Factor VIII or IX deficiency can be identified
either by the individual factor assays or by mixing studies
with normal plasma or with adsorbed plasma. Figure 15.12.4: Hemophilic arthropathy right knee joint
 Pediatric Hematology 841

DNA studies are essential only in presence of male fetus.
However, in presence of female fetus DNA studies can
help identifying the Inversion 22, Hind or other point
mutations by ARMS or by linkage analysis.
Management
Comprehensive management of hemophilia is essential
and should include control of bleeding episodes besides
educational, vocational training, knowledge of early
detection, benefits of prophylaxis therapy and
rehabilitation. Comprehensive care can be possible by a
team of pediatric hematologist, orthopedic surgeon,
physical therapist, dentist, genetic counselor, etc.
Once unit of factor VIII/kg raises factor level by 2 percent.
It is administered at 12 hours interval to maintain the
required blood levels as its half-life is 8 hours. Dose of
factor VIII for replacement therapy is given in Table
15.12.6.
Fresh Frozen Plasma
It is readily available and is useful for the management
of mild bleeding episodes. It cannot be used alone to
control intracranial bleeding, acute hemarthrosis or
muscular hemorrhage as its large volume administration
leads to cardiac overload. One ml of FFP contains one
unit of factor VIII and IX along with other plasma factors.

Replacement Therapy Cryoprecipitates

Prompt replacement therapy is essential for the effective
treatment. It controls the bleeding and prevents the
development of musculoskeletal deformities. Common
indications for the treatment are acute hemarthroses,
intracranial bleed, moderate to severe muscular bleeds,
intra-abdominal bleed and severe mucosal bleeds.
Replacement of factors with cryoprecipitates or factor
VIII concentrates and rest to the affected part are
essential. Presently in India, FFP and cryoprecipitates are
economical while factor VIII concentrates are expensive.
It contains approximately 50 percent of the F VIII-C, von
Willebrand’s factor activity, fibrinogen and F XIII. Single
bag of cryoprecipitate contains nearly 100 units of F VIII-
C. It is useful for management of hemophilia, von-
Willebrand’s disease, severe hypofibrinogenemia or
afibrinogenemia. Cryoprecipitate is preferred as it is
prepared from single unit and has lesser risk of blood
transmitted infections. Its disadvantages include: (a)
storage at –20 to 30° C, (b) difficulty to reconstitute and
(c) factor VIII-C levels vary from bag to bag.

TABLE 15.12.6: Dosage schedule for factors VIII and IX administration

Site of bleed Loading Dosage (U/Kg) maintenance Other therapy

Acute hemarthrosis 20 20 U 12 hourly × 3 days Rest to the affected part, Ice

Intramuscular bleed
Life-threatening bleeds
CNS bleeds
Major trauma
Retroperitoneal bleeding
Neck bleed with
impending airway
obstruction
Tongue and mouth
lacerations
Dental extraction
(permanent teeth)
15 U 12 hourly × 2 days packs
10 U 12 hourly Elastic bandage, non-weight
bearing, Analgesics (not
aspirin), Rarely joint aspiration
20-30 20 U 12 hourly has to be continued
for several days for extensive bleeds
50 40 U 12 hourly × 7 days or
continuous infusion 3-4 U/kg
hourly × 7 days after initial
bolus of 50 U
then
II. 20-30 U 12 hourly × 7 days
III. 15-20 U 12 hourly × 7 days
20 20 U 12 hourly × 5-7 days Nil orally,
Sedation,
EACA/tranexamic acid
30 20 U12 hourly × 3 days EACA/tranexamic acid
24 hrs before and 7 days after
842 IAP Textbook of Pediatrics
Commercially Prepared Factor VIII Concentrates
Factor concentrates form the mainstay of treatment in
the developed countries. These products are not freely
available in the developing countries. The main
advantages include: (a) ease of storage, (b) reconstitution
and infusion, (c) known level of F VIII-C concentration
and, (d) longer shelf-life. Factor VIII concentrates are heat
treated to decrease the hepatitis and AIDS virus load.
Porcine Factor VIII Concentrates
This product is prepared from pig and is highly purified
factor VIII concentrate and is useful for the management
of hemophilia with inhibitors.
Prothrombin Complex Concentrate (PCC)
These concentrates contain the vitamin K dependent
clotting factors like II, VII, IX, X and protein C. It is used
for the management of severe hemophilia B.
Activated Prothrombin
Complex Concentrates (APCC)
The product is used for management of patients with
inhibitors as it stimulates the common pathway directly.
Recombinant Factor VIII
Recombinant DNA technology has been used to produce
coagulation factor VIII. It is safe as it is not produced
from blood but is expensive. It can also be used for
treatment of patients with inhibitors.
Activated factor VII (Novoseven)
It bypasses the stage one and directly activates factor X
to facilitate the progression of coagulation systems. It can
be safely used to control bleeding in patients of
hemophilia with inhibitors. It is an expensive product
and is beyond the reach of majority.
Epsilon Aminocaproic Acid (EACA)
EACA and tranexamic acid are antifibrinolytic agents
and act by inhibiting the plasminogen activity. These
agents are useful for the management of patients with
mucosal bleeds.
Desmopressin Acetate
I-deamino-8-d-arginine vasopressin (DDAVP) is a
synthetic analogue of naturally occurring antidiuretic
hormone. DDAVP results in three fold increase of factor
VIII and plasminogen levels. It is useful for treatment of
patients with mild to moderate hemophilia.
Acute Hemarthrosis
Treatment should be initiated without any delay to
prevent the development of chronic debilitating arthritis.
Rest to the affected joints is essential during the acute
stage. Passive and active exercise should be initiated as
soon as pain subsides. Ice pack may provide relief of pain.
Chronic synovitis leads to proliferation of synovium, and
destruction of cartilage. Resorption of bone may lead to
cyst formation and joint instability.
Head Injury
Head trauma in a hemophilic child is an emergency and
replacement therapy in larger doses should be started in
the emergency room or even at home on suspicion. CT
scan should be done repeatedly to monitor the therapy.
Surgical Procedure
Surgical procedures in hemophiliacs are safe in presence
of adequate replacement therapy. These patients should
be screened for presence of inhibitors besides estimating
the factor levels. Replacement therapy should be initiated
prior to surgery with factor VIII in the dose of 40 to 50
units/kg as a bolus dose and the treatment should be on
same lines as in head injuries.
Hemophilia B
Principles of treatment of hemophilia B are identical to
hemophilia A. One unit/kg of factor IX raises the plasma
levels by one percent. Dose of factor IX for various
conditions is given in Table 15.12.6.
Inhibitors
Developments of inhibitors (IgG antibodies) have been
observed in 15 percent of patients with severe hemophilia
A and 1 to 2 percent of patients with hemophilia B.
Patients with inhibitors have been classified as high or
low responders depending upon the inhibitor levels.
Management is dependent upon: (a) patient’s inhibitor
levels, (b) nature and extent of bleeding, and (c)
availability of the products.
Inhibitor levels are measured commonly by Bethesda
units. Patients with low inhibitors (<5 Bethesda units)
can be managed easily by factor replacement and

supportive therapy. However, bleeding in patients with
high inhibitor levels (>5 BU) is difficult to control. It is
preferable to use FEIBA, APCC or activated factor VII
along with supportive care. All these agents bypass
stage1 of the coagulation pathway and stimulate the
common pathway directly. These patients should
preferably be treated at specialized centers. After
controlling the bleeding, these patients need to be treated
according to various protocols for desensitization so that
bleeding episodes in future in these patients can be
managed with conventional therapy.
BIBLIOGRAPHY
1. Chang BH, Ho SJ. Automimmune Thrombocytopenia J
Thromb Hemost 2005;3:1763-72.
2. Chaurumrit A. Treatmetn of hemophilia in the
developing countries. Haemophilia 2003;9:387-90.
3. Diane J Nugent. Immune thrombocytopenic purpura of
childhood in American society of hematology educational
program book Hematology 2006;97-103.
15.13 Disseminated
Intravascular Coagulation (DIC)
INTRODUCTION
DIC is a syndrome, secondary to an underlying disorder
and is characterized by a systemic activation of the blood
coagulation system, which results in the generation and
deposition of fibrin, leading to microvascular thrombin
in various organs and contributing to the development
of multiorgan failure. Consumption and subsequent
exhaustion of coagulation proteins and platelets, due to
activation of the coagulation system, may induce severe
bleeding complications. Derangement of the fibrinolytic
system further contributes to intravascular clot forma-
tion, but in some cases accelerated fibrinolysis (e.g. due
to consumption of α2-antiplasmin) may cause severe
bleeding. Hence, a patient with DIC can present with
simultaneous thrombotic and bleeding problem, which
obviously complicates treatment.
DIC is not a pathology in isolation. With possibly the
only exception of venom, DIC is a secondary response
Pediatric Hematology 843
4. Guidelines for investigation and management of
Idiopathic thrombocytopenic purpura in adults, children
and pregnancy. Brit J Hematol 2003;120:574-96.
5. Haya S, A Moret, A R Cid, et al. Inhibitors in Hemophilia
A: Current management and issues. Haemophilia
2007;13:52-60.
6. Kashyap R and Choudhry VP. Management of
hemophilia in developing countries. Ind J Pediatr
2001;68:151-57.
7. Paula HB Bolton-Maggs, K John Passi. Hemophilia A and
B. Lancet 2003;361:1801-9.
8. Reyhan Diz, Francisca C Gushiken and Jose A Lopez.
“Thrombocytopenia” in William’s textbook of
Hematology. Ed. Marshall A Lichtman, Ernest Beutler,
Kipps TJ, et al. 7th edition McGraw Hill Medical
2005;1749-84.
9. Saxena R, Ahmed RPH. Carrier detection in Hemophilia
A. Recent Advances in Hematology. Editors Choudhry
VP, Saxena R, Pati HP, J P Publications 2004;262-74.
10. Saxena R, Gupta PK, Mahapatra M, Choudhry VP. von
Willebrand’s disease, diagnosis and management. Ind J
Hemat Blood Transf. 2003;21:61-66.
Anupam Sachdeva, VP Choudhry
to a pre-existing primary pathology, i.e., it is an
intermediary mechanism of disease’.
The hallmark of normal hemostasis is the exquisite
regulation of a focused event, i.e., the formation of a
hemostatic plug, at the site of injury to a blood vessel.
The antithesis of this is what occurs in DIC. The events
are not confined to achieving hemostasis, i.e., they are
widely disseminated, albeit that this may be confined to
a local pathology, such as a hemangioma, or totally
systemic, as in gram-negative shock. The process is
initiated by a procoagulant event. The activation of the
fibrinolytic system is initially directed at clearing the
vasculature of unwanted deposits of fibrin, but it may
eventually compromise hemostasis.
Thus, DIC can be defined as an acquired syndrome
characterized by the activation of intravascular
coagulation upto intravascular fibrin formation. The
process may be accompanied by secondary fibrinolysis
844 IAP Textbook of Pediatrics
or inhibited fibrinolysis”. DIC involves consumption
coagulopathy although it is not always present in patients
with DIC, as microclot formation can occur without a
consumption coagulopathy.
The activation of fibrinolysis drastically intensifies the
bleeding tendency. Certainly, the activation of
fibrinolysis in the course of intravascular coagulation is
a secondary phenomenon.
Disseminated intravascular coagulation is an acquired
syndrome characterized by the activation of intravascular
coagulation up to intravascular fibrin formation. The process
may be accompanied by secondary fibrinolysis or inhibition of
fibrinolysis. This definition implies that microclot
formation and a consequent organ failure and/or a
hemorrhagic diathesis may occur.
Epidemiology
Precise numbers on the occurrence of DIC are not known.
In general, one can estimate, however, that of 1,000
patients admitted to a community hospital, only one
patient will develop DIC. The frequency of DIC should
be seen in relation to the underlying disease. The most
frequent disease states with which DIC may occur are
infections (systemic inflammatory response syndrome—
SIRS).
Pathogenesis
The characteristic pathology is a procoagulant stimulus.
The generation of thrombin is the final expression with
the formation of gel fibrin and the activation of fibrin-
stabilizing factor. Thrombin not only ‘activates’ platelets
inducing platelet aggregation and release but these also
provide specific binding sites for individual coagulation
factors as well as a coagulant active phospholipid surface.
With the help of these events thrombin promotes
dramatically its own generation following the initial
triggering of the coagulation cascade. Conversely,
thrombin generation activates potent mechanisms which
either down-regulate its generation or antagonize its
activity. In the presence of an endothelial cell co-factor
thrombomodulin activated protein C (APC), inactivates
the activated forms of factors V and VIII. In normal
hemostasis a balance exists between the coagulation and
fibrinolytic systems. The availability of tissue
plasminogen activator (tPA), required for conversion of
the inactive zymogen plasminogen to the active serine
protease plasmin, is also regulated by thrombin
promoting either directly or indirectly its release from
endothelial cell stores.There is profound increase in tPA
release and fibrinolysis following the generation of
thrombin. Although many issues relating to the inter-
regulation of these events remain unresolved, we do
know that protein C and the tissue factor pathway
inhibitor (TFPI) play a major role.
Effects of Thrombin
Procoagulant
• Converts fibrinogen to fibrin
• Activates Factor XIII
• Activates factors V and VIII
• Activates platelets
Anticoagulant
• Activates protein C
• Stimulates fibrinolysis
Initiation of Coagulation
Thrombin generation occurs 3 to 5 hours after endotoxin
release or any trigger, and a pivotal role is played by
tissue factor/factor VIIa system in the initiation of
thrombin generation. Activation of coagulation in DIC
is tissue factor driven, whereas the intrinsic pathway of
coagulation does not appear to play an important role.
But it may play an important role in other systemic
inflammatory responses, such as the occurrence of
hypotension. The monocytes express the tissue factor on
their surface and this may play a pivotal role in DIC.
Extrinsic (Tissue Factor)
Pathway-dependent Stimulus
Tissue factor extracts, on entry in the circulation result
in acute DIC as can be seen in major brain trauma.
Leukocytes express the apoprotein. Monocytes from
individuals with neoplastic conditions process tissue
factor like activity as do promyelocytic leukemic cell lines.
Endothelial cells do not normally synthesize tissue factor
but this may become up-regulated. This is associated with
down-regulation of the expression of thrombomodulin,
the essential co-factor required for the activation of
protein C by thrombin. The tissue factor-dependent
extrinsic pathway of coagulation provides the
procoagulant stimulus in the development of DIC in

conditions such as obstetric accidents or trauma,
particularly head injuries. Alternatively, tissue factor
expression is up-regulated either due to stimulation of
cells competent in tissue factor synthesis or by the
availability of neoplastic cells where the generation of
such activity is unregulated.
Intrinsic Pathway-dependent Stimulus
The role of contact activation as an initiating mechanism
in normal hemostasis remains elusive. Activation of
factor XII occurs following exposure to natural materials,
or to artificial surfaces or injury to the endothelium,
induced by endotoxin exposure or burns. This provides
the initial trigger to thrombin generation, and promotes
the generation of bradykinin and thus contributes to the
vasodilatation and hypotension commonly found in
association with the coagulant or fibrin generating
characteristics of this syndrome. It has been shown to
directly promote plasminogen activation. Thus in DIC
we see decreased levels of factor XII, prekallikrein and
kallikrein inhibitors and an increase in levels of
bradykinin-inhibitor complexes in patients with
hypotensive septicemia.
Cellular Tissue Factor and its
Procoagulant Function
Tissue factor is a 47 kDa glycosylated protein, which is
expressed on the vascular adventitia and organ capsules,
and that is usually not in direct contact with the
circulating blood. Its function may be related to
intracellular signal pathways and cell activation. TF can
be expressed on the endothelial cells and mononuclear
leukocytes. Granulocytes may also express TF upon
stimulation with endotoxin.
In sepsis and DIC, TF is critical as a mediator of DIC
and septic shock. Intracellular infections, such as with
herpes viruses, may turn quiescent vascular endothelial
cells into TF-expressing procoagulant cells.
Induction of TF and Onset of DIC
The onset of DIC is dependent on TF, and its blockade
obtained by different means, including monoclonal
antibodies, and the tissue factor pathway inhibitor (TFPI)
diminishes DIC, it may have additional anti-
inflammatory effects, such as lowering of levels of
IL-6. At the same time, clinical studies with different
inhibitors of the coagulation cascade, including
Pediatric Hematology 845
(activated) protein C and antithrombin have suggested
that direct inhibition of coagulation can, indeed, be
beneficial in reducing morbidity or mortality.
Enhancement of TF-Mediated
Coagulation in DIC
The Level of Tissue Factor Expression: This means that
activation of TF-inducible cells in the circulation
determines the trigger of coagulation. In sepsis, cytokines
may induce circulating leukocytes to generate TF and
activate coagulation. In other conditions, the trigger may
be localized and the response systemic.
The Inhibitory Mechanisms: The progression of DIC
depends on the inhibitory potential of the blood.
Impaired synthesis of inhibitory proteins by the liver may
diminish their plasma concentration. Second, available
inhibitors may be depleted by saturation, with clotting
enzymes being continuously generated. Third, the partly
irreversible enzyme-inhibitor may be proteolytically
inactivated by proteases. The overall result is reduced
concentrations of free inhibitor proteins, such as
antithrombin and proteins C and S. The degree of
reduction of inhibitor proteins, particularly protein C, is
related to a poor clinical outcome in septic patients, and
repletion with supra-physiological concentrations of
these inhibitors may improve the outcome. There is an
important role for TFPI as a coagulation and, probably,
inflammation inhibitor, but its concentration is usually
not reduced in DIC. Other inhibitory mechanisms include
thrombomodulin and sulfated heparan proteoglycans,
which are located at the vascular endothelium.
The Amplification Mechanism: TF with factor VIIa causes
proteolytic conversion of factors IX and X. Generation of
factor Xa induces thrombin formation. Thrombin acts by
feedback activation of factors XI, VIII, and V, thereby
enhancing the thrombin generation rate. Thrombin also
activates platelets and converts fibrinogen to fibrin in a
reaction catalyzed by thrombin-activated factor XIII. The
fibrin clot becomes protected against lysis by thrombin-
mediated activation of a thrombin activable fibrinolytic
inhibitor (TAFI). Local thrombin concentrations and the
inhibitory systems will determine the progression of
fibrin in DIC.
The role of the contact system in the amplification
mechanisms is still uncertain. Activation of the contact
route leads to generation of factor XIa in children with
meningococcal sepsis. In sepsis, the factor XII system may
846 IAP Textbook of Pediatrics
also play an important role in regulating vascular
permeability, as indicated by blocking antibodies and
their protective effect.
Factor XI, interposed between the contact system and
the intrinsic route of coagulation, is activated after
endotoxin infusion in humans.
Direct (non-physiological) Activation
of Coagulation
Factor X and prothrombin may in certain circumstances
be activated directly as occurs with mucin-producing
tumors leading to thromboembolic disease. A number
of venoms can directly activate prothrombin to thrombin.
Plasmin also activates and inactivates factor V and factor
VIII. Both neutrophil and pancreatic elastase activate and
subsequently inactivate factor V and probably factor VIII.
Increased Availability of
Coagulant Active Phospholipid
The phospholipids in the platelet provide a surface for
the assembly of enzymatically active complexes. Similar
phospholipids may be available from erythrocytes, which
are richly endowed with negatively charged
phospholipids on their inner leaflet but these would not
normally be externalized in contrast to the platelet which
undergoes “flip-flop” of its membrane to expose
negatively charged phospholipids following activation.
Hemolysis, e.g. during an incompatible blood transfusion
reaction, makes such lipids available and could lead to
DIC.
Inhibition of Coagulation: Inhibitors of coagulation can be
categorized into:
1. Inhibitors of thrombin generation.
2. Inhibitors of thrombin action.
Inhibitors of Thrombin Generation
The protein C/protein S system, because of its action on
the co-factors V and VIII may regulate the generation of
thrombin via the intrinsic/common pathways. Thus, the
protein C/S system clearly plays a pivotal role in
regulating thrombin generation resulting either from
increased tissue factor availability or contact activation.
α 1-antitryspin and β 2-macroglobulin become more
prominent as overflow inhibitors. Their appearance in
patients with DIC appears to be associated with a poor
prognosis.
The tissue factor pathway inhibitor (TFPI) is another
example of an inhibitor whose activity is promoted by
the availability of the product of the pathway upon which
it acts.
Inhibitors of Thrombin Activity
Plasma levels of antithrombin III, the most important
inhibitor of thrombin, tend to be markedly reduced in
patients with sepsis due to consumption by ongoing
thrombin generation and impaired antithrombin III
synthesis. Low AT III levels in DIC are associated with
higher mortality. In fact, administration of ATIII
concentrates results in improvement of coagulation
abnormalities, amelioration of organ failure and in some
instances, reduction of mortality.
There is downregulation of thrombomodulin
resulting in diminished protein C activity, which
potentially enhances the procoagulant state. Treatment
with activated protein C reduces the coagulopathy. The
anticoagulant capacity of protein C is enhanced by the
free fraction of protein S. Increased plasma levels of
C4bBP, as a consequence of the acute phase reaction in
inflammatory diseases, may result in a relative protein S
deficiency, which contributes to a further procoagulant
state during sepsis.
Tissue factor, the trigger of coagulation is inhibited
by tissue factor pathway inhibitor (TFPI). Administration
of recombinant TFPI to healthy volunteers results in a
complete inhibition of endotoxin-induced thrombin
generation.
Thrombomodulin is involved in the process of protein
C activation. It is needed for thrombin’s procoagulant
effects on fibrin generation and platelet activation to an
anticoagulant effect mediated by protein C activation.
Reduced activity of the reticuloendothelial system (RES): The
reticuloendothelial cell system in general and the liver
in particular is involved in the clearance of activated
clotting factors from the circulation. The conditions
associated with relative RES blockade may exist in a
number of the clinical situations associated with the
development of DIC.
Fibrinolysis: The progression of fibrin formation to the
formation of occlusive fibrin plugs is also determined
by the fibrinolytic system. In DIC, the fibrinolytic protein,
plasminogen, and the tissue and urokinase plasminogen
activators (t-PA and u-PA, respectively) may become
depleted, thereby impairing the potential to form

plasmin. Concentrations of plasminogen activator
inhibitor-1 (PAI-1) may, in contrast, be elevated in septic
patients and related with poor clinical outcome, which
may be partly due to impaired fibrinolytic function.
Cytokines: All systemic inflammatory responses lead to
high levels of cytokines in the circulation. TNF becomes
detectable, and there is an increase in circulating levels
of IL-6 and IL-1.
IL-1 is a potent agonist of tissue factor expression.
TNF exerts potent procoagulant effect and is the first
cytokine to appear in circulation.
IL-6 is now being implicated in the above role and it
has been proved that injection of IL-6 causes generation
of thrombin.
TNF seems to be a principal mediator in the
depression of the protein C system in DIC. It is also
responsible for the PAI-1 induced depression of the
fibrinolytic system.
Anti-inflammatory cytokines, e.g. IL-10 may
modulate the activation of coagulation.
The activation of coagulation seems to be mediated
by IL-6, whereas TNF appears to play a pivotal role in
depression of anti-coagulation mechanism and impaired
fibrinolysis.
It is very clear that, in the majority of cases and
irrespective of the source of the procoagulant stimulus,
the fibrinolytic system is activated in response to the
procoagulant stimulus leading successively to thrombin
generation and fibrin desposition in the intravascular
space. It would seem to be the exception rather than the
rule that hemorrhagic manifestations of this syndrome
occur as a result of primary fibrinolysis. The management
approach is weighed in favor of regulating the
procoagulant activity rather than the fibrinolytic
response. If the clinical situation dictates that the latter
approach should be adopted, this should never be
instituted without concurrent therapy directed at
inhibiting either thrombin generation or activity.
Pathophysiology of DIC and
its Clinical Significance
In most cases of DIC, bleeding is the presenting clinical
symptom, and only limited evidence exists for a direct
relationship between fibrin formation and multiorgan
failure in patients with DIC. Protective effects of
anticoagulant agents, including heparin and hirudin also
Pediatric Hematology 847
support this beneficial effect of coagulation inhibition.
The “crosstalk” between coagulation and inflam-
mation may form the hallmark of the clinical picture of
DIC and is responsible for the occurrence of multiorgan
failure.
The presenting bleeding complications in the course
of DIC can be explained by the combination of
thrombocytopenia, reduced coagulation reserve, and
vascular permeability, while hyperfibrinolysis may
contribute or be a predominant feature, such as in
promyelocytic leukemia. In fact, although bleeding is the
most prominent characteristic of DIC, knowledge of the
basis of this hemorrhagic syndrome is speculative at best.
Systemic and Local Derangement of Coagulation and
Fibrinolysis: It is well known that local effects on
coagulation and fibrinolysis may play an important role
in the occurrence of fibrin deposition and organ failure.
The fibrin deposition in kidneys and adrenals is most
dependent on a decrease in urokinase—type plas-
minogen activator expression.
In the lungs the tissue factor dependent thrombin
generation is insufficiently counter balanced by a reduced
urokinase—dependent bronchoalveolar fibrinolysis
activity, mainly due to high levels of PAI -2.
DIC in the Neonate: Neonatal DIC may be triggered by
infection or hypoxia as an in utero event. The fetus may
be exposed to endotoxins from the mother or the placenta
or to thromboplastin and FDP generated in the placental
circulation or from the maternal circulation or may be
precipitated by hypoxia or hypotension.
Reticuloendothelial system of the spleen and liver
removes the coagulation products. FDP are inhibitors of
both plasma and platelets and they also require the RE
system for their removal. There is evidence that the
neonate is functionally hyposplenic, which delays the
clearance of activators and fibrinogen degradation
products. In addition blood flow is responsible for
transportation of these products from the site of
generation to the RE system and the fibrin inhibits flow
of blood. This is further complicated by the presence of
polycythemia and shock.
AT-III is the main inhibitor of thrombin and the levels
of AT-III in term babies are 30-50 percent of the adults.
But these are in concert with the levels of thrombin in
these children but in sick infants these may be woefully
inadequate.
848 IAP Textbook of Pediatrics
Heparin cofactor II, which is responsible for
neutralization of nearly 30 percent of the thrombin
produced and its levels are also low as compared to the
adults.
β2 macroglobulin is another inhibitor of thrombin and
its levels are at the adult level in the newborn and remain
elevated throughout infancy.
Protein C neutralizes activated Factor V and VIII and
it develops very late in the fetus and one may see levels
as low as 0.1 U/mL in the preterm babies and these levels
may be inadequate for neutralization of activated factors
V and VIII. The levels of protein C inhibitor are at the
adult levels in the newborn at term.
Protein S bound to platelet or endothelial cell
membrane is able to accelerate the APC-mediated
neutralization of Factor Va and VIIIa to the tune of 10,000
times. This protein S is bound in the plasma to binding
protein of the C4b and is unable to participate in the
above reaction but in the neonate almost all the protein
S is in the free form as compared to the adults where
nearly 60 percent are bound, and this is because of the
extremely low levels of C4b-p.
The neutralization of the coagulation proteases occurs
primarily on the endothelial surfaces. The complex of
AT-III with thrombin is catalysed by heparin like
substances, on the other hand the complex of heparin
cofactor-II with thrombin is promoted by dermatin
sulfate. Thrombomodulin accelerates the activation of
protein C by 20,000 times. Placenta is a rich source of
thrombomodulin. Prostacyclin produced by the
endothelial cells inhibits the platelets. Nothing much is
known about the role played by endothelial cells in the
neonates.
In the neonates the levels of plasminogen are about
50 percent of the adult levels and in the preterm baby
they are 30 percent of the adult levels. The protein which
binds the plasminogen is low in the neonate and thus
almost all the plasminogen is in the active form α 2
macroglobulin is at the adult levels and remains so
throughout. Plasminogen activator inhibitor type 1
(PAI-1) are elevated in the cord blood.
Clinical conditions associated with DIC In the neonate:
Bacterial infection esp. septicemia is the most common
entity associated with DIC. Clinically, DIC occurs in
settings of severe hypoxia and acidosis with inadequate
perfusion and tissue necrosis.
• Obstetric complications
— Abruptio placentae
— Placenta accreta
— Chorioamnionitis
— Fetal demise of one twin
— Pre-eclampsia
— Ac. fatty liver of pregnancy
• Neonatal Viral Infections
— Rubella
— Herpes
— Cytomegalovirus
— Enterovirus
• Systemic Candidiasis
• Gram negative organisms
• Hypoxia and hypoperfusion
— Congestive heart failure
— Shock with poor perfusion and lactic acidosis
— Preterm babies with RDS
• Massive thrombosis
• Babies with severe liver disease
• Kasabach-Merritt syndrome
• Placental chorioangiomatous malformations
• Massive hemolysis
• Nonimmune hydrops fetalis
• Severe cold stress
Infections: It represents the single largest at-risk group,
presents as the most florid manifestation of the condition
and is responsible for the high mortality of these
conditions. The Waterhouse-Friderichsen syndrome,
with bleed in the adrenal is one of the most feared
outcomes of this condition, resulting in acute circulatory
collapse. Gram-negative bacteria are more frequently
associated with this complication than gram-positive.
DIC occurs in patients with infections due to specific
cell membrane components of the microorganisms
(lipopolysaccharide or endotoxin) and bacterial exotoxin
(e.g. staphylococcal toxins). All these components result
in a generalized inflammatory response characterized by
the systemic release of cytokines.
The mortality associated with DIC complicating
infection remains high, and its management remains
controversial. It is sobering that although one of the
fundamental principles of treating DIC is to address and
control the primary condition, despite the enormous
advances with regard to the availability of potent and
specific antibodies, the mortality remains high and does
not appear to have shown substantial improvement over
the years.
Trauma: Severe trauma leading to release of tissue
material into the circulation (fat and phospholipids),

hemolysis and endothelial damage may lead to systemic
activation of coagulation leading to DIC.
Tumors: Factors expressed on the surface of the tumor
cells may be responsible for DIC in cases of both solid
and hematologic malignancies, e.g. in APML there is a
severe hyperfibrinolytic state in addition to an activated
coagulation system.
Obstetric Accidents: The presentation may vary from the
acute fulminating and devastating hemorrhage asso-
ciated with amniotic fluid embolism to the more chronic
presentation associated with the dead fetus syndrome.
Placental abruption and amniotic fluid embolic may also cause
DIC: Vascular disorders like aortic aneurysms or giant
hemangiomas (Kasabach-Merritt syndrome) or chorio-
angiomatous malformations may result in local activation
of coagulation. Activated coagulation factors can
ultimately overflow into the systemic circulation and
cause DIC, but more commonly, systemic coagulation
factors and platelets become depleted as a result of local
consumption.
Incidence and Clinical Relevance of DIC Frequency: In the
US: Approximately 18,000 cases of DIC occurred in 1994.
DIC may occur in 30 to 50 percent of patients with sepsis.
Mortality/Morbidity: Morbidity and mortality depend on
both the underlying disease and the severity of coagulo-
pathy. Assigning a numerical figure for DIC-specific
morbidity and mortality is difficult. Following are
examples of mortality rates in diseases complicated by
DIC:
• Idiopathic purpura fulminans associated with DIC
has a mortality rate of 18 percent.
• Septic abortion with clostridial infection and shock
associated with severe DIC has a mortality rate of 50
percent.
• In the setting of major trauma, the presence of DIC
approximately doubles the mortality rate.
Due to the ambiguity of the definition and the lack of
clear-cut diagnostic criteria the incidence of DIC cannot
be evaluated. In virtually all patients with gram-negative
septicemia diffuse activation of coagulation is detectable
with sensitive assays of coagulation factor activation
clinically, overt, DIC, however with a decrease in platelet
count, consumption of coagulation factors detectable
soluble fibrin and fibrin degradation products can be
found in 30 to 50 percent of consecutive series of patients.
In fact, clinically overt DIC is as common in Gram
Pediatric Hematology 849
septicemia as in Gram negative septicemia.
Severe trauma with inflammatory response was
associated with DIC in 50 to 70 percent of cases. This is
closely related to the disease severity scores.
Giant hemangiomas are associated with clinically
significant DIC in upto 25 percent cases.
The findings in DIC are dependent on the rate and
amount of thrombin generated as well as the body’s
capacity to remove the activated products of coagulation,
the capacity of the inhibitory proteins to neutralize
coagulation enzymes, the activation of fibrinolysis to
remove the intravascular fibrin strands and the rate of
production of the platelets and clotting factors.
The clinical importance of severe depletion of
platelets and coagulation factors in patients with diffuse,
widespread bleeding or in patients who need to undergo
an invasive procedure is indisputable, but to what extent,
intravascular deposition of fibrin, due to systemic
activation of coagulation, contributes to organ failure and
mortality is not certain.
CLINICAL PRESENTATION
Disseminated intravascular coagulation is an inter-
mediary mechanism of disease an epiphenomenon and
as such the signs and symptoms will also depend on the
antecedent disease. There is a strong association with
infection which accounts for 70 percent of the cases
diagnosed in the neonates. The clinical presentation may
vary in relationship to the primary condition.
Physical
• Circulation
— Signs of spontaneous and life-threatening
hemorrhage
— Signs of subacute bleeding
— Signs of diffuse or localized thrombosis
• Central nervous system
— Nonspecific altered consciousness/stupor
— Focal deficits not usually present
• Cardiovascular system
— Hypotension
— Tachycardia
— Circulatory collapse
• Respiratory system
— Pleural friction rub
— Signs of adult respiratory distress syndrome
(ARDS)
850 IAP Textbook of Pediatrics

• Gastrointestinal system 1. Acute or chronic

— Hematemesis 2. Systemic or localized
— Hematochezia 3. The fibrinolytic activity is a primary or secondary
• Genitourinary system manifestation of the condition.
— Signs of azotemia and renal failure The importance of defining the condition as acute
— Hematuria versus chronic relates to the urgency of management
— Oliguria decision-making and is usually a priority in the patient
— Metrorrhagia presenting with laboratory rather than clinical evidence
— Uterine hemorrhage of the condition. Although a significant number of
• Dermatologic system patients with sub-clinical acute DIC will show
— Petechiae spontaneous reversal, it is individuals in this group who
— Purpura may show the most gratifying response to rapid
— Hemorrhagic bullae confirmation of the diagnosis and urgent institution of
— Acral cyanosis therapeutic intervention.
— Skin necrosis of lower limbs (purpura fulminans) DIC may be localized to an organ such as the kidney.
— Localized infarction and gangrene Although laboratory testing may provide systemic
— Wound bleeding and deep subcutaneous evidence of the condition, the pathological effects may
hematomas be confined locally and the therapeutic approach may
be optimally directed to this, e.g. aortic aneurysm and
Thrombosis (Fig. 15.13.1) cavernous hemangiomas. The systemic effects may be
General Considerations profound and some individuals may develop major
evidence of consumption of platelets and coagulation
In evaluating a patient with clinical and laboratory factors and develop life-threatening hemorrhage.
evidence of DIC, a judgment must be made as to whether Activation of the fibrinolytic system occurs leading
the condition is: to the appearance of split products.

LABORATORY EVALUATION
No single laboratory test or combination of tests is
available that is sensitive or specific enough to allow a
definite diagnosis. However, the diagnosis can reliably
be made without ambiguity by taking into consideration
the underlying disease in combination with the
laboratory findings.
Because DIC is a continuously progressing process,
it can be subdivided into three phases that might be
helpful in making the diagnosis and in treating the
patient.

Phase I: Compensated Activation of the

Figure 15.13.1: Child with DIC
Hemostatic System
During this phase, no clinical findings are observed, but
the underlying disease may raise suspicion for the
occurrence of DIC. Under these circumstances, tests
should be performed to demonstrate the activation of
coagulation (Table 15.13.1).

Phase II: Decompensated Activation of the
Hemostatic System
In contrast to phase I, the prothrombin time (PT) and the
activated partial thromboplastin time (aPTT) are
prolonged. Under these circumstances, the thrombin
time may still be normal, as the fibrinogen levels are still
adequate and the level of fibrinogen degradation
products (FDPs) is not very high. In this phase, frequent
analyses are necessary to demonstrate the dynamics of
the intravascular coagulation process. In phase II,
repeated determinations will demonstrate a continuous
drop in platelet count and in fibrinogen concentration
and coagulation factor activities, especially factor V
activity (Table 15.13.1).
TABLE 15.13.1: Phases and laboratory data of acute DIC
Phases
Phase I: Compensated Activation of the Hemostatic System
Clinical findings:
No symptoms
Laboratory analysis:
No measurable consumption of hemostasis components
Increased levels of activation markers
Increased levels of enzyme-inhibitor complexes
Phase II: Decompensated Activation of the Hemostatic System
Clinical findings:
Bleedings from injuries and venous puncture sites, as well as
decreased organ function (e.g. kidneys, lung, liver).
Laboratory analysis:
Continuous decrease in platelet count and coagulation factors
Continuous increase in activation markers
Continuous increase in enzyme-inhibitor complexes
Phase III: Full-blow DIC
Clinical findings:
Skin bleedings of different sizes, as well as multi-organ failure
Laboratory analysis:
Clearly expressed consumption of hemostasis components
PT: Prothrombin time
APTT: Activated partial thromboplastin time
F1+2: Prothrombin fragment F1+2
Pediatric Hematology 851
Phase III: Full-Blown DIC
Full-blown DIC is characterized by an extremely
prolonged, or even unclottable, PT and aPTT. Frequently,
the thrombin time is significantly prolonged or also
unclottable. During this phase, the platelet count is very
low, and the coagulation factor activities are less than 50
percent of normal. The continuous transition from phase
I to phase II or even to phase III is typical for DIC. If, in
the course of DIC, hemolysis and/or schistocytes are
observed, this indicates that microclot formation is
causing red blood cell damage.
For the laboratory evaluation of DIC, it is important
to discriminate between an approach directed at:
Laboratory data
PT, APTT, thrombin time: Within normal limits
Platelet count: Within normal limits; F1+2, TAT: Elevat
Antithrombin: Slightly decreased; Soluble fibrin; +
PT, aPTT: Prolonged or increasing prolongation,
respectively
Thrombin time: Mostly within normal limits,
but sometimes prolonged
Platelet count, fibrinogen concentration, coagulation
factor activities, antithrombin: Decreased or continuously
decreasing; F 1+2, TAT, FDPs: Clearly increased; Soluble
fibrin: Increased fibrin degradation products
PT, aPTT: Extremely prolonged or unclottable
Thrombin time: Very pronounced prolongation or
unclottable. Platelet count: Very diminished (<40% of the
initial value) fibrinogen, antithrombin, and coagulation
factor activities: Very decreased (<50% of the initial values)
F1+2, TAT, FDPs: Clearly increased; soluble fibrin: Increased
TAT: Thrombin-antithrombin complex
FDPs: Fibrin degradation products (including D-dimer)
852 IAP Textbook of Pediatrics
1. Formation of a data base that confirms or improves
our understanding of the pathogenetic factors
involved in DIC.
2. Forming the diagnosis of DIC in an individual patient
with particular reference to the source of the
procoagulant stimulus in a given primary condition.
3. Monitoring the progress/severity of the condition
with particular reference to the response to
therapeutic intervention.
The best approach is to rely on the classical screening
tests, i.e., the activated partial thromboplastin time
(APTT), the prothrombin time (PT), the thrombin time
(TT), platelet count, FDP or D-Dimer and peripheral
blood smear examination. The one stage PTT is a sensitive
indicator of clotting factor deficiency. Thrombocytopenia
is a primary feature of the vast majority of patients with
DIC and in approximately 50 percent the count will be
less than 50 × 109/liter. Given the accuracy and facility
of modern particle counters, this test is one of the most
useful screening tests available except in those patients
with conditions such as leukemia where other factors
may be involved. Classically, the microangiopathic blood
picture and the associated anemia have been considered
hallmarks of the condition. It should be realized,
however, that this is a relatively non-specific finding that
is frequently seen in the primary conditions associated
with the risk of developing DIC, e.g. Kasabach-Merritt
syndrome, vascular protheses, etc. without DIC actually
being present.
It should be emphasized that normal findings do not
exlude a significant consumptive process. For example,
in pregnancy, a normal PTT and TT does not exclude
significant consumption of clotting factors such as factor
VIII and fibrinogen due to the substantial elevation of
these factors during the final stages of normal pregnancy.
Fibrinogen and Fibrinogen
Degradation Products
If the first laboratory analysis is done in phase II of the
disease, fibrinogen concentration, as well as FDP
concentration, should always be determined, in addition
to the screening tests mentioned here. This is important
because elevated FDP titers in combination with
thrombocytopenia and a decrease in clotting factor
activities allow the diagnosis of DIC (Table 15.13.2). An
increased FDP level is almost always seen from the
beginning of DIC when fibrinolysis is activated, whereas
in the advanced course of DIC fibrinolysis may be
exhausted or even inhibited. If, in the beginning of
suspected DIC, FDPs are not elevated, one can reliably
exclude DIC because experience has taught that
activation of fibrinolysis is almost always present in
patients with DIC.
Single Factor Determinations
Plasma Factor Activities, Antithrombin, and Plasminogen
Activity: If, in addition to pathologic screening test results,
the activities of these factors and inhibitors are below 50
percent of normal, acute or high-grade DIC can be
assumed. On examining the relationship between
outcome of DIC patients and hemostasis parameters,
antithrombin activity, protein C levels, plasminogen
activity PAP complexes, and PAI-I activity were related
to outcome.
Indicators of Activation of Coagulation
Activation markers: FPA, F1+2, soluble fibrin, and
thrombin
Anti-thrombin Complexes
The dynamics of DIC can be judged by measuring the
activation markers, such as fibrinopeptide A (FPA),
prothrombin fragment F1+2, and soluble fibrin, although
these tests may not be immediately available in the
routine laboratories. These three markers indicate the
generation of thrombin and the effect of thrombin on
coagulation factors. Because coagulation can take place
extravascularly, such as in pneumonia or periotonitis,
FPA and F1+2 are not specific parameters for the
diagnosis of DIC. In contrast, soluble fibrin in plasma
can only be generated intravascularly and, thus, it
represents a specific test for the diagnosis of
hypercoagulability. A drawback may be that useful FPA,
F1+2 and soluble fibrin measurements are very much
dependent on optimal venous puncture. Relatively easy
to perform is the determination of thrombin-
antithrombin (TAT) complexes which, similarly to the
mentioned activation markers indicate thrombin
generation.
Indicators of Fibrinolysis Activation
Fibrinogen Degradation Products, D-dimer, α 2-antiplasmin,
and Plasmin-Antiplasmin Complexes
FDP is an important parameter to be determined for
making the diagnosis in combination with other assays.

In recent years, it has been shown that D-dimer tests are
more sensitive than the FDP assays and that normal D-
dimer levels have a high negative predictive value for
the presence of intravascular fibrin degradation. Since
fibrinogen is also degraded extravascularly, an elevated
FDP or D-dimer level does not prove intravascular
fibrinolysis. Because FDPs are metabolized by the liver
and secreted by the kidneys. FDP levels are influenced
by liver and kidney function. Different FDP assays,
including D-dimer tests, are commercially available and
measure different subpopulations of FDPs. These assays
are not specific for a certain type of FDP because the
different FDP populations form complexes with each
other and even with soluble fibrin. As extreme hyper-
fibrinolysis does not occur until circulating α 2-anti-
plasmin has been depleted, the determination of α 2-
antiplasmin is helpful for judging the dynamics of
fibrinolysis.
The Disseminated Intravascular
Coagulation Score
A relatively precise, but somewhat tedious, DIC score
was proposed by the Japanese Working Party on DIC in
1988 and published as a modification in 1995. The score
is a compilation of varied points given to changes of the
PT ratio, fibrinogen concentration, FDP concentration,
platelet count and symptoms of bleeding and organ
failure due to microthrombosis.
MANAGEMENT
Acute Disseminated Intravascular Coagulation
As DIC usually complicates other pathologies, it is
important to recognize and institute appropriate
therapeutic measures directed at the primary disease as
well as basic life support consideration such as find and
electrolyte balance, adequate oxygenation, etc.
Fundamental to the management of the complicating
DIC is the implementation of aggressive therapy directed
at forestalling or eradicating the primary pathology as
the source of the procoagulant stimulus. For example,
institution of appropriate antibiotic therapy in specific
infections may bring about a spontaneous reversal of the
DIC process without additional therapy directed at DIC
itself.
Removal of the products of conception in obsteric
accidents. In those patients where the primary pathology
is not so amenable to correction or where DIC continues
Pediatric Hematology 853
despite therapeutic measures directed at the DIC itself
will be required. The overall approach is to restrain and
eventually eliminate thrombin generation and replace
blood components whose deficiency might either
promote the hemorrhagic tendency or diminish the
physiological anticoagulant response in endogenously
regulating thrombin generation.
Replacement of factors V and VIII and fibrinogen
using fresh frozen plasma or cryoprecipitate is
clearly essential in the acutely bleeding patient with
evidence of major consumption of these factors but this
may ‘stoke the fire’ inferring that the hypocoagulable
state induced by DIC protects the individual from further
thrombin generation but this view is untenable.
Currently, opinion rests between either replacement as
the primary approach or replacement after initiating
anticoagulant therapy. In the latter, anticoagulation is
instituted only in those patients where replacement alone
may be predictably inadequate or proves to be so as the
condition progresses. This may occur in association with
any of the known primary disease conditions where the
severity and rate of consumption is so great that it
becomes physically impossible to keep pace with
replacement, e.g. amniotic fluid embolism are classic
examples of this situation. Thus, heparinization is
reserved for selected patients esp. in those condi-
tions where the thrombotic tendency appears to
predominate, such as purpura fulminans, the use of
heparin may be life-saving. This observation together
with the association of this condition with homozygous
deficiency of protein C system and suggests that the use
of protein C concentrates may assume a significant role
in the management of these conditions in the future.
Moreover, although optimal replacement would not be
achieved with the use of fresh frozen plasma alone, some
degree of replacement would be achieved which could
explain why, supplementation of replacement therapy
by heparin is not always necessary despite theoretical
predictions to the contrary.
The overall goal of therapy is to remove the source of
the procoagulant stimulus. There is potential for
controlling the coagulant response by the use of
therapeutic concentrates of physiological inhibitors such
as protein C and tissue factors pathway inhibitor (TFPI).
Furthermore, as our knowledge of the basic mechanisms
of hemostasis improves and with better supportive care
occurring in the intensive care setting, infection control,
etc. more and more patients are likely to be saved.
854 IAP Textbook of Pediatrics
Unfortunately, the comments that the letters ‘DIC’ could
be taken as standing for ‘Death Is Coming’ is not an
unreasonable reminder of the progress that remains to
be made in our understanding and management of this
not uncommon condition.
Drotrecogin alfa (Activated Protein C) has been used
in adults with a marked reduction in mortality. The dose
used is 24 microgms/kg/hr for 96 hr continuous
intravenous infusion and is provided as 5 mg and 20 mg
vials and concentration should be 100 to 200 mg/mL.
Chronic Disseminated Intravascular Coagulation
and Primary Fibrinolysis
This condition is rarely if ever seen in the neonatal and
the pediatric period.
CONCLUSIONS
Disseminated intravascular coagulation (DIC) is not a
clinical entity in itself. Instead, it always occurs secondary
to a broad spectrum of various diseases. DIC may be
defined as an acquired syndrome characterized by the
activation of intravascular coagulation up to
intravascular fibrin formation. The generation of soluble
fibrin in plasma is the prerequisite for microclot
formation, which contributes to multiple organ failure.
15.14 Bleeding Disorders in the Newborn
Bleeding is a frequently encountered medical emergency
in the newborn. Newborn babies, especially those who
are low birth weight or premature are particularly at risk
for bleeding due to immaturity of a number of
components of the hemostatic system.
Causes of Bleeding in the Newborn
I. Deficiency of vitamin K dependent clotting factors
A. Hemorrhagic disease of the newborn (HDN) now
more appropriately termed "vitamin K deficiency
bleeding (VKDB)" occurs due to a transient
deficiency of the vitamin K dependent factors II,
VII, IX, X. Vitamin K is necessary for conferring
The massive and ongoing activation of coagulation may
result in the depletion of platelets and coagulation factors.
Activation of the fibrinolytic system may cause
proteolysis of plasmatic coagulation factors, as well as
generation of FDPs inhibiting fibrin polymerization and
platelet aggregation. Thus, intravascular coagulation, as
well as hyperfibrinolysis, result in a hemorrhagic
diathesis (consumption coagulopathy).
The diagnosis of DIC is based on the presence of an
underlying disease and a combination of laboratory tests
that indicate activation of the coagulation system, soluble
fibrin formation, and consumption of platelets and
coagulation factors. At present, no single laboratory test
is available to definitively assess the presence or absence
of DIC, but the combination of clinical findings and
laboratory analysis allows one to make the diagnosis and
differentiate three phases of DIC:
Phase II-decompensated activation of the hemostatic
system;
Phase III-full-blown DIC. There is a need to have a
test available which specifically and quantitatively
measures soluble fibrin, as the demonstration of soluble
fibrin in plasma early in the disease process would allow
prophylactic treatment of the patients in order to prevent
microclot formation and bleeding complications.
Jayashree A Mondkar,
Mamta Manglani, Armida Fernandez
biological coagulant activity on these factors.
Though colostrum contains adequate amount of
vitamin K, lesser colonization by bacterial flora
of the gut of exclusively breastfed infants that are
necessary for synthesizing vitamin K, contributes
to a lower plasma level of vitamin K. Lower
concentration of vitamin K in breast milk also
further contributes to VKDB. Bleeding classically
occurs between day 2-7, in a well baby. Presenting
features include hematemesis, hemtochezia,
hematuria or hematoma at the site of trauma.
B. Early onset (<24 hours) and late onset VKDB>2
weeks) are also known to occur in certain
predisposed babies.

Maternal anticonvulsant therapy with phenytoin or
phenobarbitone, anticoagulant therapy with warfarin can
aggravate VKDB and can cause an early onset of
bleeding, an entity known as early VKDB or early HDN.
A rare late form also occurs in breastfed infants after
the 1st 2 weeks of life, especially if prolonged antibiotics
have been used. It is also seen in babies with prolonged/
recurrent diarrhea.
II. Inherited factor deficiencies
Afibrinogenemia, hypofibrinogenemia, factor VIII, IX
and von Willebrand's disease, factor XIII deficiency and
factor II (prothrombin) deficiency may present in the
neonatal period.
III. Thrombocytopenia
In normal neonates, the platelet count usually is 1.5 to 4
lac/cu.mm. Thrombocytopenia can be confirmed when
platelet count is less than 1 lac/cu.mm, although
spontaneous bleeding seldom occurs until the count
drops to <40,000 cells/cu.mm, unless there are other
confounding factors such as prematurity, sepsis, etc.
A. Neonatal alloimmune thrombocytopenia (NAIT):
This condition is similar to hemolytic disease of
the newborn and results from transplacental
passage of maternal specific IgG antiplatelet
antibodies from a platelet antigen negative,
sensitized mother. Petechiae, GI bleeds, hematuria
and occasionally intracranial hemorrhage (ICH)
may be the presenting features.
B. Autoimmune neonatal thrombocytopenia occurs
in babies due to passive transfer of IgG platelet
autoantibodies from mothers who have idiopathic
thrombocytopenic purpura, systemic lupus
erythematosus, etc.
C. Infections: Congenial viral infection especially
cytomegalovirus and rebella may cause
thrombocytopenia. Spirochetal infections,
toxoplasmosis, bacterial infections especially gram
negative septicemia also produce bleeding due to
thrombocytopenia.
D. Maternal drugs such as anticonvulsants,
antihistaminics, tolbutamide, etc. also cause
thrombocytopenia.
E. Bone marrow infiltration by leukemia, histiocy-
tosis X and metastatic neuroblastomas can also
produce thrombocytopenia.
Pediatric Hematology 855
F. Thrombocytopenia is also associated with
syndromes like thrombocytopenia with absent
radii (TAR).
IV. Platelet functional disorders with normal count can
also cause hemorrhage in the newborn.
A. Glanzmann's thrombasthenia, Storage Pool
Disease and Bernard Soulier Syndrome are some
of the common inherited platelet functional
disorders. These are diagnosed if a direct (non
EDTA) peripheral blood smear shows absence of
platelet clumps with near normal counts. In
Bernard Soulier syndrome, large sized (giant)
platelets are seen on peripheral blood smear.
B. Salicytes, NSAIDs and thiazine diuretics affect
platelet function. Drugs like aspirin, indo-
methacin, and carbenicillin can also cause
acquired platelet dysfunction.
V. Disseminated Intravascular Coagulation
Due to hypoxia, acidosis or placental causes
(chorioangioma), dead twin, abruption placentae, gram
negative sepsis, severe asphyxia, shock renal vein
thrombosis may also present with bleeding in a neonate.
Approach to Diagnosis
Diagnosis can be reached as per the clinical approach in
a bleeding neonate as elucidated in Table 15.14.1A,
followed by specific investigations and their inter-
pretation as shown in Table 15.14.1B.
Investigations
Apt.test : It is carried out to distinguish swallowed
maternal blood from neonatal gastrointestinal bleed.
1 part of vomitus is centrifuged with 5 parts of water for
1 minute at 2000 rpm. 1 ml of 1% NaOH is then added to
4 ml of the supernatant. Resistant pink color of the
solution indicates the presence of fetal blood.
Other Routine Tests
Every neonate who presents with bleeding should
undergo the following tests: platelet count, prothrombin
time (PT), activated partial thromboplastin time (aPTT).
Tests such as bleeding time and clotting time are not
sensitive and do not help in reaching a diagnosis.
856 IAP Textbook of Pediatrics

TABLE 15.14.1A: Clinical approach in a bleeding neonate

Condition Interpretation

I. Maternal History
1. Antenatal infections (TORCHES & HIV) Thrombocytopenia
2. Drug ingestion: Phenytoin, Early onset of VKDB
Phenobarbitone, aspirin, warfarin
3. H/O bleeding in mother: ITP, SLE Thrombocytopenia
II. Family History
Bleeding in other sibling Inherited coagulation, platelet disorder
III. Present History
1. Birth History
Birth asphyxia, acidosis, shock DIC
Day 1 bleeding Early VKDB Afibrinogenemia,
Hypofibrinogenemia
Factor XIII deficiency, DIC
Day 2- Day 6 bleed Classic VKDB
GI bleed, LBW baby.
Not received Vit K
At brith. Exclusive breastfeeding
III. Site of Bleeding
GIT Swallowed maternal blood, VKBD
Mucosa, Skin Thrombocytopenia, trauma, DIC
Umbilicus Factor I, XIII deficiency
Postsurgery, from wound site Inherited clotting factor disorder

TABLE 15.14.1B: Differential diagnosis of bleeding in neonate: Laboratory profile

Platelet count PT aPTT Diagnosis

Sick neonate Decreased Prolonged Prolonged DIC

Decreased Normal Normal Platelet consumption, hypoxia, sepsis,
necrotizing enterocolitis, renal vein thrombosis
Normal Prolonged Prolonged Liver disorder
Well neonate Normal Prolonged Prolonged HDN
Normal Normal Prolonged Herditary clotting factor VIII, IX, XI, XII deficiency
Normal Prolonged Normal F VII deficiency
Decreased Normal Normal Immune thrombocytopenia, occult infection
Normal Normal Normal Bleeding due to local factors trauma, anatomic
abnormalities, qualitative platelet abnormality,
factor XIII deficiency

Other Specific Tests Management

I. Fibrin spilt products with values greater than the
kit specific cut-off indicate DIC. However, D-dimers
are more specific and available today.
II. Qualitative function tests for platelets: Aggregation
with various agonists test the function of platelets.
III. Specific factor assays.
Appropriate management of an infant with a
hemorrhagic disorder is dependent on the correct
identification of the hemostatic defect and replacement
of the component found to be deficient. Platelet
transfusions, coagulation factors in the form of specific
factor concentrates, fresh frozen plasma (FFP), crypreci-

TABLE 15.14.2: Therapy for acquired hemostatic defects in the newborn
Indications Product
Thrombocytopenia Platelet
Concentrate
Coagulopathy Fresh Frozen
(DIC, Liver disease) Plasma
Severe fibrinogen deficiency Cryoprecipitate
pitate, etc. are used depending upon the diagnosis. Table
15.14.2 summarizes the therapies needed in the
management of these disorders.
VKDB: Parenteral vitamin K in the dose of 1 mg is given
initially IV or SC. Intra-muscular route is avoided as
hematomas may form. This dose can be repeated after
6-8 hours, if bleeding continues. Fresh frozen plasma
10-15 cc/kg may be given if severe bleeding occurs. This
may be repeated 12 hourly if necessary. If Hb is less than
13 gm/dl, packed red cells need to be Given. VKDB can
be prevented by administering 1 mg vit K, IM to every
newborn in the labor room.
Bleeding due to inherited deficiency of factor VIII or
IX, is managed by use of factor concentrates. For severe
von Willebrand's disease, vWF containing factor VIII
concentrates should be used. Cryoprecipitate is the best
concentrated source of fibrinogen or factor XIII. For other
factor deficiencies, FFP will transiently raise the factor
levels.
DIC: Treat the underlying cause, i.e. appropriate
antibiotics in sepsis, correction of acidosis, hypoxia.
Replacement therapy may be given with fresh frozen
plasma (FFP) 10-15 cc/kg every 12 hourly. Platelet trans-
fusions may be required if counts are less than 40,000/
cu.mm.
Thrombocytopenia due to Maternal ITP
Antenatal Management
I. High dose immunoglobulins may be of some use as
they cross the placenta after 32 weeks gestation.
(Prednisolone: 10-20 mg/day, two weeks prior to
delivery may be given.
II. Intrapartum fetal platelet count from scalp vein may
be done and delivery by cesarean section is done if
Pediatric Hematology 857
Dosage
1 pack/5kg will raise platelet
count by 75-100 x 103/cu.mm
10-15 ml/kg will raise factor
level by 10-15 units/kg.
1 pack/3 kg will raise
fibrinogen level to > 60 mg/dl
platelet counts in fetal blood are less than 50,000/
cu.mm.
Post Natal Management of Neonatal Thrombocytopenia
Platlet counts are monitored and infant is treated with
intravenous immunoglobulins. Corticosterioids
may need to be considered if there is poor response to
IVIG.
Isoimmune Thrombocytopenia
Maternal steroids are not helpful. Elective cesarean
section is indicated if fetal scalp platelet counts are less
than 50,000/cu.mm. Intravenous immunoglobulins have
been tried. In severe cases, with platelet count below
30,000, washed and preferably irradiated maternal
platelets or platelets from other known specific platelet
antigen negative donors is indicated. In infants with
platelet counts between 30,000 to 50,000/cu. mm,
intravenous IgG in a dose of 1 gm/kg/day for two
consecutive days may be used.
BIBLIOGRAPHY
1. Al Mofada S M, Osman M, Kides E, et al. Risk of throm-
bocytopenia in the infants of mothers with idiopathic
thrombocytopenia. Am Perinatol 1994;11:423-26.
2. Ballin A, Andrew M, Ling E, et al. High-dose intravenous
gammaglobulin therapy for neonatal autoimmune
thrombocytopenia. J Pediatr 1988;112:789-92.
3. Bauer K. Rare hereditary coagulation factor abnor-
malities. In: Nathan DG, Orkin SH, Ginsburg D, Eds.
Hematology of infancy and childhood. WB Saunders,
2003;1577-96.
4. Blanchette VS, Johnson J, Rand M. the management of
alloimmune neonatal thrombocytopenia. Baillieres Best
Pract Res Clin Haematol 2000;13:365-90.
5. Bussel JB: Alloimmune thrombocytopenia in the fetus
and newborn. Semin
858 IAP Textbook of Pediatrics

6. Montgomery RR, Gill JC, Scott JP. Hemophilia and von
Willebrand’s disease. In: Nathan DG, Orkin SH,
Ginsburg D, Eds. Hematology of infancy and childhood.
Philadelphia: Hematology of infancy and childhood
Philadelphia: WB Saunders, 2003;1547-76.
7. Poncz M. Inherited platelet disorders. In: Nathan DG,
Orkin SH, Ginsburg D, Eds. Hematology of infancy and
childhood. Philadelphia: WB Saunders, 2003;1527-46.
8. Thromb Hemost 2001;27:245-52.
9. Turner T. Treatment of premature infants with abnormal
clothing parameters, Br J Hematol 1981;47:65.

15.15 Hematopoietic Growth Factors

Purvish M Parikh, MR Lokeshwar

Hematopoiesis is a complex process with a simple

underlying concept. A finite population of self-renewing
pleuripotent stem cells in the bone marrow generate the
entire spectrum of mature blood cells [erythrocytes,
platelets, granulocytes (neurophils, eosinophils, baso-
phils), monocytes/macrophages and lymphocytes]. This
production of 3.5 × 1011 cells/day under the control of a
variety of hematopoietic growth factors which intricately
regulate the process of hematopoiesis.
Hematopoietic growth factors are glycoproteins that
promote growth and differentiation of blood cells by
activating specific receptors expressed on the surface of
blood progenitor cells (Fig. 15.15.1).
Figure 15.15.1: Hematopoietic growth factors and
cell lineages
HEMATOPOIETIC FACTOR STIMULATING
RBC PRODUCTION
Darbepoietin alfa (anaresp; also called novel
Erythropoietin erythropoiesis stimulating protein) is a new long-acting
erythropoietin, with a half-life 3 times longer than the
Erythropoietin, a glycoprotein produced primarily by the
old epoetins. Its recommended dose is 0.25 to 1.5
kidney regulates production of red blood cells. It acts
through EPO receptor (EPO-R). The gene for EPO is on microgram/kg once a week (suggested conversion index:
weekly erythropoietin dose/200 = weekly darbepoietin
chromosome 7(pter-q-22) and the gene for EPO-R is on
dose) making it a very convenient administration
chromosome 19(p). EPO stimulates proliferation of
mature brust-forming units erythroid (BFU-E) and schedule. Hypertension is the only major side effect
reported.
colony forming units erythroid (CFU-E). EPO leads to
increase in DNA synthesis in BFU-E and increase in Hb
Use of Erythropoietin
synthesis in CFU-E. EPO also maintains viability of CFU-
E and allows them to bypass apoptosis. The normal 1. Chronic renal insufficiency: The anemia of chronic
human serum erythropoietin level is 5 to 32 m U/ml. renal failure is caused primarily by a deficiency of
Recombinant human erythropoietin (rHuEPO) for EPO. 50 to 150 units/kg subcutaneously three times
clinical use is available as erythropoietin alpha (epoetin a week is the recommended dosage. Iron stores must
alpha) and erythropoietin beta (epoetin beta). be adequate for optimal response. Shunt thrombosis

and exacerbation of hypertension are important side
effects of rHuEPO in this patient population.
2. Zidovudine-induced anemia: Zidovudine (AZT)
causes direct bone marrow suppression and also
inhibits heme synthesis. The recommended dose is
100 U/kg thrice in a week for 8 weeks.
3. Anemia in cancer patients receiving chemotherapy:
HuEPO is useful in reducing transfusion require-
ments and maintaining hematocrit in patients with
multiple myeloma and those treated with cisplatin.
4. Anemia of prematurity: This is due to inadequate
EPO production by immature kidneys. rHuEPO (with
iron supplementation to all patients) in 241 such
patients showed that EPO group required less
transfusion (0.87 vs 0.25; p = 0.013). No transfusions
were required in 27.4% cases as compared to 4.1
percent of control group (p = 0.008). However, it may
take as much as 10 to 12 days before the Hb levels
start increasing. Hence high risk premature neonates
must be started on EPO as soon as possible.
5. Bone marrow transplantation: rHuEPO has been
shown to be of help in reducing transfusion require-
ments in autologous marrow transplantation.
6. Preoperative autologous donation: rHuEPO has been
used to stimulate hematopoiesis and increase the
volume of blood collected during autologous
donations. In the preoperative period its uses include
(i) in patients who are anemic and alloimmunized
where we might be unable to meet anticipated needs
(ii) to correct anemia in patients who refuse blood
transfusion (for religious reasons) and also to prevent
anemia in bone marrow donors who should not be
exposed to the risk of sensitization by allogenic blood.
7. Sickle cell anemia and thalassemia: Recombinant
human erythropoietin has been shown to increase the
production of fetal hemoglobin (HbF). This may be
of benefit in reducing sickling attacks and crises. In
thalassemia intermedia, increase in Hb has been
documented.
8. Myelodysplastic syndromes.
9. Other disorders: Anemia of chronic disease (like in
rheumatoid arthritis) has been successfully treated
with rHuEPO since these patients have elevated levels
of various cytokine (IFN gamma, TNF alpha, Il-1) that
prevent increase in EPO following hypoxic
stimulation.
Pediatric Hematology 859
HEMATOPOIETIC FACTORS STIMULATING
GRANULOCYTE PRODUCTION
GM-CSF and G-CSF
The gene for GM-CSF is located on the long-arm of
chromosome 5(5q21-32). Genes for IL-3, IL-4, IL-5,
macrophage CSF (M-CSF), C-fms (M-CSF receptor) and
an early growth response gene EGR-1 are also localized
to the long arm of chromosome 5. The GM-CSF gene
codes for a protein of 127 amino acids. The molecular
weight of the purified native human GM-CSF is 18,000-
22,000 daltons. The molecular weight of the recombinant
protein varies from 18,000 to 30,000 daltons. These
differences are due to glycosylation. The gene for G-CSF
is located on chromosome 17(q21-22). The native protein
contains 174 amino acids and has molecular weight of
18 to 22 kilodaltons depending on the extent of
glycosylation.
USES
1. Cancer chemotherapy induced myelosuppression:
They are established agent to hasten neutrophil
recovery post-chemotherapy and also to reduce
potential hematopoietic toxicity after more dose
intensive regimen.
2. Bone marrow transplantation: It is done for acce-
leration of myeloid recovery in autologous bone
marrow transplantation and for treatment of graft
failure.
3. Bone marrow failure syndrome: They have a limited
role in aplastic anemia, myelodysplastic syndromes
and congenital, cyclical, autoimmune and idiopathic
neutropenias.
4. Harvesting normal granulocytes for transfusions.
5. Kostmann’s syndrome: It is a disease characterized
by decreased number of peripheral blood neutrophils
and arrested maturation of myeloid progenitor cells
due to a nonsense mutation in the gene for G-CSF
receptor.
6. Collection of peripheral blood progenitor cells.
7. Ex-vivo expansion of progenitor cells.
8. Infectious diseases.
Stimulation of neutrophil production can enhance the
inflammatory response and lead to a better outcome of
infection community acquired pneumonia, sepsis
syndrome and high risk preterm neonates.
860 IAP Textbook of Pediatrics
The American society of clinical oncology has brought
out guidelines for optimal use of hematopoietic growth
factors (G-CSF). One important indication that is
understated is the potential lifesaving benefit of the use
of G-CSF in neonatal sepsis and premature neonates.
Administration—Dose and Route of
Administration, Side Effects
At the recommended doses of 5 to 10 microgram/kg (or
250 microgram/sq.M) both G-CSF and GM-CSF are well
tolerated. The commonest side effect is bone pain. Others
include skin rashes, lethargy and myalgia. A syndrome
of flushing, hypotension, tachycardia, dyspnea, nausea
and vomiting with arterial oxygen desaturation has been
described after the first injection and was found to be
reversed by oxygen and intravenous fluids. At doses >
20 μg/kg per day. GM-CSF has been associated with
pleural and pericardial effusions, venous thrombosis and
pulmonary embolism.
Hematopoietic Factors Stimulating
Platelet Production
Thrombopoietin is a glycoprotein consisting of 353 amino
acids with a molecular weight of 30 KD. Its gene is located
on chromosome 3q27. Structurally, it has 46 percent
sequence similarity with human erythropoietin. It is
produced in the liver following a fall in the platelet count
– the thrombopoietin levels rising maximally by 8 hours
and peaks at 24 hours. Circulating levels of
thrombopoietin are inversely related to platelet mass.
Platelets contain an avid thrombopoietin receptor that
efficiently binds and removes thrombopoietin from
circulation. Thus normal or elevated levels of platelets
inhibit the action of TPO on bone marrow by binding to
circulating TPO. It is important to remember that:
1. Platelet transfusions may blunt the recovery of
megakaryocytes
2. Other cytokines or disorders may modify the
constitutive hepatic production of thrombopoietin,
similar to reduced erythropoietin levels in renal
disease
3. Small molecules could be developed to decrease the
platelet’s clearance of thrombopoietin and in turn
stimulate platelet production
4. Disease related abnormalities in the platelet’s ability
to clear thrombopoietin may alter thrombopoietin
levels. For example, diminished clearance of
thrombopoietin by abnormal platelets may account
for the elevated platelet counts seen in myelo-
proliferative syndromes such as essential
thrombocythemia.
5. In conditions associated with marrow failure (e.g.
aplastic anemia), thrombopoietin levels are high
whereas in ITP thrombopoietin levels are low. Thus
TPO levels may be used for the differentiation of
thrombocytopenia due to bone marrow failure or
increased destruction.
Among the various hematopoietic growth factors,
thrombopoietin has got the longest half-life, i.e. 30 hours.
The platelet count begins to increase 3 to 5 days after
starting therapy. This is because thrombopoietin acts by
stimulating the production and maturation of
megakaryocytes.
Potential Clinical Uses of Thrombopoietin
1. Chemotherapy of solid tumors: Both rhTPO and
MDGF are effective in attenuating both the degree
and duration of thrombocytopenia.
2. Bone marrow transplantation:
3. Chemotherapy of acute leukemias: As severe
thrombocytopenia is routinely observed after
induction therapy of AML, TPO might be beneficial
in this setting.
4. Radiation therapy
5. Aplastic anemia and other bone marrow failure states
6. ITP and thrombocytopenia of HIV
7. Harvesting peripheral blood progenitor cells
8. Platelet apheresis (with a single dose of 3 μg per
kilogram of body weight, the circulating platelet
count and yield increases by two to three times).
In addition to thrombopoietin, several other
recombinant cytokines (including interleukin-1, inter-
leukin-3, interleukin-6, interleukin-11, granulocyte-
macrophage colony-stimulating factor, steel factor (SCF),
PIXY-321 and promegapoietin (interleukin-3-
thrombopoietin fusion protein) have some stimulatory
effects megakaryocytic cells. However, majority of these
cytokines have not had beneficial effects on platelet
recovery after myelosuppressive therapy or have had
serious side effects. Only interleukin-11 is approved by
FDA for chemotherapy induced thrombocytopenia. IL-
11(oprelvekin) is available as Neumega and its dose is
50 mg/kg/day for 10-14 days.

BIBLIOGRAPHY
1. Allen RC, Stevens PR, Price TH, Chatta GS, Dale DC. In
vivo effects of recombinant human granulocyte colony-
stimulating factor on neutrophil oxidative functions in
normal human volunteers. J Infect Dis 1997;175:1184-92.
2. Auerbach M, Ballard H, Trout JR, McIlwain M, Ackerman
A, Bahrain H, et al. Intravenous iron optimizes the
response to recombinant human erythropoietin in cancer
patients with chemotherapy-related anemia: a multi-
center, open-label, randomized trial. J Clin Oncol.
2004;22(7):1301-7.
3. Chatta GS, Price TH, Allen RC, Dale DC. Effects of in
vivo recombinant methionyl human granulocyte colony-
stimulating factor on the neutrophil response and
peripheral blood colony-forming cells in healthy young
and elderly adult volunteers. Blood 1994;84:2823-29.
4. Dale DC, Liles WC, Llewellyn C, Price TH. Effects of
granulocyte-macrophage colony-stimulating factor
(GM-CSF) on neutrophil kinetics and functions in normal
human volunteers. Am J Hematol 1998;57:7-15.
5. De Palo T, Giordano M, Palumbo F, Bellantuono R,
Messina G, Colella V, et al. Clinical experience with
darbepoietin alfa (NESP) in children undergoing
hemodialysis. Pediatr Nephrol. 2004;19(3):337-40.
6. Garcia-Carbonero, Mayordomo JI, Tornamira MV, et al.
Granulocyte colony-stimulating factor in the treatment
of high-risk febrile neutropenia: A multicenter randomi-
zed trial. Journal of the National Cancer Institute
2001;93:31-38.
7. Johnston E, Crawford J, Blackwell S, et al. Randomized,
dose-escalation study of SD/01 compared with daily
filgrastim in patients receiving chemotherapy. Journal
of Clinical Oncology 2000;18:2522-28.
15.16 Transfusion Medicine and Component
Therapy in Pediatrics
RK Marwaha, Sudeshna Mitra, Deepak Bansal
Blood transfusions can be life saving. It is a precious
commodity in India, where the demand frequently
exceeds the amount that is collected. Blood transfusions
are not without risks and should be administered
judiciously, when genuine benefits are expected.
Advances in transfusion therapy have enabled
separation of whole blood into its component parts,
which can be transfused selectively depending on the
need of an individual patient and the underlying
condition. Thus blood component therapy meets specific
Pediatric Hematology 861
8. Kaushansky K. Thrombopoietin. N Engl J Med 1998;339:
746-54.
9. Macdougall LC. Novel erythropoiesis stimulating
protein. Seminars in Nephrology 2000;20:375-81.
10. Molineaux G, Kinstler O, Briddell B, Harelty C, et al. A
new form of filgrastim with sustained duration in vivo
and enhanced ability to mobilize PBPC in both mice and
humans. Exp Hematol 1999;27:1724-34.
11. Ozer H, Armitage JO, Bennett CL, Crawford J, Demetri
GD, Pizzo PA, et al. Update of recommendations for the
use of hematopoietic colony-stimulating factors:
Evidence-based, clinical practice guidelines. J Clin Oncol
2000;18:3558-85.
12. Price TH, Chatta GS, Dale DC. Effect of recombinant
granulocyte colony-stimulating factor on neutrophil
kinetics in normal young and elderly humans. Blood
1996;88:335-40.
13. Quirt I, Micucci S, Moran LA, et al. Erythropoietin in the
management of cancer patients with non-hematologic
malignancies receiving chemotherapy (Practice
Guideline No. 12-1).
14. Rusthoven J, Bramwell V, Stephenson B, et al. Use of
granulocyte colony-stimulating factor (G-CSF) in patients
receiving myelosuppressive chemotherapy for the treat-
ment of cancer. Cancer Prevention and Control
1998;2:179-190.
15. Turner KJ, Neben S, Weich N, Schaub RG, Goldman SJ.
The role of recombinant interleukin 11 in megakaryocyto-
poiesis. Stem Cells. 1996;14(Suppl)1:53-61.
16. Welte K, Gabrilove J, Bronchud MH, Platzer E, Morstyn
G. Filgrastim (r-metHuG-CSF): the first 10 years. Blood
1996;88:1907-29.
requirements and minimizes the risk of transfusion
related complications. The principles of preparations and
use of blood component derivatives are enunciated in
this chapter.
Blood components are prepared from single donations by
conventional blood bank methods (e.g. centrifugation
where blood components are separated due to differ-
ences in their relative densities). They require stringent
storage systems. Blood group compatibility between the
components and the patient is important. In contrast,
862 IAP Textbook of Pediatrics
blood derivatives (e.g. factor concentrates) are prepared
from large pools of donor plasma by fractionation and
purification. They have more lenient storage require-
ments and are administered without regard to ABO
compatibility. More and more blood banks are now able
to provide small volume transfusion products for
children and neonates (e.g. pentavalent transfer bags)
with minimal wastage of blood inventory.
Blood Components and their Preparation
Whole blood is made up of cellular elements and plasma
which is further composed of protein, salts and water.
The cells are separated out from whole blood and from
one another by centrifugation techniques as depicted in
Figure 15.16.1.
Apheresis is a specialized procedure which removes
whole blood from the donor and separates it into
component parts by centrifugation (Figure 15.16.2). The
desired component is harvested and remainder returned
to the donor. The procedure allows selective collection
of platelets or granulocytes in sufficient amounts from a
single matched and ABO compatible donor.
Figure 15.16.1: Component separation techniques
Whole blood
Whole blood should be used when a patient requires
replacement of both circulatory volume and an increase
in oxygen carrying capacity. The specific indications for
transfusion of whole blood are enumerated in Table
15.16.1.
Previously whole blood was prescribed instead of a
specific blood component, a practice which did not serve
the purpose in most situations. Blood stored for >24 hours
at 2-6º C has few viable platelets and granulocytes. Labile
coagulation factors also decreased with time. Almost 90%
platelets and 40% factor VIII activity are lost within 24
hours at this temperature. This is in addition to the
complications associated with whole blood transfusions
especially after prolonged storage and when massive
transfusions are required. Stored blood contains citrate,
TABLE 15.16.1: Indications for transfusion of whole blood
• Acute massive blood loss (>10ml/kg body weight in <24 hrs.
• Exchange transfusion in neonates (<72 hrs old blood)
• Cardiovascular bypass surgery
• Hyperleucocytosis in leukemia

Figure 15.16.2: Cell separator used for collection of specific
components from whole blood and/or plasmapheresis
TABLE 15.16.2: Complication of massive whole blood
transfusion
• Platelet depletion
• Coagulation factor depletion
• Hypocalcemia; Hyperkalemia
• Hypothermia secondary to transfusion of cold blood
• Acidosis
• Hyperglycemia
• Respiratory distress syndrome
adenine and increasing levels of potassium. Correcting
the hypovolemia with crystalloids/colloids and attaining
the restoration of hemoglobin with packed red cells, is a
more judicious transfusion policy. The potential
problems after massive transfusions are enlisted in Table
15.16.2.
To prevent these complications, it is essential to
replenish labile clotting factors by fresh frozen plasma
(1 unit for each 3 to 5 units of whole blood) and platelets
(6 units of platelet concentrates for each 10 units of whole
blood). During exchange transfusion in neonates and
rarely in older children, whole blood transfusions may
lead to hypocalcemia due to citrate toxicity, which can
be prevented by intravenous administration of calcium
gluconate.
Packed Red Blood Cells
RBC’s, the most frequently transfused blood component,
are given to increase the oxygen carrying capacity of the
blood in anemic patients who do not require restoration
of blood volume.
Pediatric Hematology 863
Preparation
Packed RBC’s are obtained from whole blood by
sedimentation or by heavy spin (i.e. centrifugation at
4000 × g for 5 min) at 4ºC from 1 unit of blood (450 ml)
after expression of about 225- 250 ml of plasma, 1 unit of
packed RBC is obtained with a PCV of approximately
70%. It should be stored at 2-6ºC and has the same shelf
life as whole blood, provided PCV does not exceed 80%.
Removal of plasma decreases the amount of electrolytes
and ammonia, which is beneficial in patients with
incipient CHF, renal failure and hepatic failure.
Moreover, chances of allergic/ anaphylactic reactions
are minimized.
Each 8 ml/ kg of body weight of packed RBC’s in
children and 3ml/ kg of body weight in infants is
expected to raise Hb by 1gm/dl and PCV by 3%.
Indications
Factors, other than the hemoglobin concentration that
must be considered in the decision to transfuse RBC’s
include:
a. Signs, symptoms and functional cardiac capacity.
b. Manifest cardiorespiratory disease.
c. Cause and the anticipated course of the underlying
anemia.
d. Alternative therapies such as iron and recombinant
human erythropoietin (EPO). EPO reduces the need
for RBC transfusion and improves the overall
condition of children with chronic renal failure.
Packed Red Cell Transfusion in Neonates and
Young Infants
Guidelines for transfusing RBCs to neonates are
controversial, and practices vary. Generally, RBC
transfusions are given to maintain hemoglobin at an
optimal level, which would be decided on a case to case
basis. The quantum of RBC transfusion will depend on
the specific neonatal disorder.
Packed Red Cell Transfusion would be Indicated in
Neonates in the Following Situations
a. Hemoglobin <13.0g/dl in neonates <24 hours old.
b. Hemoglobin <13.0g/dl in neonates with severe
respiratory disease.
c. Hemoglobin <13.0g/dl in infants with congenital
heart disease severe enough to cause cyanosis or
congestive heart failure.
864 IAP Textbook of Pediatrics

d. Hemoglobin <10.0g/dl in infants facing major Hb level is observed within days of therapy. Children
surgery. with severe nutritional anemia with incipient or overt
e. Hemoglobin <8.0g/dl in clinically stable neonates manifestations of congestive cardiac failure need RBC
with clinical manifestations of anemia (poor weight transfusion.
gain, tachycardia, tachypnea, recurrent apnoea). 5. Significant preoperative anemia individual approach
f. Replacement of phlebotomy blood losses, milliliter is necessary; most children who do not have
for milliliter not of proven benefit. RBC transfusion cardiorespiratory disease, do not require Hb levels
recommended to maintain hemoglobin at a level of greater than 10g/dl before, during or after surgery.
deemed appropriate for the clinical condition. 6. Postoperative Hb <8g/dl with symptoms or signs of
anemia. Most children can quickly restore normal Hb
Packed Red Blood Cells In Older Children if given oral iron therapy and there should be a
Guidelines for RBC transfusions in older children and compelling reason to administer a postoperative RBC
transfusion to a pediatric patient.
adolescents are similar to those for adults. But
7. Hb <13g/dl in patients with severe pulmonary
transfusions may be given more stringently to children
because normal haemoglobin levels are lower in healthy disease, requiring assisted ventilation.
Children with high counts (>100 × 10 9 /L) and
children than in adults. Moreover, children have greater
superior mediastinal syndrome should not be transfused
ability to compensate for anemia and may be transfused
at lower hemoglobin or hematocrit levels. The most till the general condition is stable.
frequent indications for packed RBC transfusion include
Amount of Transfusion
hematologic disorders like thalassemia, leukemia and
aplastic anemia. The standard transfusion volume is 10 ml/kg. The
1. In hemolytic anemia (e.g. thalassemia) life-long maximum that can be safely administered in one
transfusions are required. RBC transfusions are
initiated when Hb drops to <7g/dl. A hyper-
transfusion regimen, wherein Hb is maintained at
levels in excess of 9-10g/dl is widely practiced.
Leukocyte poor RBCs are recommended to minimize
transfusion reactions and can be attained by using
commercially available filters or by washing RBCs in
normal saline. A leukocyte filter used for
leukodepletion in multiply transfused patients is
shown in Figure 15.16.3.
2. Bone marrow failure syndrome: RBC transfusions are
recommended when Hb is <7 g/dl. They must be
sparingly used in case a bone marrow transplantation
is a feasible therapeutic option.
3. Malignancies: There is agreement that transfusions
are necessary when Hb is <7g/dl. Children with mild
anemia (Hb 9-12 g/dl) with no associated symptoms,
when recovery of counts is imminent, do not require
transfusion support. Transfusion should be given,
even in the absence of symptoms, during or following
an intensive cycle of chemotherapy or during
radiation therapy. Myelosuppression is predictable
in these situations.
4. In nutritional deficiency anemia the decision to
transfuse or not is made on a case to case basis. If the Figure 15.16.3: Bedside leukocyte filter used for leukodepletion
diagnosis is correct, an increase in reticulocyte and in multiply transfused patients to minimize transfusion reactions

transfusion is 15 ml/kg and this too only if the patient is
hemodynamically stable. In severe anemia (hemoglobin
<5 gm/dl), child should receive multiple small
transfusions of 3-5 ml/kg over 3 hours separated by few
hours. The advantage of partial exchange transfusion is
that anemia is corrected rapidly and isovolemically. This
method is advisable when there is CHF.
Leukocyte-poor RBCs
Patients requiring multiple transfusions, (e.g.
thalassemics) are prone to develop antibodies against
antigens on leucocytes and platelets leading to non-
hemolytic febrile reactions. Transfusion of leukocyte-
poor RBCs is recommended to minimize the risk of
transfusion reactions. The various techniques employed
to remove WBCs are as follows:
i. Kentrifugation (at 5000 g for 7 min) followed by
removal of plasma and buffy coat: (approximately
80% WBCs are removed).
ii. Filtration using microaggregate, cotton wool or
polyester filters at the time of transfusion or just
prior to issue from blood bank: (>99% WBCs are
removed).
iii. Washing RBCs in normal saline removes 85% WBCs.
It can be used with at least 5 washings in patients
with anti-IgA antibodies.
iv. Deglycerolizing frozen, thawed RBCs (98% WBCs
are removed). The procedure is, however, more
expensive.
PLATELET TRANSFUSIONS
Preparation
Platelet rich plasma (PRP) must be separated from whole
blood by light spin (2000 g for 3 minutes) at 20-24oC
within 6 hours of collection. The supernatant PRP is
expressed into a transfer bag to be used as such or for
processing to platelet concentrates (PC). PCs are made
by further centrifuging PRP at 5000 g for 5 minutes at
20-24 oC. The supernatant platelet poor plasma is
expressed. About 50 ml of plasma is left with the platelet
button to ensure a pH of >6.2. An alternative approach
involves the collection of single donor platelets by
apheresis using a cell separator. Unlike red blood cells,
platelets are stored at 20-24°C, under constant gentle
agitation to avoid aggregation. Storage is recommended
only for 3-5 days because of risk of bacterial
contamination. Platelet concentrates (PC) are stored at
20- 24º C under constant agitation and have a shelf-life
Pediatric Hematology 865
of 3 to 5 days. Concentrates stored at 2-6ºC do not require
agitation but have a shelf-life of less than 24 hours and
are hemostatically less effective.
One unit PC prepared from 450 ml whole blood
contains at least 5.5 × 1010 platelets in 50 ml plasma.
Indications
The indications for platelet transfusion in children with
quantitative and qualitative platelet disorders are similar
to those for adults, but neonates and infants < 4 months
form a special group and may need platelet support at
even higher platelet counts than indicated for children
and adults.
Besides the absolute platelet count, the underlying
condition giving rise to thrombocytopenia is an
important factor determining the need for platelet
transfusion. Patients with marrow failure (leukemia and
aplastic anemia) require frequent platelet support while
patients with immune thrombocytopenias are never
transfused except in the event of life threatening bleeds
or prior to splenectomy. More vigorous transfusions are
also needed during certain phases of chemotherapy and
during therapy with ATG.
One unit PC prepared from 450 ml whole blood
contains at least 5.5 × 1010 platelets in 50 ml plasma. One
unit PRP has the same amount in 250 ml plasma. One
unit PC harvested by apheresis is equivalent to 5-6 units
prepared manually. This is particularly useful when HLA
matched platelets are required. The guidelines for platelet
transfusions in pediatric practice are outlined in Table
15.16.3.
Studies in patients with thrombocytopenia caused by
poor marrow production indicate that spontaneous
bleeding increases markedly when platelet levels fall to
< 20 × 109 /L, particularly in patients who are ill with
infection, anemia or dysfunction of liver. These
observations form the basis of the 20 × 109 /L cut off
platelet count for patients with bone marrow failure. This
threshold has been challenged by adult studies, and some
favour a platelet transfusion trigger of 5 to 10 × 109 /L
for patients with uncomplicated conditions. However,
in practice, severe thrombocytopenia commonly occurs
in association with fever, antimicrobial therapy, active
bleeding, an invasive procedure, DIC and other
coagulation defects. Platelet counts in oncology and
transplant patients are frequently maintained at 20 × 109
/L or higher. However, prophylactic platelet transfusions
are difficult to implement as the demand for blood
components exceeds the patient requirements.
866 IAP Textbook of Pediatrics
TABLE 15.16.3: Guidelines for pediatric platelet transfusion
Children and Adolescents(platelet count (x109/L)
PLTs <50 and bleeding
PLTs <50 and invasive procedure
PLTs <20 and marrow failure with hemorrhagic risk factors
PLTs <10 and marrow failure without hemorrhagic risk factors
PLTs at any count, but with platelet dysfunction plus bleeding
or invasive procedure
Infants within first 4 months of life
PLTs <100 and bleeding
PLTs <50 and invasive procedure
PLTs <20 and clinically stable
PLTs <100 and clinically unstable
PLTs at any count, but with platelet dysfunction plus bleeding
or invasive procedure
Indications
Qualitative Platelet Disorders (Abnormal platelet
functions)
Qualitative platelet disorders may be inherited or
acquired. The acquired conditions are either reversible
(drugs, uremia, DIC, scurvy) or irreversible
(myelofibrosis/leukemia). In these disorders, minor
bleeds are managed by local measures. Treatment of the
underlying disease usually corrects the bleeding
diathesis. Platelet transfusions may be required before
invasive procedures.
Inherited disorders with platelet dysfunction include:
von Willebrand’s disease, Glanzmann thrombasthenia,
Bernard Soulier disease, Wiskott Aldrich syndrome etc.
Since platelet dysfunction is a long term problem and
repeated transfusions may lead to alloimmunisation and
refractoriness, platelets should be transfused only in
extreme need (if significant bleeding actually occurs).
Prophylactic transfusions are rarely justified, unless an
invasive procedure is planned. In such situations, a
bleeding time twice the upper limit of laboratory normal
may be taken as a rough guide but is poorly predictive
of hemorrhagic risk or need to transfuse platelets. In these
patients, alternative therapies, including desmopressin
acetate, should be considered to avoid platelet
transfusion.
Recommendations for Platelet
Transfusion During Infancy
Multiple pathogenic mechanisms are operative in high
risk neonates including (i) accelerated platelet destruction
due to shortened platelet survival time (ii) increased
platelet associated immunoglobulin G (iii) inadequate
increment of platelet values after PLT transfusion, and
(iv) diminished platelet production, as evidenced by
decreased number of megakaryocyte progenitors and
relatively low levels of thrombopoietin in response to
thrombocytopenia.
Preterm infants, in particular ,exhibit thrombo-
cytopenia commonly. Two firm indications for neonatal
PLT transfusions are to treat hemorrhage that has already
occurred and to prevent hemorrhage from complicating
an invasive procedure. Most neonatologists use a PLT
count <50 × 109 / L as a transfusion trigger in these
circumstances,while some choose to transfuse when
platelet count falls below 100 x 109/L.
The majority agree that it is reasonable to give
platelets to any neonate whose platelet count is <20 ×
109 L. However, there is no documented benefit to
transfusing prophylactic platelets to maintain a
completely normal platelet count even in neonates.
Currently, there are no alternatives to platelet
transfusion to treat thrombocytopenia in neonates.
Recombinant thrombopoietin and Interleukin 11 are
promising agents. However, neither is recommended for
use during infancy and both have potential toxicities. The
present use is only under experimental settings.
It is best to use the ABO and Rh group compatible
platelets. In an emergency situation, platelet concentrates
may be given without regard to the ABO group. This
usually causes no problems unless the platelets are
grossly contaminated with red cells. When long term
platelet support is likely, platelets obtained by apheresis
procedure from HLA compatible donors are
recommended. In such patients use of leucofiltered
platelets reduces the frequency of alloimmunization.
Infusion of one unit of platelet concentrate raises the
platelet count, one hour after transfusion, by 5 - 10 × 109/
L/sqm body surface area. The usual dose of platelets in
a child is 3 to 4 units when the count is < 20 × 109/ L. PCs
are administered with a standard infusion set with 170 –
200 microfilter and are usually given as rapidly as
possible.
Granulocyte Transfusions
Several advances, in particular, the use of recombinant
granulocyte colony stimulating factor (G-CSF) to
stimulate donors – have made it possible to collect
excessively large number of normal neutrophils for
transfusion into neutropenic patients who have life
threatening infections.

Preparation
Granulocyte concentrates can be prepared manually by
harvesting the buffy coat layer from a single unit of blood
or by leucopheresis. As the specific gravity of
granulocytes is very similar to RBCs, separation by
centrifugation is not satisfactory. This yields 0.5 – 0.6 ×
109 granulocytes per unit of whole blood. One such unit
prepared by apheresis contains 1 × 1010 granulocytes, i.e.
an equivalent of 18-20 units of buffy coat. Granulocyte
concentrates can be stored at 20 – 24ºC for 24 hrs. The
product must be ABO compatible with the recipient
because they are frequently contaminated with
significant amounts of red blood cells.
Indications
The use of granulocyte transfusion has remained limited
in clinical practice, largely due to the availability of newer
antibiotics and use of agents like IVIg, G-CSF, other
recombinant cytokines and immune modulating agents.
Infected neutropenic patients usually respond to
antibiotics alone, provided bone marrow function
recovers early in infection.Because children with newly
diagnosed leukemia respond rapidly to induction
chemotherapy, only rarely are they candidates for GTX.In
contrast ,infected children with sustained bone marrow
failure (e.g. malignant neoplasms resistant to treatment,
aplastic anaemia,bone marrow transplantation)may
benefit from the addition of GTX to antibiotic therapy.
The use of GTX for bacterial sepsis that is
unresponsive to antibiotics in patients with severe
neuropenia (<0.5 × 109 / L is supported by most of the
controlled studies).
Guidelines for Transfusing Neutrophils in Children
• Blood neutrophils <0.5 × 109/L and bacterial infection
unresponsive to antibiotics
• Blood neutrophils <0.5 × 109/L and yeast or fungal
infection progressing or appearing during treatment
with antimicrobials.
• Neutrophil dysfunction with bacterial, yeast, fungal
infection unresponsive to antimicrobials.
Guidelines for Transfusing Neutrophils in
Infants <4 months
• Blood neutrophils <3 × 109/L. and fulminant sepsis
during the first week of life
Pediatric Hematology 867
• Blood neutrophils <1 × 109 /L and fulminant sepsis
after first week of life
Plasma Components
Fresh frozen plasma
Preparation
Plasma is separated from single units of whole blood by
heavy spin at 2-6ºC or derived from plasmapheresis. If
frozen within 6-8 hours of collection, it yields fresh frozen
plasma (FPP). The volume from a single donation is about
200 ml.
FFP contains factors II, V,VII,VIII,IX,X and fibrinogen.
It should be thawed in a water bath at 37ºC and
administered within half-an hour after thawing as the
activity of factors V and VIII are rapidly lost. FFP has a
shelf life of 1 year if kept at –30ºC or below.
Indications
FFP transfusions are indicated in the following situations:
i. Replacement of coagulation factors in liver disease,
deficiency of vitamin K dependent factors (II, VII,
IX, X), DIC, overdose of oral anticoagulants,
cardiopulmonary bypass, massive blood trans-
fusions; ii) Specific deficiencies of factors V, XIII, XI.
iii) Replacement of hemostatic factors when specific
concentrate preparations are not available, e.g.
hemophilia A and B; deficiencies of VII, X,
fibrinogen and prothrombin; von Willebrand‘s
disease; antithrombin III deficiencies; and iv) in
sitiuations where certain plasma constituents are
lacking e.g. fibronectin in septicemia, C1 esterase in
hereditary angioneurotic edema, and PGI2 inducing
activity in thrombotic thrombocytopenic purpura.
The volume and frequency of FFP transfusions
would depend upon the indication and the
assessment of an individual patient. Usually a dose
of 10-15 ml/kg body weight is recommended at a
flow rate not exceeding 10 ml/min.
TABLE 15.16.4: Patients at risk of transfusion induced GVHD
• Bone marrow transplant recipients
• Recipients of cellular blood products from 1st degree
relatives
• Neonatal exchange transfusion, especially after intrauterine
transfusion
• Children with immunodeficiency
868 IAP Textbook of Pediatrics
Cryoprecipitate
Preparation
Cryoprecipitate is prepared by rapid low temperature
freezing at -70ºC of freshly separated plasma (within 6-8
hours of collection) with subsequent rapid thawing at
2-6ºC and centrifugation using heavy spin for 7 minutes.
10-15 ml plasma is left with the cryoprecipitate in the
primary bag. Cryo-poor plasma is expressed in the
second satellite bag. Cryoprecipitate is stored at -30ºC or
lower for 12 months. It contains factors V, VIII,
fibrinogen, XIII and fibronectin. One unit of
cryoprecipitate of 10- 20 ml usually contains 80 – 120 IU
of factor VIII and 250 to 300 mg of fibrinogen.
Indications
Cryoprecpitate is used in moderate and severe
hemophilia A in the absence of factor VIII concentrates
and is the product of choice in : i) von Willebrand’s
disease and mild hemophilia A; ii) Dysfibrinogenemia,
hypofibrinogenemia and consumptive coagulopathies;
iii) Intractable bleeding in uremia and platelet storage
pool disease and iv) Congenital factor XIII deficiency. It
may also be of benefit in patients with septicemia or burns
because of the fibronectin content. Occasionally, it is used
for correcting factor VIII deficiency caused by massive
transfusion.
Cryopoor Plasma, Liquid Plasma,
Single Donor Plasma
Preparation
FFP from which cryoprecipitate has been removed is
called cryopoor plasma. Plasma in a unit of whole blood
can be separated at any time during storage upto 5 days
after the expiration date of whole blood. If this plasma is
stored at < – 18oC it is called single donor plasma and
can be stored upto 5 years after date of collection. If not
frozen, it is called liquid plasma which is stored at 2-6oC
and can be transfused upto 5 days after expiration date.
FFP which has exceeded a shelf-life of one year is
subsequently called single donor plasma.
Indications
These products have normal amounts of factors II, VII,
IX and X and can be used in patients requiring warfarin
reversal or liver disease. In resource constrained
situations, where patients cannot afford albumin
concentrates, these products can be given.
Specific Factor Concentrates
Specific factor concentrates include antihemophilic factor
concentrate (AHF, factor VIII) and prothrombin complex.
Both are prepared by fractionation of large pools of
plasma. They can be stored at 6-8º C for 2 years.
Intermediate purity factor VIII concentrates contain
15-20 IU/ ml. It is the product of choice for moderate
and severe hemophilia A.
Prothrombin complex when reconstituted contains
30-100 IU/ml of all factors in it. Heparin and/or ATIII
are added to some products to prevent coagulant activity.
It is recommended for replacement therapy in
hemophilia B (factor IX deficiency) but may also be used
for congenital or acquired deficiency of factors II, VII or
X, and bleeding in hemophiliacs with antibodies against
factor VIII. The dose and frequency of administration of
these products would need to be tailored to the severity
of bleeding manifestations in an individual patient.
Concentrates of fibrinogen, XIII and XI have been
used in the past but are no longer recommended because
of the safety, availability and efficacy of cryoprecipitate
and FFP.
Antithrombin III concentrates are used for treating
thrombotic episodes in patients with congenital AT III
deficiency in a dose of 50 units/kg body weight. Anti-
inhibitor complexes have been designed for use in
patients with inhibitors to factor VIII. These activated
procoagulant and coagulant mixtures bypass
requirement of factor VIII in patients who have
developed inhibitors to the same.
In addition to plasma derived factor concentrates,
high purity FVIII concentrates prepared by recombinant
technology are available, though these are more
expensive as compared to the former.
Albumin
Albumin preparations are available in concentrations of
5% (called plasma protein fraction or PPF) and 20% PPF
has 90% albumin, the rest being α and β- globulins.
It may be used to replace plasma proteins in : i) Burns;
ii) Extensive surgery; and iii) Hemorrhagic shock while
awaiting blood (crystalloid solutions are as effective). The
main indication for use of 20% albumin solution is severe
hypoproteinemia in nephrotic syndrome associated with
massive anasarca, the dose being 0.5 to 1g/kg.
Diuretics are essential when edema is present because
every 10 ml of 20% albumin draws 35 ml of extravascular
fluid into the circulation within 15 minutes of
administration.
 Pediatric Hematology 869

Normal and Specific Immunoglobulins (Ig) Autologous Blood Transfusion

Normal Immunoglobulins (Ig) are obtained by
fractionation of plasma whilst specific Ig are separated
from plasma from donors who possess a high titre of
specific antibodies. The indications for use are:
i) Prevention and treatment of diseases such as hepatitis,
rubella, varicella-zoster, tetanus, measles, rabies, etc;
ii) Replacement therapy, antibody deficiency syndrome;
iii) Treatment of immune disorders such as immune
thrombocytopenic purpura; iv) Prevention of
sensitization in Rh (D) Negative women by administering
anti-D immunoglobulin; v) Prophylaxis and treatment
of neonatal sepsis and vi) Kawasaki disease.
Irradiated Blood Components
Cellular blood components need to be irradiated to
prevent transfusion-associated graft vs host disease in
immunocompromised patients (Table 15.16.4). The
recommended dose of gamma radiation is 25 Gy to the
central portion of the unit and at least 15 Gy at the
periphery. Irradiation destroys viable lymphocytes. The
shelf-life of platelets remains unchanged, but red cells
expire 28 days after irradiation or at the end of storage
period, whichever is earlier. Irradiated blood is
recommended for intrauterine transfusions and for
patients undergoing hematopoietic stem cell
transplantation or those receiving donor units from first
degree relatives.
It is the transfusion of blood into its own donor. Such
transfusions are used primarily in patients undergoing
elective surgical procedures. Blood is collected by
bleeding the patient on several occasions pre-operatively.
The Hb should be >11 gm/dl before collection of each
unit and the patient is administered iron supplements.
Units of blood thus obtained are stored and used in the
donor when required. Advantage gained is the avoidance
of blood of any other person, thus eliminating risk of
transmission of infections. In children volume of blood
and anticoagulant is to be adjusted to body weight.
Hazards of Blood Transfusion
Adverse reactions to blood transfusion can be subdivided
according to whether they are immediate or delayed and
whether they are immunologically mediated. Table
15.16.5 outlines the adverse effects of transfusion. Acute
hemolytic reaction is the dreaded complication of blood
transfusion, one of the common causes being clerical
errors of mislabeling, resulting in the infusion of the
wrong patient’s blood. Signs and symptoms include fever
with chills, back and chest pain, flushing, nausea and
dark urine due to hemoglobinuria. These can progress
to shock with acute renal failure. Management of acute
hemolytic transfusion reaction is outlined in Table
15.16.6.

TABLE 15.16.5: Adverse effects of transfusion

Types of reactions Usual cause

Immunologic
Hemolysis with symptoms Red cell incompatibility
Anaphylaxis Antibody to IgA in donor
Febrile, nonhemolytic Antibody to donor leukocyte antigens
Urticaria Antibody to donor plasma proteins
Noncardiogenic pulmonary edema Donor antibody to leukocytes of patient
Graft versus host disease Functional lymphocytes in blood
Non-immunologic
Congestive heart failure Volume overload
Fever with shock Bacterial contamination
Hypothermia Rapid infusion of cold blood
Hemolysis without symptoms Physical or chemical destruction of blood (e.g. freezing)
Air embolus Air infusion in line
Hyperkalemia Rapid infusion of multiple units of stored blood
Hypocalcemia Massive transfusion of citrated blood
Disease transmission HIV, Hepatitis C, B,cytomegalovirus, malaria, syphilis
Iron overload Multiple transfusions in chronically anemic patients without blood loss
870 IAP Textbook of Pediatrics

Future Perspectives in Transfusion Medicine: of transmission during the window period cannot be
Blood Substitutes completely eliminated. Moreover, emerging diseases
pose new threats. Specific blood component therapy
Red cell substitutes that have been in the process of
suited to the requirements of an individual patient must
development since almost three decades are still in
be recommended whenever possible. It is advisable to
clinical trial phases. Hemoglobin derived oxygen carriers
take informed consent of the parent(s) or guardian
and perfluorocarbons are being tried as oxygen delivery
because of the inherent immunological and infectious
agents. However, their short half-life (<24 hours) and
risks of transfusions.
inability to replicate oxygen delivery of the intact RBCs
have limited their clinical utility. Platelet substitutes are
TABLE 15.16.7: Indications for use of blood components
largely platelet derived and include frozen platelets, cold
stored liquid platelets and platelet derived Component Indications
microparticles. The non-platelet derived substitutes Whole blood Acute massive blood loss
include red cells coated with fibrinogen, fibrinogen Exchange transfusion
coated albumin microcapsules and liposome based Packed red cells Thalassemia
platelet glycoproteins and activated coagulation factors. Aplastic anemia
However, there is still a long way to go before these Nutritional anemia
products become licensed for clinical use. Childhood cancers
Recently enzymatic removal of A and B antigens by Platelets Thrombocytopenia
- with decreased production
bacterial glycosidases has raised the hope of converting
- with increased/normal
red cells to the ‘universal’ O type of red cells. These dis- production
coveries are at present laboratory achievements, but their Abnormal platelet function
translation to patient bedside may still be a long journey. - Acquired
In addition in-vitro erythropoiesis has been induced from - Congenital
hematopoietic stem cells under specific conditions. Granulocytes Severe neutropenia
Septicemia not controlled with
Summary antibiotics
Fresh frozen plasma Liver disease
Blood and blood products should be transfused only Cardiopulmonary bypass
when there are clear and specific therapeutic indications Massive blood transfusions
(Table 15.16.7). The risks of transfusion reactions and Specific clotting factor
transfusion related infections deserve careful conside- deficiencies if factor
concentrate is not available
ration. Although blood units are screened for transfusion
Cryoprecipitate von Willebrand’s disease
transmitted diseases by sensitive technologies, the risk
Hypofibrinogenemia
Factor XIII deficiency
TABLE 15.16.6: Management of acute Hemophilia A if factor
hemolytic transfusion reaction concentrate is not available
• Discontinue blood transfusion but maintain IV access Factor VIII concentrate Hemophilia A
• Alert blood bank and send back unit of blood
Prothrombin complex Hemophilia B
• Draw clotted and anticoagulated blood specimens from a vein
other than the one being used for transfusion. Requisition the Albumin Burns
following tests: DCT, plasma Hb, full blood counts, blood urea, Shock
serum creatinine, serum bilirubin, serum electrolytes Severe edema in neophrotic
• Collect urine sample for urinary hemoglobin syndrome
• Investigate for disseminated intravascular coagulation; blood Before exchange transfusion
culture if fever is a prominent feature Immunoglobulins Prevention and treatment of
• Monitor urine output some disease, e.g. hepatitis
• Treatment is largely supportive: infusion of normal saline to Antibody deficiency syndrome
maintain adequate urine output, furosemide and dopamine to Immune disorders, e.g. ITP
enhance renal cortical perfusion. Dialysis may be required if Neonatal sepsis
acute tubular necrosis develops. Kawasaki disease

BIBLIOGRAPHY 5.
1. Brecker ME. American Association of Blood Banks.
Technical Manual 15th Edition, 2005. Chapter 8 6.
Collection, Preparation, storage and distribution of
components from whole blood donations, 175-202.
2. Brozovic B. Brozovic M. Manual of Clinical Blood 7.
Transfusion. 1st edn. Edinburgh, Churchill Livingstone,
1986;20-79.
8.
3. Blajchman MA. Substitutes and alternatives to platelet
transfusions in thrombocytopenic patients. J Thrombosis
Haemostasis 2003;1:1637-41. 9.
4. Liv QP, Sulzenbacher G, Yuan H, et al. Bacterial
glycosidases for the production of universal red blood
cells. Nature Biotechnology 2007; published online 1 10.
April 2007 doi: 10.1038/nbt1298.
Pediatric Hematology 871
Napler JAF. Blood transfusion therapy. A problem
oriented approach, New York, John Wiley and Sons,
1987;54-135.
Petz LD, Swisher SN, Clinical Practice of Transfusion
Medicine, 2nd Edn. New York, Churchill Livingstone,
1989;239-69.
Pizzo PA, Poplack DG. Principles and Practice of
Pediatric Oncology. 2nd Edn., Philadelphia. JB. Lippincot
company 1989;943-75.
Rutman RC, Miller WV. Transfusion therapy. Principles
and procedures, 2nd Edn, Maryland. Aspen System
Corporation, 1985;29-46.
Saran RK. Transfusion Medicine Technical Manual.
Directorate General of Health Services.Ministry of Health
and Family Welfare, Govt. of India.2003;193-243.
Stowell CP. Whatever happened to blood substitutes.
Transfusion 2004;44:1403-4.
16.1 Malignancies in Children: Purna A Kurkure ......................................................................................................................................... 874
16.2 Acute Leukemia: Anupama Borker, SH Advani .................................................................................................................................... 874
16.3 Hodgkin’s Disease: Purna A Kurkure, Brijesh Arora, Roshni Bhagwat ................................................................................................ 880
16.4 Non-Hodgkin’s Lymphoma: Purna A Kurkure, Brijesh Arora, Roshni Bhagwat .................................................................................. 883
16.5 Wilms’ Tumor: Purna A Kurkure, Brijesh Arora, Shailesh Kanvinde ..................................................................................................... 887
16.6 Neuroblastoma: Purna A Kurkure, Brijesh Arora, Shailesh Kanvinde .................................................................................................. 890
16.7 Soft Tissue Sarcoma: Sajid Qureshi, Purna A Kurkure ........................................................................................................................ 895
16.8 Retinoblastoma: Sripad Banavali .......................................................................................................................................................... 901
16.9 Bone Marrow Transplantation: Brijesh Arora, Purvish M Parikh, MR Lokeshwar .............................................................................. 903
874 IAP Textbook of Pediatrics
16.1 Malignancies in Children
The recent understanding and advances in the total
management of pediatric cancers forms one of the most
exciting chapters in the entire field of oncology. With
increasing control of infectious disease, eradication of
malnutrition and the rapid strides of the pediatric
surgeons in correcting benign surgical problems, more
children are now going to be affected by cancer. In U.S.
cancer is second to accidents as a cause of mortality in
children beyond first year of life. There is paucity of
accurate vital statistics in our country. Children constitute
approximately 40% of India’s population which is more
than 1 billion. Annual incidence rates of cancer are about
75 and 80 per 105 men and women respectively or around
8 lacs new cancers per year. Approximately 5% of these
are in pediatric age group as estimated by population
based cancer registries. Thus 40,000 new pediatric cancers
are estimated to be diagnosed annually. Leukemias and
Lymphomas comprise nearly half of pediatric cancers
followed by tumors of the CNS, sympathetic nervous
system, soft tissues, kidney, bone, eye liver and germ
cells. “Child is not a miniature adult”. The types of
childhood cancers and response to therapy totally differ
from those in adults.
The hallmark of success in pediatric oncology is
multidisciplinary approach executed through carefully
orchestrated combine modality team comprising of a
pediatric oncologist, a pediatric surgeon, a radiation
oncologist, diagnostic specialists and supportive care
services. Burchenal succinctly characterised the basic
tenet of multidisciplinary approach by stating that “the
pride of discipline must be put aside”. All the experts
should work together, keeping well being of the child as
the central issue. First chance is the best chance and
giving optimum treatment at outset is the most important
16.2 Acute Leukemia
INTRODUCTION
Acute leukemia is a malignancy arising due to the clonal
proliferation of abnormal hematopoietic cells leading to
the disruption of normal marrow function.
Purna A Kurkure
factor in deciding the outcome. Any advances in health
care is only as valuable as it is available and accessible to
those who need it. It has been well documented that
organised and co-ordinated treatment programme
carried out by experienced pediatric oncologist in well
staffed and well equipped Pediatric cancer unit is
effective. But at the same time early referral for prompt
diagnosis and for ensuring efficient follow-up, the
community pediatrician’s role is crucial. The “National
Training Project In Practical Pediatric Oncology” has
been initiated under the auspices of Pediatric
Hematology Oncology chapter of IAP in collaboration
with the International Society of Pediatric Oncology
(SIOP) since 1998 with an aim to train educate and
encourage pediatricians to participate in shared care of
childhood cancer patients.
Advances in the treatment of childhood cancers have
dramatically increased survival rates to around 70% in
developed countries. It has been estimated that by the
year 2010, approximately 1 in 250 young adults will be
survivor of childhood cancer in U.S.A. Although this
constitutes a remarkable medical achievement, the late
morbidity in this growing survivor population has
become an area for concern. The need to predict the
future impact of current therapeutic strategies is a major
challenge for the pediatric oncologist. A balance of
reassurance to the survivor and vigilance in monitoring
for relapse, second malignancies and other sequelae is
required. Recent concept of a truly “Cured child” in
pediatric oncology envisages not only a biological cure
of the disease but a child on par with peers in growth
and development physically and in achievements and
aspirations, both mentally and emotionally.
Anupama Borker, SH Advani
Acute leukemias account for about 40% of childhood
cancers. Acute lymphoblastic leukemia (ALL) comprises
about 70- 80% and acute myeloid leukemia (AML) about
10-15 % of childhood leukemias. The remaining subset
 Pediatric Oncology 875

consists of the uncommon childhood leukemias viz. TABLE 16.2.1: Co-relation of ALL subtypes with
chronic myeloid leukemia (CML) and juvenile myelo- surface markers
monocytic leukemia (JMML). Pre B-cell CD10+, CD19+, CD20+, Presence of CD10
CD21+, HLA DR+ (Common ALL antigen
Etiology - CALLA) connotes a
favourable prognosis
Although the etiology of acute leukemia is unknown, Mature CD19+, CD20+, CD21+, Corelates with L3
several genetic conditions and environmental agents are B-cell sIg+ leukemia—Burkitt’s
known to be associated with childhood leukemia. Certain leukemia, needs
inherited conditions like Downs Syndrome (trisomy 21), intensified therapy
T-cell CD3+, CD5+, CD7+ Associated with older
Fanconi syndrome, Bloom syndrome, Schwachman age, high initial WBC
syndrome, Klienfelter syndrome, Turner syndrome count, mediastinal
(45,XO), neurofibromatosis, ataxia telangiectasia, severe mass and higher risk
combined immunodeficiency and Li Fraumeni syndrome of CNS disease
(p53 deletion) are known to predispose to leukemia.
Ionizing radiation, exposure to benzene and certain drugs
like alkylating agents, nitrosureas and epipodo- TABLE 16.2.2: Common chromosomal abnormalities
phyllotoxins have been incriminated in the pathogenesis associated with childhood ALL
of acute leukemias. Translocation Affected genes Comments

Classification T (1,19) PBX1 E2A High risk

The classification of ALL has evolved from one, which T (4,11) MLL Associated with infantile
leukemia, high risk
was based predominantly on morphology to one, which
is based on immunophenotyping, karyotyping and T(9,22) BCR ABL Philadelphia chromosome,
high risk
molecular biology techniques. For ALL, the results of
T (12,21) TEL AML1 Good prognosis
immunophenotyping are used to classify the leukemia
as either B-cell derived or T-cell derived. The morpho- T (8,14) MYC IgL Burkitts leukemia, Needs
short duration intensive
logic classification (FAB classification - French American
therapy
British classification) is still used by many centres, due
to its ease and familiarity. It classifies the blasts as L1, L2
and L3 depending on the cell size, amount of cytoplasm
and the presence of nucleoli and vacuoles. Progenitor B- The changes are easily summarized: the leukemias
cell derived ALL constitutes 80-85% of childhood ALL. with consistent cytogenetic abnormalitites and those that
Fifteen percent are derived from T-cells and 1-2 % from are MDS related were taken into separate groups; the
mature B-cells. (Table 16.2.1) Certain chromosomal rest of the old FAB classification was put under the “AML
abnormalities are associated with a favourable prognosis not otherwise categorized” entry.
viz. t (12; 21) and simultaneous presence of trisomy 4 The presence of t (8; 21), trisomy 8, inv (16) and t (15;
and 10. Others like t (4; 11) and the Philadelphia 17) is associated with favourable prognosis whereas Del
chromosome t (9; 22) connote a poor prognosis. The (7) and t (4; 11) are poor prognostic chromosomonal
presence of t (8, 14) is associated with Burkitt leukemia abnormalities.
where short duration intensive chemotherapy gives high
cure rates (Table 16.2.2). In general, patients with Clinical Features
hyperdiploidy (DNA index > 1.16) fare better than those
with hypodiploidy. Clinical features of acute leukemia are related to the
For AML, the FAB classification is widely used. decrease in the normal cells in the bone marrow viz. Red
However, the new WHO classification is now gaining blood cells (RBCs), white blood cells (WBCs) and
acceptance. According to this classification, presence of platelets, as well as the leukemic cell infiltration of
more than 20% blasts in the bone marrow is diagnostic various organs. The average duration of symptoms
of acute leukemia (Table 16.2.3). before diagnosis varies from 1-2 weeks to 1-2 months.
876 IAP Textbook of Pediatrics

TABLE 16.2.3: FAB and WHO classification of acute myeloid leukemias (AML)

AML classification
FAB WHO

M0: minimally differentiated AML with recurrent cytogenetic translocations

M1: myeloblastic leukemia without maturation
M2: myeloblastic leukemia with maturation
M3: hypergranular promyelocytic leukemia
M4: myelomonocytic leukemia
M4Eo: variant, increase in marrow eosinophils
M5: monocytic leukemia
M6: erythroleukemia (DiGuglielmo’s disease)
M7: megakaryoblastic leukemia
AML with t(8;21)(q22;q22) AML1/CBFalpha/ETO
Acute promyelocytic leukemia: AML with
t(15;17)(q22;q12) and variants PML/RARalpha
AML with abnormal bone marrow eosinophils
inv(16)(p13;q22) t(16;16)(p13;q22) CBFbeta/MYH1
AML with 11q23 MLL abnormalities
AML with multilineage dysplasia
With prior MDS
Without prior MDS
AML with myelodysplastic syndrome, therapy related
Alkylating agent related
Epipodophyllotoxin related
Other types
AML not otherwise categorized
AML minimally differentiated
AML without maturation
AML with maturation
Acute myelomonocytic leukemia
Acute monocytic leukemia
Acute erythroid leukemia
Acute megakaryocytic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis

Initial symptoms may be vague like anorexia,
fatigability and low-grade fever.
Bleeding tendencies like easy bruising, gum bleeding,
epistaxis or petechiae and ecchymosis are common. Fever
may be due to an infection like otitis media, pneumonitis
or an abscess, or due to leukemia itself. Oral ulcers or
thrush may be present at diagnosis. Bone and joint pains
and occasionally joint swelling are common symptoms.
Patients are usually pale with evidence of petechiae,
purpura or ecchymosis. Generalized lymphadenopathy
and hepatosplenomegaly is present in patients with high
tumor burden. Tachypnea and respiratory distress may
be present secondary to severe anemia leading to
congestive cardiac failure or secondary to the presence
of a mediastinal mass leading to tracheal compression.
A large mediastinal mass may also cause superior vena
cava syndrome with facial edema and plethora,
throbbing headache, conjunctival congestion and dilated
neck veins.
Patients with high tumor burden can occasionally
present in tumor lysis syndrome with decreased urine
output and azotemia secondary to uric acid nephropathy.
About 5-10% patients have central nervous system
(CNS) involvement at diagnosis and present with
headaches or cranial nerve palsies. It may be associated
with papilledema and other signs of raised intracranial
pressure. Testicular involvement at diagnosis is
extremely rare but can be present, usually with painless
testicular enlargement.
Patients with acute myeloid leukemia are more likely
to present with bleeding manifestations. Acute promye-
locytic leukemia (APML ie AML-M3) can present with
disseminated intravascular coagulation due to the release
of thromboplastin from the promyelocytic granules. Gum
hypertrophy and skin deposits (leukemia cutis) are
characteristic of AML M4/M5. Rarely patients may
present with a soft tissue mass (granulocytic sarcoma)
which is an extramedullary myeloid cell tumor and this
may precede the leukemia in the bone marrow by several
weeks.
Laboratory Features
The complete blood count at diagnosis usually shows
decreased hemoglobin level and low platelet count. The

WBC count may be elevated or depressed, in either case
it is characterised by neutropenia. Blasts may or may
not be present in the peripheral blood or may be reported
as atypical lymphocytes.
Bone marrow aspiration smears confirm the diagnosis
when more than 30% blasts are present (>20 % for AML
by the WHO classification).
Morphology along with cytochemistry can accurately
diagnose about 80% acute leukemias. Immunopheno-
typing is useful for further subtyping according to the
lineage and for tailoring treatment and for prognos-
tication. Rarely a bone marrow biopsy is necessary for
adequate tissue to rule out other causes.
Cerebrospinal fluid (CSF) analysis, including cytology
is necessary for staging. The presence of elevated CSF
leucocyte count and the presence of blasts in the CSF
indicate CNS leukemia and connote a poorer prognosis.
Biochemical evaluation including liver and renal
function tests, serum lactate dehydrogenase (LDH), uric
acid, electrolytes and calcium, phosphorus and magne-
sium levels should be performed to establish baseline
organ function and to rule out tumor lysis syndrome.
Serology for human immunodeficiency virus (HIV),
hepatitis B and C and Epstein Barr virus (EBV) and
cytomegalovirus (CMV) should be performed at
diagnosis. Coagulation profile with prothrombin time
(PT), partial thromboplastin time (PTT), fibrinogen level
and fibrinogen degradation products (FDP) should be
done to rule out disseminated intravascular coagulation
(DIC).
Differential Diagnosis
The differential diagnosis of acute leukemia includes
several benign and malignant conditions. The commo-
nest cause for transient pancytopenia is viral infection
induced myelosuppression. Drug induced cytopenia can
be ruled out by careful history. Immune mediated
thrombocytopenia (ITP) can be differentiated from acute
leukemia by the presence of acute onset isolated
thrombocytopenia in an otherwise well child. In case of
doubt a bone marrow aspiration is required to rule out
leukemia. Other hematologic malignancies like chronic
myeloid leukemia, juvenile myelomonocytic leukemia,
and chronic myeloid leukemia in blast crisis or
lymphoma evolving to leukemic phase and bone marrow
failure secondary to marrow infiltration by metastatic
deposits in neuroblastoma, rhabdomyosarcoma and
Ewing’s sarcoma can occasionally mimic acute leukemia.
Pediatric Oncology 877
Myelodysplastic syndromes, constitutional bone
marrow failure syndromes and hypoplastic or aplastic
anemia also present with pancytopenia and need to be
differentiated from acute leukemia.
Management
The management of acute leukemia is intense and
prolonged. It needs the combined efforts of the pediatric
oncologist, the radiation oncologist, the nursing team,
the dietician, the psychologist and the medical social
workers to treat these children with intent to cure.
Principles of Treatment of ALL
At diagnosis the leukemic tumor burden approximates
1012 cells. Chemotherapy given in phases reduces the
leukemia cells by log cell kill. After the initial 4-6 months
of intensive chemotherapy, oral maintenance chemo-
therapy is given for 18-24 months to prevent resurgence
of leukemia cells and to achieve a cure.
Induction Chemotherapy
Induction chemotherapy is the first few weeks of
intensive treatment given to produce remission. It
includes 3-4 drugs including vincristine, prednisone or
dexamethasone, L-Asparginase and daunorubicin.
Intrathecal chemotherapy includes methotrexate or
cytosine arabinoside. About 95% patients achieve a
morphologic remission at the end of induction chemo-
therapy.
Consolidation Chemotherapy
Consolidation chemotherapy decreases the leukemic
burden further. Drugs used include vincristine,
cyclophosphamide, and daunorubicin and cytosine
arabinoside.
CNS Directed Therapy
The concept of CNS preventive therapy is based on the
assumption that undetectable CNS leukemia is present
at diagnosis. Since systemic chemotherapy may not
achieve adequate drug levels across the blood brain
barrier, cranial irradiation with intrathecal chemotherapy
has been in use since the 1970’s as CNS preventive
therapy. This is associated with neurocognitive dysfunc-
tion and secondary malignancies in some survivors. High
dose chemotherapy using methotrexate or cytosine
arabinoside achieves good CNS penetrance and newer
878 IAP Textbook of Pediatrics

protocols reserve cranial irradiation for patients with

CNS disease at presentation and for those who are at
high risk for CNS relapse.

Maintenance Chemotherapy
Maintenance chemotherapy using oral mercaptopurine and
methotrexate is given for 18 to 24 months in order to
eradicate dormant leukemia cells.
Different institutes use different treatment protocols
for childhood ALL. Most European and American
protocols use aggressive chemotherapy regimens with 5
year survival rates over 80-85%. In India the multi-centric
protocol MCP841 has been used in three major centres
across the country with cure rates of 50%.

TABLE 16.2.4: Protocol MCP 841 for ALL

Cycle Chemotherapy Dose and Schedule

Induction 1 (I1) Prednisone 40 mg/m² p.o.days 1-28

Vincristine 1.4 mg/m² i.v.days 1,8,15 and 22
Methotrexate* 12 mg IT, days 1,8,15 and 22
L-Asparaginase 6000 u/m² i.m on alternate days × 10 doses, days 2-20
Daunorubicin 30 mg/m² .i.v days 8,15 and 29
Induction 2 (I2) Mercaptopurine 75 mg/m² p.o. daily days 1-7 and days 15-21
Cyclophosphamide 750 mg/m² i.v days 1 and 15
Methotrexate* 12 mg/m² IT days 1,8,15and 22
Cranial Radiation 180 cGy daily x 10 days ( total 1800 cGy)
Repeat induction (RI1) Same as I1 Doses and schedule as per I1
Consolidation (C) Cyclophosphamide 750 mg/m² i.v day 1
Vincristine 1.4 mg/m² i.v days 1 and day 15
Mercaptopurine 75 mg/m² p.o.daily days1-7 and days 15-21
Cytarabine 100 mg/m² sc every 12 hours × 6 doses on
days 1-3 and days 15-17
Daunorubicin 30 mg/m² i.v days 15
Maintenance Prednisone 40 mg/m² p.o.days 1-7
(M, six cycles) Vincristine 1.4 mg/m² i.v on day 1
Daunorubicin 30 mg/m² i.v on day 1
L-Asparaginase 6000 u/m² i.m days 1,3,5 and 7
Methotrexate 15 mg/m² p.o., once a week. Missing every
4th for a total of 12 weeks. Begin on day 15
Mercaptopurine 75 mg/m² p.o. daily, 3 weeks out of every 4
For total of 12 weeks. Begin on day 15

Each cycle subsequent to I1, began as soon as the neutrophil count is >/= 1000/m3 and the platelet count is >/= 100,000/mm³
*Dose for patient >/=3 years: patients aged 2-3 years 10 mg: patients aged 1-2 years received 8 mg, and patients less than one year
received 6 mg

Treatment of AML or Idarubicin) is used in combination with cytosine

Induction chemotherapy for AML consists of aggressive arabinoside, given over 7-10 days with or without
multiagent protocols. An anthracycline (daunorubicin etoposide. The resultant myelosuppression takes about

3-4 weeks to recover. About 70% patients achieve
remission at the end of induction chemotherapy. Post
remission treatment consists of 2 courses of high-dose
chemotherapy using cytosine arabinoside. There is no
definitive role of maintenance chemotherapy in
childhood AML.
Acute promyelocytic leukemia (APML) or AML M3
is characterised by the presence of t (15:17) involving the
retinoic acid receptor α (RARα). The use of all trans-
retinoic acid (ATRA) causes the differentiation of the
promyelocytes leading to their maturation with
resolution of the coagulopathy. Its use in combination
with chemotherapy like anthracycline leads to complete
remission. Maintenance therapy with ATRA improves
long-term disease free survival. Arsenic trioxide, alone
or in combination with ATRA has also produced
excellent response rates in APML patients.
Supportive Care
Supportive care is extremely important in the treatment
of acute leukemias. This includes blood component
therapy and aggressive management of infectious
complications. Packed red blood cell transfusions are
indicated to maintain hemoglobin over 8 gm/dl in well
children and over 10 gm/dl in patients with fever and
infection. Platelet transfusions are indicated if platelet
count is less than 10000/cmm or in the case of overt
bleeding, especially in patients with fever and infection.
Every episode of febrile neutropenia should be treated
aggressively with broad-spectrum antibiotics after
drawing blood cultures. All patients should receive
prophylaxis for Pneumocystis carinii pneumonia with
cotrimoxazole and for fungal infections with clotri-
TABLE 16.2.5: Prognostic features in acute lymphoblastic leukemia
Feature Standard risk
Age 2-10 years
Sex Females
Initial WBC count < 50000/cmm
Hepatosplenomegaly Absent
Lymphadenopathy Absent
Mediastinal mass Absent
CNS leukemia Absent
Phenotype Pre B (T-cell- intermediate)
Ploidy Hyperdiploidy
Cytogenetics T (12:21), trisomy 4 and 10
Response to treatment Good early response
Pediatric Oncology 879
mazole. Maintenance of oral and perianal hygiene
reduces the risk of infections to a significant extent. The
use of hematopoietic growth factors (GCSF and
GMCSF) reduces the period of neutropenia but are
expensive and do not improve the overall outcome of
the patients.
Bone Marrow Transplantation
The indications for bone marrow transplantation or stem
cell transplantation in ALL in first remission include
those patients who are at very high risk for relapse. These
include those patients with presence of t (9, 22), those
who continue to have minimal residual disease after first
few months of intensive chemotherapy or those who fail
to achieve remission at the end of induction. It is also
indicated for those patients who have an early relapse
i.e. while still on treatment. In AML it is indicated in first
remission in those who have adverse cytogenetic features
and for all patients who relapse.
Prognosis
Survival in ALL has improved from 1%in 1965 to 50% in
the mid-70s and up to 70% in the mid-90s. ALL is a
heterogeneous disease and prognosis depends on the
subtype, the tumor burden at presentation, the associated
cytogenetic abnormality, the ploidy, and most
importantly, the response to treatment. Early clearance
of blasts from the peripheral blood (day 7 absolute blast
count) after initiation of treatment and evidence of bone
marrow remission on day 14 of induction therapy has
been associated with a very good prognosis. Table 16.2.5
lists the prognostic factors in childhood ALL.
High risk
< 1 year, >10 years
Males
>50000/cmm
Massive
Massive
Present
Present
Mature B-cell
Hypodiploidy
T (9:22), t (4,11),t (8:14)
Poor early response
880 IAP Textbook of Pediatrics
BIBLIOGRAPHY
1. Advani SH. Treatment of ALL in India: An analysis of
risk factors and results at three major centers. Med Ped
Oncol 2002;39:259.
2. Advani SH, Pai SK, Venzon D, et al. ALL in India: An
analysis of prognostic factors using a single treatment
regimen. Ann Oncol 1999;10:167-76.
3. Arico M, Valsecch MG, Camitta B, et al. Outcome of
treatment in children with Ph chromosome positive ALL.
New Eng J Med 2000;342:998-1006.
4. Chessels JM. The management of high risk lymphoblastic
leukemia in children. Br J Hema 2000;108:204-16.
5. De Boton S, Coiteux V, Chevret S, Rayon C, Vilmer E, et
al. Outcome of childhood acute promyelocytic leukemia
with all-trans retinoic acid and chemotherapy. J Clin
Oncol 2004;15;22(8):1404-12.
6. Gaynon P S, Trigg ME, Heerma NA, et al. Children’s
Cancer Group trials in ALL from 1983-1995. Leukemia
2000;14:2223-33.
7. Golub TR, Arceci RJ. Acute myelogenous leukemia. In:
Pizzo PA, Poplack DG, editors. Principles and Practice
of Pediatric Oncology. Philadelphia: Lippincott-Williams
and Wilkins 2006;591-644.
8. Hill FG, Richards S, Gibson B, Hann I, Lilleyman J,
Kinsay S, et al. Successful treatment without cranial
irradiation of children receiving intensified chemo-
therapy for acute lymphoblastic leukemia: Results of a
risk stratified randomised central nervous system
treatment trial, MRC UKALL XI Br J Hematol 2004;
124(1):33-46.
16.3 Hodgkin’s Disease
Purna A Kurkure, Brijesh Arora, Roshni Bhagwat
INTRODUCTION
Hodgkin’s disease (HD) is a malignant disorder of
lymphoreticular system. Hodgkin’s disease occurs in 5
to 7 per 1,00,000 population. The incidence is highest in
late childhood and early adulthood (15-35 years). It is
very uncommon under 5 years of age and almost never
seen under 2 years of age. In asian population, HD is
common even at younger ages. The sex ratio progresses
from male preponderance of 10:1 under the age of 7 years
falling to 1.1:1 after the age of 12 years.
Etiology
Variation in the incidence of HD in different ethnic
groups and association with human leukocyte antigen
9. Kanerva J, Saarinen PihkalaUM, Niini T, Riikonen P,
MottonenM, Makipernaa A, Salmi TT, Vettenraata K,
Knuutila S. Favourable outcome in 20 year follow-up of
children with very low risk ALL and minimal standard
therapy with special reference to TEL-AML1 fusion.
Pediatric Blood Cancer 2004;42(1):30-5.
10. Magrath I, Shantha V, Advani SH, Adde M, Arya LS,
Banavali SD, et al. Treatment of acute lymphoblastic
leukemia in countries with limited resources; lessons
learnt from a single protocol in India over a twenty year
period. Eur J Cancer 2005;41:1570-83.
11. Margolin JF, Steuber CP, Poplack DG. Acute lympho-
blastic leukemia. In: Pizzo PA, Poplack DG, editors.
Principles and Practice of Pediatric Oncology.
Philadelphia: Lippincott-Williams and Wilkin 2006;
538-90.
12. Pui CH, Evans W. Treatment of acute lymphoblastic
leukemia. N Engl J Med 2006;364:166-78.
13. Schrappe M, Reiter A, Ludwig WD, et al. Improved
outcome in childhood ALL despite reduced use of
anthracyclins and cranial RT–Results of trial. ALL- BFM
90 Blood 2000;95:3310-22.
14. Silverman LB, Sallan SE. Newly diagnosed childhood
ALL. An update on prognostic factors and treatment.
Current Opinoions Hematol 2003;10(4):290-96.
15. Woods W G, Neudorfs, Gold S, et al. A comparison of
allogenic bone marrow transplant, autologous bone
marrow transplant and aggressive chemotherapy in
children with AML in 1st remission. A report from the
CCG. Blood 2001;97:56-62.
suggests that inherited susceptibility plays an important
role in the pathogenesis. Environmental factors such as
Epstein-Barr virus infection, familial clustering of cases
and higher incidence in twins may be some of the other
contributing factors.
Pathology (Table 16.3.1)
Hodgkin lymphoma can be dividea
Nodular Lymphocyte-Predominant
Hodgkin Lymphoma (NLPHL)
This pathologic class of Hodgkin lymphoma is charac-
terized by large cells with multilobed nuclei, referred to
as popcorn cells. NLPHL is most common in males
 Pediatric Oncology 881

younger than 10 years. Patients with NLPHL generally
present with localized, nonbulky disease. Almost all
patients are asymptomatic.
Classical Hodgkin Lymphoma
The hallmark of classic Hodgkin lymphoma is the R-S
cell. This is a binucleated or multinucleated giant cell
that is often characterized by a bilobed nucleus, with two
large nucleoli, giving an owl’s eye appearance to the cells.
The classical subtypes are defined according to the
number of Reed-Sternberg (R-S) cells, characteristics of
the inflammatory milieu, and the presence or absence of
fibrosis. A striking characteristic is the rarity (about 1%)
of the malignant R-S cell in specimens and the abundant
reactive cellular infiltrate of lymphocytes, macrophages,
granulocytes, and eosinophils. The histologic features
and clinical symptoms of Hodgkin lymphoma have been
attributed to the numerous cytokines secreted by the R-
S cells, which include interleukin-1, interleukin-6, and
tumor necrosis factor. Classical HD is divided into four
TABLE 16.3.2 : Modified Ann Arbor classification of
Hodgkin’s disease
Stage Description
I Involvement of single lymph node region (I) or of a
single extralymphatic or site (IE) by direct extention.
II Involvement of two or more lymph node regions on
the same side of diaphragm or localized
involvement of an extra-lymphatic organ or site and
of one or more lymph node regions on the same
side of the diaphragm (IIE)
III1 Involvement of lymph node regions on both sides
of the diaphragm Abdominal disease is limited to
the upper abdomen (i.e. spleen, splenic hilar
nodes, celiac nodes, porta hepatitis nodes)
III2 Involvement of lymph node regions on both sides
of the diaphragm Abdominal disease includes para-
aortic, mesenteric, and iliac involvement with or
without disease in the upper abdomen.
IV Disseminated involvement of one or more
extralymphatic organs or tissues with or without
associated lymph node disease.

subtypes as detailed in the Table 16.3.1.

Staging (See Table 16.3.2) E Limited involvement of a single extranodal site

A No symptoms
B Fever, night sweats, or weight loss of more
than 10% of body weight in the previous
6 months.
X Bulky disease (greater than 10 cm in
maximum dimension; greater than 1/3rd of
the internal transverse diameter of the
thorax at the level T5/T6.
CS Clinical stage: When based solely on
physical examination and imaging technique.
PS Pathologic stage: When based on biopsies
Clinical Presentation
HD has an insidious onset. The most frequent presen-
tation in up to 80% of patients is painless cervical
lymphadenopathy, of which 60% have asymptomatic

TABLE 16.3.1: Histopathologic classification of classical Hodgkin’s disease

Rye Distinctive features Relative frequency (%)

1. Lymphocyte Rich (LR)
2. Nodular sclerosis (NS)
3. Mixed cellularity*
(MC)
Benign appearing lymphocytes with or without histiocytes. 10-15
Few Reed-Sternberg (R-S) cells
No fibrosis
Thickened capsule with proliferation of orderly collagenos 20-50
bands, that divide lymphoid tissue in nodules: Lacunar
variant of R-S cells.
5-15 R-S cells per high power field. Fine fibrosis in interstitium 20-40
Focal necrosis may be present

4. Lymphocyte depletion (LD) Abnormal cells with relative paucity of lymphocytes. 5-16
Fibrosis and necrosis common but diffuse

*Most common in developing countries and in children.

882 IAP Textbook of Pediatrics
involvement of the mediastinum. Constitutional or class
“B” symptoms are more common with advanced disease
(stage I-5%, stage IV-81%) and are associated with a
poorer outcome. Uncommon extranodal sites are CNS,
bone, GIT and skin. A reduced cell mediated immunity
results in an increase susceptibility to infections.
Evaluation of a Patient
• History and Physical examination
• Complete blood count
• Liver and renal function tests, Serum LDH, Serum
albumin
• Lymph node biopsy
• Bone marrow aspiration and biopsy: This is done in
advanced disease (III,IV), B-symptoms, bony
involvement or abnormal counts.
• Radiological studies: Chest X-ray, CT Scan of neck,
chest and abdomen and pelvis, Imaging of other sites
as and when indicated
• Positron emission tomography (PET) Scan of the
whole body:
PET scanning may identify more sites of initial disease
than conventional imaging and is more accurate in
detecting viable Hodgkin lymphoma in posttherapy
residual masses., PET scanning should be performed at
baseline and a minimum of 3 weeks post chemotherapy
completion and 8 to 12 weeks post radiation.
Prognostic Factors in Hodgkin Lymphoma
Several factors influence the success and choice of
therapy. Pretreatment factors associated with an adverse
outcome include advanced stage of disease, presence of
B symptoms, bulky disease, extranodal extension, male
sex, and elevated erythrocyte sedimentation rate. These
factors are interrelated in the sense that disease stage,
bulk, and biologic aggressiveness are frequently
codependent. There is some controversy as to whether
histology is an important prognostic factor. The rapidity
of response to initial cycles of chemotherapy based on
PET is also prognostically important and is being used
to determine subsequent therapy.
Treatment
Treatment of HD in pediatric population is different in
certain respects from adults. Devising the ideal
therapeutic approach for children with HD is compli-
cated by their increased risk for late adverse effects. In
particular, radiation therapy can cause profound
musculoskeletal growth retardation and increase the risk
for cardiovascular disease and secondary solid malig-
nancies in children. Further complicating the treatment
of children are gender-specific differences in chemo-
therapy-induced gonadal injury. The desire to cure young
children with minimal side effects has stimulated
attempts to reduce the intensity of chemotherapy
(particularly alkylating agents) and radiation dose or
volume. In general, the use of combined chemotherapy
with radiation broadens the spectrum of potential
toxicities, while reducing the severity of individual drug-
related or radiation-related toxicities. Current approaches
use chemotherapy alone with or without low-dose
involved-field radiation therapy (LD-IFRT). The volume
of radiation and the intensity/duration of chemotherapy
are determined by prognostic factors at presentation,
including presence of constitutional symptoms, disease
stage, and bulk.
All children generally receive combination chemo-
therapy as initial treatment. While regimens containing
alkylating agents are associated with an increased risk
for infertlity and therapy-related leukemia; in non-
alkylator-containing regimens, doxorubicin is associated
with cardiac damage and bleomycin can produce
pulmonary fibrosis. Common regimens currently utilized
for treatment include non-alkylator-containing regimens
such as ABVD (doxorubicin [Adriamycin], bleomycin,
vinblastine, and dacarbazine), Hybrid regimens with
lower total cumulative doses of alkylators, doxorubicin,
and bleomycin such as COPP/ABV (cyclophosphamide,
vincristine, procarbazine, prednisone/doxorubicin,
bleomycin, and vinblastine), DBVE (doxorubicin,
bleomycin, vincristine, etoposide), BEACOPP
(bleomycin, etoposide, Adriamycin, cyclophosphamide,
vincristine (Oncovin), prednisone, procarbazine) and
VAMP (vincristine, doxorubicin, methotrexate, and
prednisone). The current therapeutic strategy and
outcome for children with HD is outlined in Table 16.3.3.
TABLE 16.3.3: Treatment modalities and results in
Hodgkin’s disease
Risk Group Treatment modality Survival DFS%
Low Risk VAMP/DBVE/ABVD 96-98
(Stage I, IIA, 2-4 cycles + Low-dose
no Bulk, field RT
No B symptoms)
High Risk COPP-ABV/ DBVE- 70-75
(IIB, III, IV, PC/ABVD 6 cycles +
bulky disease) Involved field RT
RT = Radio therapy

Nodular Lymphocyte-Predominant Hodgkin
Lymphoma (NLPHL)
Children with NLPHL have a favorable outcome,
particularly when the disease is in early stage. Thus,
treatment for NLPHL focuses on reducing initial therapy
to reduce long-term treatment-related morbidity and
mortality. Although current standard therapy for
children with NLPHL is chemotherapy plus LD-IFRT,
patients have also been successfully treated with either
chemotherapy alone or complete resection of isolated
nodal disease.
Principles of Radiotherapy
Most newly diagnosed children are treated with risk-
adapted chemotherapy alone or in combination with LD-
IFRT. LD-IFRT involves the use of meticulous and
judiciously designed fields to achieve local control of
disease and to minimize damage to normal tissue. The
LDRT treatment volume includes the initially involved
lymph node region(s). In general, doses of 15 Gy to 25
Gy are used, with modifications based on patient age,
the presence of bulk or residual (postchemotherapy)
disease, and normal tissue concerns. Transposition of
ovaries to midline and midline pelvic block to protect
ovarian function and testicular shield or sperm banking
in male children is routinely considered.
Late Effects
Survivors of Hodgkin lymphoma are at risk for numerous
late complications of treatment. Alkylating agents and
etoposide have been associated with acute myeloid
leukemia (AML) and myelodysplastic syndromes.
Doxorubicin can lead to cardiomyopathy and bleomycin
can cause pulmonary fibrosis. Steroid use can produce
16.4 Non-Hodgkin’s Lymphoma
Purna A Kurkure, Brijesh Arora, Roshni Bhagwat
INTRODUCTION
Non-Hodgkin’s Lymphoma (NHL) is neoplasm of a wide
range of cell types that comprise the immune system.
All lymphomas are generalized diseases from the outset
Pediatric Oncology 883
avascular necrosis. Radiation therapy can lead to thyroid
dysfunction, increased risk for myocardial atherosclerotic
heart disease, and is associated with solid tumor
development in radiation fields. All these potential
complications mandate a close long-term follow-up after
completion of therapy.
CONCLUSIONS
Hodgkin’s disease is one of the most curable cancers in
children. Current use of appropriate staging techniques
and treatment protocols has resulted in an excellent
overall survival. The formidable challenge is to maintain
high cures and ameliorate treatment sequelae.
BIBLIOGRAPHY
1. AB Thomson, WHB. Wallace Treatment of Pediatric
Hodgkin’s Disease—a balance of risks European Journal
of Cancer 2002;38(4):468-77.
2. G Schellong. The balance between cure and late effects
in childhood Hodgkin’s lymphoma: The experience of
the German-Austrian Study-Group since 1978. Annals
of Oncology 1996;7(Suppl 4):S67-S72.
3. H Van den Berg, J Zsiros, H Behrendt. Treatment of
childhood Hodgkin’s disease without radiotherapy
Annals of Oncology 1997;8(Suppl.1):S15-S17.
4. Karayalcin G, Behm FG, Gieser PW, et al. Lymphocyte
predominant Hodgkin disease: Clinico-pathologic
features and results of treatment—the Pediatric Oncology
Group experience. Med Pediatr Oncol 1997;29(6):519-25.
5. Meany HJ, Gidvani VK, Minniti CP. Utility of PET scans
to predict disease relapse in pediatric patients with
Hodgkin lymphoma. Pediatr Blood Cancer 2007;
48(4):399-402.
6. R Potter. Pediatric Hodgkin’s Disease European Journal
of Cancer 1999;35(10):1466-74.
7. Schwartz CL. Special issues in pediatric Hodgkin’s
disease. Eur J Hematol Suppl 2005;(66):55-62.
and have patterns of spread that mimic the migration
patterns of their normal cellular counterparts. Lym-
phoma (Hodgkin and non-Hodgkin) is the third most
common childhood malignancy, and NHL accounts for
approximately 7% of cancers in children younger than
884 IAP Textbook of Pediatrics

20 years. NHL occurs most commonly in the second
decade of life, and occurs less frequently in children
younger than 3 years. Immunodeficiency, both congeni-
tal and acquired (HIV infection or posttransplant),
increases the risk of NHL. With current treatments, about
80% of children and adolescents with NHL will survive
at least 5 years.
Classification and Clinical Presentation
(Table 16.4.1)
In children, NHL is distinct from the more common
forms of lymphoma observed in adults. While lympho-
mas in adults are more commonly low or intermediate
grade, are dominantly nodal, have variable growth
fraction and poor long-term outcome; almost all NHL
that occurs in children is high grade, extranodal, has
higher growth fraction and good outcome. Classification
of NHL in childhood is based on clinical behavior,
response to treatment and immunophenotype.
NHL of childhood currently falls into three therapeu-
tically relevant categories: (1) B-cell NHL (Burkitt
lymphoma/leukemia and diffuse large B-cell lympho-
ma); (2) lymphoblastic lymphoma (primarily precursor
T-cell lymphoma and, less frequently, precursor B-cell
lymphoma); and (3) anaplastic large cell lymphoma (T-
cell or null-cell lymphomas). Each type of childhood NHL
is associated with distinctive molecular biological
characteristics.
Clinical Features
Burkitt Lymphoma
Burkitt lymphoma accounts for about 50% of childhood
NHL and exhibits consistent, aggressive clinical
behavior. The malignant cells show a mature B-cell
phenotype. Burkitt lymphoma expresses a characteristic
chromosomal translocation, usually t(8;14) and more
rarely t(8;22) or t(2;8). Each of these translocations
juxtaposes the c-myc gene to immunoglobulin locus
regulatory elements, resulting in the inappropriate
expression of c-myc, the gene involved in cellular
proliferation.The two most common primary sites of
disease are the abdomen and head-neck region. Other
sites of involvement include testes, bone, peripheral
lymph nodes, skin, bone marrow, and central nervous
system (CNS).
Diffuse Large B-cell Lymphoma
DLBCL is a mature B-cell neoplasm that represents 10%
to 20% of pediatric NHL. DLBCL occurs more frequently

TABLE 16.4.1: Major histopathological categories as per WHO classification

NHL type Immuno-phenotype Clinical Presentation Chromosome Translocation Genes Affected

Burkitt and Mature B-cell Intra-abdominal t(8;14)(q24; q32), C-MYC, IGH, IGK, IGL
Burkitt-like (sporadic), head and t(2;8) (p11;q24),
lymphomas neck (non-jaw, sporadic), t(8;22)(q24; q11)
jaw (endemic)
Diffuse large Mature B-cell Nodal, abdomen, No consistent
B-cell bone, primary cytogenetic
CNS, mediastinal abnormality
identified
Lymphoblastic Pre-T-cell Mediastinal, MTS1/ TAL1, TCRAO, RHOMB1,
lymphoma bone marrow p16ink4a RHOMB1, HOX11
(precursor Pre-B-cell Skin, bone deletion TAL1
T-cell or t(1;14) (p34;
precursor B-cell) q11), t(11;14)
(p13;q11)
Anaplastic large CD30+ Lymph node, t(2;5) (p23; ALK-NPM
cell lymphoma (Ki-1+) skin, bones, q35)
(systemic) T-cell or null cell visceral, soft tissues

during the second decade of life than during the first.
Pediatric DLBCL may present clinically similar to Burkitt,
though it is more often localized and less often involves
the bone marrow or CNS. Outcomes for children with
DLBCL are more favorable than those observed in adults,
with overall 5-year event-free survival (EFS) rates of
approximately 90% in children.
About 20% of pediatric DLBCL present as primary
mediastinal disease (primary mediastinal B-cell lympho-
ma [PMBCL]). This presentation is more common in
older children and adolescents and is associated with an
inferior outcome compared with other pediatric DLBCL.
Lymphoblastic Lymphoma
Lymphoblastic lymphoma makes up approximately 20%
of childhood NHL. More than 75% of lymphoblastic
lymphomas have a T-cell immunophenotype and the
remainder have a precursor B-cell phenotype.
Nearly 75% of patients with lymphoblastic lympho-
ma present with anterior mediastinal mass, and
symptoms of dyspnea, wheezing, stridor, dysphagia, or
swelling of the head and neck. Pleural effusions may be
present, and the involvement of lymph nodes, usually
above the diaphragm, may be a prominent feature. There
may also be involvement of bone, skin, bone marrow,
CNS, abdominal organs (but rarely bowel), and
occasionally other sites such as lymphoid tissue of
Waldeyer ring and testes. Patients with more than 25%
marrow blasts are considered to have leukemia, and
those with fewer than 25% marrow blasts are considered
to have lymphoma.
Anaplastic Large Cell Lymphoma
Anaplastic large cell lymphoma (ALCL) accounts for
approximately 10% of childhood NHL. While the
predominant immunophenotype of ALCL is mature T-
cell; null-cell disease (i.e. no T-cell, B-cell, or NK-cell
surface antigen expression) does occur. More than 90%
of ALCL cases have the translocation t(2;5)(p23;q35)
leading to the expression of the fusion protein NPM/
ALK. Clinically, ALCL has a broad range of presen-
tations, including involvement of lymph nodes and a
variety of extranodal sites, particularly skin, bone,
gastrointestinal tract, lung, pleura, and muscle.
Involvement of the CNS and bone marrow is uncommon.
ALCL is often associated with systemic symptoms (e.g.
fever, weight loss) and a prolonged waxing and waning
course, making diagnosis difficult and often delayed.
Pediatric Oncology 885
Evaluation of Children with NHL
• History and physical examination
• Complete blood count, peripheral smear
• Renal function, uric acid, liver function, serum
albumin, lactate dehydrogenase
• Examination of cerebrospinal, peritoneal, pericardial
or pleural fluid-cytomorphology and immuno-
phenotyping
• Surgical biopsy
• Chest radiograph or CT-scan of the chest
• Ultrasonography/CT-Scan of the abdomen with
contrast
• Bone marrow aspiration and Biopsy
• Plain radiogram/ CT-scan of other affected sites
• PET scan of whole body (optional)
Staging
The most widely used staging scheme for childhood non-
Hodgkin lymphoma (NHL) is that of the St. Jude
Children’s Research Hospital (Murphy’s Staging), which
is outlined in Table 16.4.2. In general, treatment for
childhood NHL depends on localized versus dissemi-
nated disease. Localized disease is usually defined as
stage I or II disease, while stage III or IV disease is
generally considered disseminated.
Management
Childhood NHL is an extremely chemosensitive disease.
Surgery plays a very limited role, mainly for arriving at
TABLE 16.4.2: St Jude’s staging system for childhood NHL
Stage Definition
(localized)
I Single tumor (extranodal)Single anatomic area
Low risk
(nodal) excluding mediastinum or abdomen
II Single tumor (extranodal) with regional node
involvement. Primary gastrointenstinal tumor with
or without involvement of mesentric node.or
On same side of diaphragm:
a. Two or more nodal areas
b. Two single extranodal tumors with or without
regional node involvement
III All primary intrathoracic tumors. All extensive
(advanced)
High risk
primary intra-abdominal disease. Two or more
nodal or extranodal areas on both sides of
diaphragm
IV Any of the above with CNS or bone marrow
involvement
886 IAP Textbook of Pediatrics
a diagnosis. Radiation of primary sites is used very rarely
in emergency situations. Hence, multi-agent chemo-
therapy directed to the histologic subtype and stage of
the disease remains the cornerstone of therapy.
There are two potentially life-threatening clinical
situations that are often seen in children with NHL: (1)
superior vena cava syndrome (SVCS) often seen in
lymphoblastic lymphoma; and (2) tumor lysis syndrome,
most often seen in lymphoblastic and Burkitt NHL. These
emergent situations should be anticipated in children
with NHL and addressed immediately.
Patients with large mediastinal masses and SVCS are
at risk of cardiac or respiratory arrest during general
anesthesia or heavy sedation. Due to these risks, the least
invasive available procedure to establish the diagnosis
of lymphoma such as bone marrow examination,
thoracocentesis, a lymph node biopsy under local
anesthesia or a computed tomography–guided core
needle biopsy should be contemplated. Tumor lysis
syndrome results from the rapid breakdown of malignant
cells resulting in a number of metabolic abnormalities,
most notably hyperuricemia, hyperkalemia, and
hyperphosphatemia. Hyperhydration and allopurinol or
rasburicase (urate oxidase) are essential components of
therapy. Gastrointestinal bleeding, obstruction, and
(rarely) perforation may also occur in abdominal NHL.
Therapy of Pediatric NHL
Localized Non-Hodgkin Lymphoma in Children
Stage I and II patients with grossly resected (>90%)
disease regardless of histology have an excellent
prognosis, with 90% or better disease-free survival (DFS).
For localized B-NHL (Burkitt’s or DLBL), use of short,
intensive, pulsed chemotherapy for 2-3 months with
aggressive CNS-directed chemotherapy without cranial
radiation is standard. Common drugs used are
dexamethasone, cyclophosphamide, methotrexate,
cytarabine, prednisolone (IT), intrathecal methotrexate,
ifosfamide, etoposide and doxorubicin.
For localized lymphoblastic lymphoma (grossly
resected, i.e. >90% stage I/II disease), a leukemia like
approach with induction, consolidation, CNS-directed
therapy and maintenance for a total of 18-24 months leads
to more than 90% DFS.
For localized anaplastic large cell lymphoma (ALCL),
pulsed chemotherapy similar to B-NHL therapy is
preferred.
Disseminated Childhood B-cell Non-Hodgkin
Lymphoma
Patients with disseminated B-lineage NHL (Burkitt or
DLBCL) have an 80% to 90% long-term survival through
the use of short, intensive, pulsed chemotherapy with
aggressive CNS-directed chemotherapy without cranial
radiation. The use of high-dose methotrexate (>5 g/m2),
cytarabine, and etoposide have appeared to be helpful
in addition to the drugs mentioned above. Patients with
Burkitt leukemia should be treated with protocols
designed for Burkitt lymphoma. Rituximab is a mouse/
human chimeric monoclonal antibody targeting the
CD20 antigen and is routinely used against DLBCL in
adults. In children, rituximab in combination with the
intensive chemotherapy regimen is being evaluated.
Disseminated Childhood
Lymphoblastic Lymphoma
Patients with disseminated lymphoblastic lymphoma
have long-term survival rates higher than 80%. As
opposed to other pediatric NHL, lymphoblastic lympho-
ma responds much better to leukemia like therapy over
2 years than with shorter, intensive, pulsed chemo-
therapy regimens. Common drugs used are prednisone,
dexamethasone, vincristine, daunorubicin, doxorubicin,
L-asparaginase, cyclophosphamide, cytarabine, metho-
trexate, 6-mercaptopurine and 6-thioguanine. Cranial
radiation is currently used only for patients with CNS
disease at diagnosis.
Disseminated Childhood Anaplastic
Large Cell Lymphoma
Children and adolescents with disseminated anaplastic
large cell lymphoma (ALCL) have a disease-free survival
(DFS) of approximately 60% to 75%. Both short pulse
intensive as well as leukemia like strategies are effective
for the treatment of disseminated ALCL.
CONCLUSIONS
Intensive combination regimens with optimal supportive
care have been shown to be feasible and curative for most
children with NHL. The current focus is now on reducing
therapy for low risk disease and intensifying treatment
for high risk NHL for optimum long term survival.
Management of relapses continues to be a challenge and
warrants high dose chemotherapy with stem cell rescue
in selected cases.

BIBLIOGRAPHY
1. Anderson JR, Jenkin DT, Wilson JF, et al. Long-term
follow-up of patient treated with COMP or LSAL2
therapy for childhood non Hodgkin’s lymphoma: report
of CCG – 551 from the Children’s Cancer Group. J Clin
Oncol 1993;11:1024-32.
2. Magrath. The treatment of pediatric lymphomas:
Paradigms to plagiarize?Annals of Oncology 8 (Suppl 1):
S7-S14, 1997.
3. Patte C, Michon J, Frappaz D, et al. Short-pulse B Non
Hodgkin’s lymphoma type chemotherapy is efficacious
treatment for pediatric anaplastic large cell lymphoma:
16.5 Wilms’ Tumor
Purna A Kurkure, Brijesh Arora, Shailesh Kanvinde
INTRODUCTION
Wilms’ tumor is the commonest childhood renal tumor
and is named after a German surgeon Max Wilms, who
described it first in 1899. Wilms’ tumor develops as a
result of abnormalities in the development of meta-
nephric blastema. Wilms’ tumor is the model tumor for
multidisciplinary treatment approach in pediatric
malignant solid tumors.
Epidemiology
The median age at presentation is 4 years for unilateral
tumors and 2.5 years for bilateral tumors. Approximately
1.5 % cases of Wilms’ tumor are familial. It constitutes 6
% of all childhood cancers.
Wilms tumor normally develops in otherwise healthy
children; however, approximately 10% of patients with
Wilms tumor have recognizable phenotypic syndromes
which have been divided into overgrowth and non-
overgrowth categories. Overgrowth syndromes result in
macroglossia, nephromegaly, and hemihypertrophy such
as Beckwith-Wiedemann syndrome ( BWS; 10% to 20%
of Wilms tumor incidence), isolated hemihypertrophy
(3% to 5% of Wilms tumor incidence), Perlman syn-
drome, and Sotos’ syndrome etc. Examples of non-
overgrowth syndromes are isolated aniridia; Wilms
tumor, aniridia, ambiguous genitalia, and mental
retardation (WAGR) syndrome; Bloom’s syndrome, and
Denys-Drash syndrome (characterized by intersexual
Pediatric Oncology 887
a report of the Berlin-Frankfurt-Munster group trial NHL
BFM 90. Blood 2001;97:3699-3706.
4. Reiter A, Schrappe M, Parwaresch, et al. Non Hodgkin’s
lymphomas of childhood and adolescence: results of a
treatment stratified for biologic subtypes and stage - a
report of the Berlin-Frankfurt-Munster group. J Clin
Oncol 1995;13:359-372.
5. Reiter A, Schrappe M, Tiemann M, et al. Improved
treatment results in childhood B-cell neoplasms with
tailored intensification of therapy: a report of the Berlin-
Frankfurt-Munster group Trial NHL - BFM 90. Blood
1999;94:3294-3306.
disorders, nephropathy, and Wilms tumor). Children
with a predisposition to develop Wilms tumor (e.g.,
Beckwith-Wiedemann syndrome, WAGR, hemihyper-
trophy, or aniridia) should be screened with ultrasound
every 3 months until they reach age of 8 years.
Although most patients with Wilms’ tumor are
karyotypically normal, genomic studies have led to the
localisation and subsequent cloning of WT genes in two
regions - 11p13 and 11p15. The former is WT1 gene and
is associated with WAGR Syndrome and the latter is WT2
gene which is associated with Beckwith Wiedemann
Syndrome. Additional tumor-suppressor or tumor-
progressive genes may lie on chromosomes 16q and 1p
as evidenced by LOH for these regions in 17% and 11%
of Wilms tumors, respectively. Patients classified by
tumor-specific loss of these loci have significantly worse
relapse-free and overall survival rates, and warrant more
aggressive therapy.
Pathology
Most Wilms’ tumors are unicentric, 11% are multicentric
but unilateral and 7% are bilateral. Histologically, Wilms
tumor mimics development of a normal kidney consis-
ting of three-cell types (triphasic): blastemal, epithelial
(tubules), and stromal. Not all tumors are triphasic, and
monophasic patterns may present diagnostic difficulties.
There is no anaplasia in 90% of Wilms’ tumors.
Approximately 10% cases may have anaplastic histology
(extreme cellular pleomorphism and atypia), which may
888 IAP Textbook of Pediatrics

be focal or diffuse. Focal anaplasia does not confer a poor Investigations

prognosis, while diffuse anaplasia does. Anaplasia is
Investigation Purpose
associated with resistance to chemotherapy and may still
1. Abdominal USG Organ of origin
be detected after preoperative chemotherapy. Clear cell
and Doppler Identify contralateral
sarcoma of the kidney, rhabdoid tumor of the kidney,
Kidney involvement
neuroepithelial tumor of the kidney, and cystic partially-
Presence/absence of
differentiated nephroblastoma are childhood renal
tumor thrombus in IVC
tumors distinct from Wilms’ tumor.
2. CT-Scan Further evaluation of
Clinical Features extent of tumor extension
into adjoining structures
Most commonly patients present with a palpable such as liver, spleen and
abdominal mass accidentally noted by the parents or colon.Visualisation and
during the course of a routine clinical examination. function of contralateral
However, about one third of patients present with
kidney
abdominal pain, anorexia, vomiting, malaise, or a
3. Chest Xray/CT-Scan Pulmonary metastasis
combination of these symptoms. Gross or microscopic
4. Fine needle aspiration Cytological confirmation
hematuria is found in 30% of patients. Hypertension is
cytology of mass of diagnosis prior to
present in about 25% and is attributed to increase in renin
prenephrectomy
activity. Occasional presentation in a subset of patient is
chemotherapy
rapid enlargement of the abdomen associated with fever,
anemia and hypertension as a result of sudden sub- Staging: Due to the different treatment approaches
capsular hemorrhage. In rare cases of renal vein or caval adopted by the two large cooperative study groups, two
extension of tumor, varicocele, hepatomegaly, ascites or major staging systems are currently used: american early
congestive heart failure may be present. Acquired von surgery-based system developed by the National Wilms
Willebrand’s disease may occur in less than 10% of Tumor Study group (NWTSG Table 16.5.1) and an
patients. Features of congenital syndromes may be european delayed surgery-based system developed by
present in 13-28% of patients. SIOP (International society of Pediatric Oncology).

TABLE 16.5.1: Staging system of the National Wilms’ Tumor Study (NWTS)

Stage I Tumor limited to the kidney and completely excised

a. The tumor was not ruptured before or during removal
b. The vessels of the renal sinus are not involved beyond 2 mm
c. There is no residual tumor apparent beyond the margins of excision
Stage II Tumor extends beyond the kidney but is completely excised
a. No residual tumor is apparent at or beyond the margins of excision
b. Tumor thrombus in vessels outside the kidney is stage II if the thrombus is removed en bloc with the tumor
Stage III Residual tumor confined to the abdomen:
a. Lymph nodes in the renal hilum, the periaortic chains, or beyond are found to contain tumor
b. Diffuse peritoneal contamination or implants are found on the peritoneal surfaces
c. Tumors was biopsied before surgery (tru-cut, open or FNAC)
d. Tumor extends beyond the surgical margins either microscopically or grossly
e. Tumor is not completely resectable because of local infiltration into vital structures
Stage IV Presence of hematogenous metastases or metastases to distant lymph nodes
Stage V Bilateral renal involvement at the time of initial diagnosis

Although a direct comparison is not practical due to the
difference in surgical timing, both staging systems are
valuable in predicting outcomes.
Prognostic Factors
The tumor stage at diagnosis, histological features
(favorable vs unfavorable, presence of diffuse anaplasia)
and patient age are the most important prognostic
determinants which impact on treatment selection and
outcome. Loss of heterozygosity at chromosome 1p and
16q are also considered for treatment plan in current
trials.
Treatment
WT can be considered a model for successful multi-
disciplinary management of cancer, with improvement
in survival from a mere 30% in 1930s to more than 85%
at present. The most important contributions have been
from NWTSG and SIOP. However, there is a philo-
sophical difference in their treatment approach. The
NWTSG recommends primary surgery before adminis-
tration of chemotherapy while SIOP advocates adminis-
tration of 4 weeks of chemotherapy prior to surgery.
NWTS approach allows accurate documentation of
histology and tumor extent prior to chemotherapy. The
SIOP approach downstages the disease, makes surgery
easier and reduces the chances of spillage with
consequent reduction in abdominal and distant relapse
but carries a risk of non-WT histology being present in
the primary tumor. The NWTSG advocates preoperative
chemotherapy only in presence of WT in a solitary or
horseshoe kidney, bilateral tumors and venal caval
thrombus above hepatic veins. Since both these
approaches have yielded excellent results; individua-
lization of treatment based on tumor size and extent,
general condition of patient and surgeon’s experience is
Figure 16.5.1: Algorithm for Management (Based on NWTS)
CPM = cyclophosphamide; DAM = dactinomycin ; DOX = doxorubicin;
VCR = vincristine; RT = radiotherapy; FH = favourable histology;
UH= unfavourable histology; wk = week; PI = pulse intensive.
NWTS – National Wilms’ Tumour Study Group
Pediatric Oncology 889
required. The NWTS treatment approach and outcome
is illustrated in Figure 16.5.1.
Principles of Surgery
Surgical resection is the most important component in
the multimodal management of WT. Radical nephrec-
tomy with lymph node sampling through the trans-
peritoneal route is the standard of care. Tumor spillage
and intraperitoneal dissemination increases the risk of
intraabdominal relapse. Partial nephrectomy is only
recommended for patients with synchronous or
metachronous bilateral tumors, tumors in solitary
kidneys, renal insufficiency of any etiology and children
with risk of multiple neoplasms such as in BWS.
Chemotherapy
Chemotherapy plays a very important role in the
management of WT. The current first line drugs for WT
are vincristine, dactinomycin and doxorubicin. The
second line drugs for non-responsive or relapsed disease
are ifosfamide, etoposide, carboplatin and cyclo-
phosphamide. The SIOP group has favored the use of
preoperative chemotherapy in attempt to down stage the
tumor, whereas the NWTS advocates upfront nephrec-
tomy without preoperative therapy in order to precisely
identify the tumor stage.
Radiotherapy
Radiation to flank or abdominal irradiation is considered
for stage III favorable-histology (FH) tumors and stage
II–III diffuse anaplastic WT. Radiotherapy should be
planned starting within 10 day of surgery. Whole lung
irradiation is administered for patients with pulmonary
metastases.
890 IAP Textbook of Pediatrics

NWTS Treatment and Results CONCLUSION

Patients with stages I-II/FH or stage I/anaplastic Wilms’ Since Wilms’ tumor is one of the most curable malig-
tumor are classified as low risk (LR) and those with stages nancies of childhood; current emphasis is on maximizing
III-IV/FH Wilms’ tumor or stages I-IV/anaplasia are cure, minimizing late effects and continued surveillance
classified as high risk (HR). for late effects of therapy.

BIBLIOGRAPHY
1. D’Angio GJ, Breslow N, Beckwith JB, et al. Treatment of
Risk Group Treatment Stage 2 yrs OS (%) Wilms’ tumor. Results of the Third National Wilms’
Tumor Study. Cancer 1989;64(2):349-60.
Low risk Low-intensity I-II ( FH) More than 2. Green DM, Breslow NE, Beckwith JB, et al. Effect of duration
CT I(anaplasia) 95% of treatment on treatment outcome and cost of treatment
High Risk High intensity III-IV/FH 85-95% for Wilms’ tumor: a report from the National Wilms’ Tumor
Study Group. J Clin Oncol 1998;16(12): 3744-51.
CT+ RT II-IV/UFH 40-80%
3. Grundy PE, Breslow N, Li S, et al. Loss of Heterozygosity
OS - Overall survival , CT-Chemotherapy, RT- radiotherapy for Chromosomes 1p and 16q is an Adverse Prognostic
Factor in Favorable Histology Wilms’ Tumor. A Report
from the National Wilms’ Tumor Study Group. J Clin
Oncol 2005;23:7312-21.
Long Term Sequelae 4. J De Kraker. Commentary On Wilms’ Tumour. European
Journal of Cancer 1997;33(3):419-20.
Renal failure after surgical management of unilateral WT 5. Kalapurakal JA, Dome JS, Perlman EJ, et al. Management
is rare. Cardiac problems secondary to anthracycline of Wilms’tumor: current practice and future goals. Lancet
Oncol 2004;5:37-46.
administration compounded by whole lung radiotherapy 6. Reinhard H, Semler O, Burger D, et al. Results of the
as well as pulmonary complications secondary to whole SIOP 93-01/GPOH trial and study for the treatment of
lung radiotherapy are real concerns in long-term and patients with unilateral nonmetastatic Wilms’ Tumor.
Klin Padiatr 2004;216:132-140.
need to be addressed. Gonadal dysfunction secondary 7. Tournade MF, Com-Nougue C, de Kraker J, et al. Optimal
to chemo and or radiotherapy may occur. Children duration of preoperative therapy in unilateral and
treated for WT are also at an increased risk of second nonmetastatic Wilms’ tumor in children older than 6
months: results of the Ninth International Society of
malignancy, especially if they have received radiotherapy Pediatric Oncology Wilms’ Tumor Trial and Study. J Clin
in addition to chemotherapy. Oncol 2001;19:488-500.

16.6 Neuroblastoma
Purna A Kurkure, Brijesh Arora, Shailesh Kanvinde

INTRODUCTION children younger than 5 years. It accounts for 7-10% of

Neuroblastoma is the most common extracranial solid
tumor in children and the most common tumor in
infancy. Neuroblastoma and related neoplasms arise
from those neural crest cells which differentiate in to cells
of the sympathetic ganglia and adrenal medulla. Hence,
Neuroblastoma originates in the adrenal medulla or
paraspinal sites where sympathetic nervous system
tissue is present (Fig. 16.6.1).
Epidemiology
Neuroblastoma is predominantly a tumor of early
childhood, with two thirds of the cases presenting in
all childhood cancers. The etiology is unknown.
Occasionally, it is congenital or is discovered prenatally
by fetal ultrasonography.
Clinical Features
The most common presentation of neuroblastoma is an
abdominal mass. The most common symptoms are due
to a tumor mass or bone pain from metastases. Approxi-
mately 70% of patients with neuroblastoma have
metastatic disease at diagnosis. Proptosis and periorbital
ecchymosis are common in these patients and arise from
retrobulbar metastasis (Fig. 16.6.2) Extensive bone

Figure 16.6.1: Location of sympathetic chain
Figure 16.6.2: Neuroblastoma—Raccoon’s sign with
bilateral proptosis
marrow metastasis may result in pancytopenia. Abdo-
minal distention with respiratory compromise due to
massive liver metastases may occur in infants. Because
they originate in paraspinal ganglia, neuroblastomas may
invade through neural foramina and compress the spinal
cord extradurally, causing paralysis. Horner syndrome
may be caused by neuroblastoma in the stellate ganglion,
and children with Horner syndrome without apparent
cause should be examined for neuroblastoma and other
tumors. Fever, anemia, and hypertension are occasionally
Pediatric Oncology 891
found. On rare occasions, children may have severe,
watery diarrhea due to the secretion of vasoactive
intestinal peptide by the tumor. Children with neuro-
blastoma rarely present with paraneoplastic neurologic
findings, including cerebellar ataxia or opsoclonus/
myoclonus. The opsoclonus/myoclonus syndrome
appears to be caused by an immunologic mechanism that
is not yet fully defined.
Pathology
Neuroblastoma is one of the small blue round cell tumors
of childhood (others are Non-Hodgkin’s lymphoma,
Ewing’s/Primitive neuroectodermal tumor and Rhabdo-
myosarcoma). The typical neuroblastoma is composed
of small, uniform cells with hyperchromatic nuclei and
scanty cytoplasm. The presence of neuritic processes
(neurophil) and Homer-Wright pseudorosettes helps to
distinguish neuroblastoma from other round cell tumors.
The fully differentiated, benign counterpart of neuro-
blastoma is the ganglioneuroma which is composed of
mature ganglion cells, neurophils and schwann cells.
Ganglioneuroblastoma has features intermediate
between the other two.
Evaluation of Patient (Figs 16.6.3 and 16.6.4)
• Primary site
X-Ray, USG, CT-Scan/MRI scan
24 hr-Urinary VMA
131I MIBG scan
• Metastatic disease
Bone marrow aspiration and trephine biopsy
Technetium Bone scan
131I MIBG scan
Figure 16.6.3: Abdominal neuroblastoma with calcification
892 IAP Textbook of Pediatrics

INSS EVANS

Stage 1 Stage I
Localized tumor confined to Tumor limited to organ
the area of origin; complete or structure of origin
gross excision with or
without microscopic residual
disease, ipsilateral and
contralateral lymphnodes
negative microscopically
Stage 2 A Stage II
Unilateral tumor with Tumor with regional
incomplete gross excision; spread that does not
identifiable ipsilateral and cross the midline;
Figure 16.6.4: Posterior mediastinal mass in
contralateral lymphnodes ipsilateral lymphnode
thoracic neuroblastoma
negative microscopically may be involved
Stage 2 B
Diagnostic Criteria Unilateral tumor
The gold standard for the diagnosis of neuroblastoma is with complete
or incomplete
examination of tumor tissue by histopathology. Some
gross excision;
neuroblastomas cannot be differentiated, via conven- with positive ipsilateral
tional light microscopy, from other small round blue cell lymph nodes, identifiable
tumors of childhood. In these cases, evidence for contralateral nodes
negative microscopically
sympathetic neuronal differentiation may be demons-
trated by immunohistochemistry, electron microscopy Stage 3 Stage III
or by finding elevated levels of serum catecholamines Tumor with spread to Regional tumor crossing
(e.g., dopamine and norepinephrine) or urine catecho- midline with or without the the midline; bilateral
involvement of regional lymph nodes may be
lamine metabolites, such as vanillylmandelic acid (VMA)
lymph node or unilateral involved
or homovanillic acid (HVA). tumor with contralateral
regional lymph node
The International Neuroblastoma diagnostic criteria involvement or midline
(INDC) are: tumor with bilateral regional
1. An unequivocal pathological diagnosis made from lymphnode involvement
tumor tissue by light microscopy (with or without
Stage 4 Stage IV
immunohistochemistry and electron microscopy Dissemination of tumor Tumor with metastases
and/or increased urine catecholamines or metabolites to distant lymph nodes, bone, to distant sites
Or bone marrow, liver and/or
other organs
2. Bone marrow aspirate or biopsy containing unequi-
vocal tumor cells, and increased urine catecholamines Stage 4-S Stage IV-S
or metabolites. Localised primary tumor as Localized primary tumor
defined for Stage I or II and disseminated disease
Staging of Neuroblastoma with dissemination limited limited to liver, skin
to liver, skin and/or bone and/or bone marrow
Clinical staging as per Evans (CCSG) staging system is marrow
done if surgery is not done upfront. International
neuroblastoma staging system (INSS) is used when To facilitate comparison of results obtained with
surgical details are available and is one of the most different treatment regimens, a radiology-based
important prognostic factors. international risk group staging system has been recently
 Pediatric Oncology 893

developed. Here in, localized or metastatic disease is
determined by the absence or presence of image-defined
surgical risk factors.
RISK STRATIFICATION
Depends upon many factors.
Age and Stage
Children of any age with localized neuroblastoma and
infants younger than 1 year with advanced disease and
favorable biological characteristics have a high likelihood
of long-term, disease-free survival. Older children with
advanced-stage disease, however, have a significantly
decreased chance for cure, despite intensive therapy.
Pathology
The Shimada’s pathologic classification appears to have
prognostic significance. it is based on histological features
such as presence or absence of stroma, degree of
differentiation and mitosis-karrhyorexis index.
Biological Factors
Treatment decisions are based on important factors such
as tumor cell chromosome number, amplification of the
MYCN oncogene within tumor tissue, unbalanced 11q
loss of heterozygosity (LOH), and LOH for chromosome
1p. An open biopsy is usually needed to obtain adequate
tissue for determination of these biological charac-
teristics. Other biological prognostic factors that have
been extensively investigated include tumor cell telomere
length, telomerase activity, and RNA; urinary vanillyl-
mandelic acid (VMA), homovanillic acid (HVA), and
their ratio; TrkA gene expression; neuron-specific enolase
level, serum lactic dehydrogenase level, and serum
ferritin level.
Treatment
Treatment strategies vary according to the risk groups
(See Table 16.6.1). The risk of progression of the tumor
causing morbidity and mortality is gauged based on the
stage of the tumor, the age of the child at diagnosis, and
tumor biology. The biological features considered are the
Shimada classification, amplification of the MYCN gene,
and the number of chromosomes in tumor cells. For
identical age, stage and NMYC status, presence of
unfavorable histology upgrades the patient to the next
risk category.
This risk-based neuroblastoma treatment plan assigns
each patient to a low-, intermediate-, or high-risk group.
(Risk groups are defined in the Table 16.6.1). In patients
without metastatic disease, initial surgery is performed
to establish the diagnosis, to resect as much of the
primary tumor as possible, to accurately stage disease
through sampling of regional lymph nodes that are not
adherent to the tumor, and to obtain adequate tissue for
biological studies.

TABLE 16.6.1: Treatment strategy based on risk categories of the patients

Risk category Treatment Survival

Risk Stage Age NMYC

(months)

Low 1 Any Any Surgery 90%

2A/2B# Any Non-amp Surgery followed by low dose chemotherapy 85-90%
(cyclophosphamide and doxorubicin)
4S* <12 Non-amp Observation if asymptomatic, chemotherapy/RT
if symptomatic
Intermediate 3# Any Non-amp Multiagent chemotherapy (cyclophosphamide, 75%
4 < 18 Non-amp cisplatin, etoposide, doxorubicin) +
4S** < 12 Non-amp 2nd look surgery ± RT to tumor bed if gross
residual disease
High 2A/2B > 12 Amp Multiagent chemotherapy as induction followed by
3 Any Amp surgery, high dose chemotherapy with autologous
4S < 12 Amp BMT as consolidation and biological therapy (13 cis-
4 > 18 Any retinoic acid) as maintenance treatment for minimal 20-40%
residual disease

*DNA index > 1, **DNA index = 1, # - stage 2/3 with favorable histology
894 IAP Textbook of Pediatrics
INTERNATIONAL NEUROBLASTOMA
RISK GROUP SYSTEM
A new risk group system has been developed based on
13 prognostic factors including stage, age, histology,
grade, MYCN status, 11q or 1p status, DNA ploidy, LDH
etc. It classifies patients in to 4 groups; very low risk
(>85% event free survival), Low-risk (75-85% EFS),
intermediate risk (50-75% EFS) and high risk (< 50%
survival). It is likely to be internationally adopted soon
for treatment planning and prognostication in all new
cases.
Low Risk
Treatment for patients categorized as low risk is with
surgery alone, but surgery may be combined with 6 to
12 weeks of chemotherapy. Chemotherapy is reserved
for patients who are symptomatic, such as from spinal
cord compression or, in stage 4S, respiratory compromise
secondary to hepatic infiltration. The chemotherapy
agents include carboplatin, cyclophosphamide, doxo-
rubicin, and etoposide. The cumulative dose of each
agent is kept low to minimize permanent injury from
the chemotherapy regimen.
Observation in Special Low-Risk Cases
Selected presumed neuroblastomas incidentally detected
in infants by screening or ultrasound with low urinary
VMA and HVA levels, no involvement of great vessels
or invasion into the spinal canal, and small tumor size
may safely be observed without obtaining a definitive
histologic diagnosis and without surgical intervention,
thus avoiding potential complications of surgery in the
newborn.
Intermediate Risk
Patients categorized as intermediate risk are treated with
surgery and 12 to 24 weeks of the same chemotherapy
regimen as in low-risk. Radiotherapy may be required
in selected cases.
High Risk
Patients categorized as high risk are generally treated
with aggressive multiagent chemotherapy consisting of
very high doses of carboplatin, cyclophosphamide,
doxorubicin, etoposide, ifosfamide and high-dose
cisplatin. After the induction chemotherapy, resection
of the primary tumor should be attempted, followed by
consolidation with myeloablative chemotherapy,
sometimes total-body irradiation, and autologous stem
cell transplantation. Radiation of residual tumor and
original sites of metastases is often performed before,
during or after myeloablative therapy. After recovery,
oral 13-cis-retinoic acid for 6 months is given for
treatment of minimal residual disease. Both myelo-
ablative therapy and retinoic acid improve outcome in
patients categorized as high risk.
Newer Therapies
A slew of novel chemotherapeutic as well as biological
molecules are being evaluated in clinical trials. Many of
these including monoclonal antibody therapy with anti-
GD2 antibody, tandem myeloablation and stem cell
transplantation, 131I-MIBG therapy, and topotecan
might become part of frontline therapy in future.
CONCLUSIONS
Neuroblastoma represents one of the most enigmatic and
challenging malignancies for treatment decisions because
of its unusual biological behavior which includes
spontaneous regression at one end to treatment resistant
progression at other end of the spectrum. The main
achievements in the management of Neuroblastoma
during the last two decades have been the reduction of
chemotherapy in patients with low risk disease and the
intensification of chemotherapy in high risk disease.
BIBLIOGRAPHY
1. Brodeur GM, Pritchard J, Berthoid F, et al. Revisions of
the International criteria for Neuroblastoma diagnosis
staging and response to treatment. J Clin Oncol
1993;11(8):1466-77.
2. George RE, London WB, Cohn SL, et al. Hyperdiploidy
plus nonamplified MYCN confers a favorable prognosis
in children 12 to 18 months old with disseminated
neuroblastoma: a Pediatric Oncology Group study. J Clin
Oncol 2005;23(27):6466-73.
3. Katherine K. Matthay, Judith G. Villablanca, Robert C.
Seeger, et al. Treatment of high risk Neuroblastoma with
intensive chemotherapy, Radiotherapy, Autologous
Bone Marrow Transplantation, and 13-CIS-Retinoic Acid.
New England Journal of Medicine 1999;341(16):1165-73.
4. LC Bowman, ML Hancock, VM Santana, et al. Impact of
intensified therapy on clinical outcome in infants and
children with neuroblastoma: The St Jude Children’s
Research Hospital experience, 1962 to 1988 Journal of
Clinical Oncology 9:1599-1608.

5. Nickerson HJ, Matthay KK, Seeger RC, et al. Favorable
biology and outcome of stage IV-S neuroblastoma with
supportive care or minimal therapy: a Children’s Cancer
Group study. J Clin Oncol 2000;18(3):477-86.
6. Nishihira H, Toyoda Y, Tanaka Y, et al. Natural course
of neuroblastoma detected by mass screening: s 5-year
prospective study at a single institution. J Clin Oncol
2000;18(16):3012-7.
7. RP Castleberry, JJ Shuster, G Altshuler, et al. Infants with
neuroblastoma and regional lymph node metastases
have a favorable outlook after limited postoperative
16.7 Soft Tissue Sarcoma
Soft tissue sarcomas in children are relatively rare. They
are conveniently divided into two broad categories
rhabdomyosarcoma (RMS) and nonrhabdomyosarcoma
soft tissue sarcomas (NRSTS). The incidence of these soft
tissue sarcomas is age dependent; RMS accounts for 60%
of cases in children younger than 5 years; in contrast,
more than three-fourths of all soft tissue sarcomas in
patients aged 15 to 19 years are NRSTS. Surgery is the
prime treatment modality for all pediatric soft tissue
sarcomas. Chemotherapy has a major role in the
treatment of RMS while its role in NRSTS is restricted
for high grade and large size tumors.
Rhabdomyosarcoma
RMS is the most common soft tissue sarcoma in children
and adolescents, accounting for approximately 5% of all
pediatric cancers and approximately half of all soft tissue
sarcomas. 1 The multidisciplinary approach for the
treatment of RMS led to the formation of the Intergroup
Rhabdomyosarcoma Study Group (IRSG) in 1972. The
IRSG (now the Soft Tissue Sarcoma Committee of the
Children’s Oncology Group) has completed four
consecutive cooperative group trials (IRS-I: 1972–1978;
IRS-II: 1978–1984; IRS-III: 1984–1991; IRS-IV: 1991–1997)
evaluating new drug combinations, chemotherapy
intensity, radiologic evaluation of tumors, radiotherapy
and tumor biology. 2 These studies and therapeutic trials
have lead to an increase in 5 years survival from 25% to
70% over the past 40 years (Fig. 16.7.1).
Most cases of RMS occur sporadically, but the disease
has been associated with familial syndromes, including
Pediatric Oncology 895
chemotherapy: A Pediatric Oncology Group Study.
Journal of Clinical Oncology 10:1299-1304.
8. Schmidt ML, Lal A, Seeger RC, et al. Favorable prognosis
for patients 12 to 18 months of age with stage 4
nonamplified MYCN neuroblastoma: A Children’s
Cancer Group Study. J Clin Oncol 2005;23(27):6474-80.
9. Shimada H, Ambros IM, Dehner LP, et al. Terminology
and morphologic criteria of neuroblastic tumors:
recommendations by the International Neuroblastoma
Pathology Committee. Cancer 1999;86(2):349-63.
Sajid Qureshi, Purna A Kurkure
Figure 16.7.1: Chart showing study of rhabdomyosarcoma:
Increase in 5-year survival from 25% to 70%; over the past 40
years
Li Fraumeni (caused by germline mutation of p53) and
neurofibromatosis (caused by mutation in NF1).
Pathology
RMS belongs to the family of small, round, blue cell
tumors which also include neuroblastoma, lymphoma
and PNET. Three general pathologic types of RMS have
been described: embryonal, alveolar, and pleomorphic.
A rare primitive tumor, undifferentiated sarcoma, has
also been included in the IRSG. Subsets of embryonal
RMS include botryoid and spindle cells. The contem-
porary International Classification of RMS categorizes
(a) botryoid and spindle-cell RMS, as having a superior
prognosis; (b) embryonal RMS, with an intermediate
prognosis; (c) alveolar RMS and undifferentiated
sarcoma having a poorer prognosis.
896 IAP Textbook of Pediatrics
Embryonal RMS is the most common histology seen
in children, comprising more than two-thirds of all RMS.
The head and neck and genitourinary tract RMS are
frequently embryonal type. Ten percent are botryoid, and
these tumors commonly arise in hollow organs like the
vagina, nasopharynx, biliary tract, and urinary bladder.
Spindle cell tumors are common in the paratesticular site.
Alveolar RMS is seen in approximately 20% of children
and is most frequently found in the extremities, trunk,
and perineum.
Molecular studies of embryonal RMS have shown loss
of heterozygosity at the 11p15 locus. Alveolar RMS are
associated with translocations of the FKHR gene on
chromosome 13 with PAX3 (chromosome 2) or PAX 7
(chromosome 1) in 55% and 22% respectively.
Clinical Presentation
The clinical presentation of a child with rhabdomyo-
sarcoma varies depending on the primary site. Approxi-
mately 40% of rhabdomyosarcoma occur in the head and
neck region; another 20% arise from the genitourinary
sites, 20% in the extremities, and 20% other locations.1
Head and Neck
Approximately 25% head and neck RMS arise in the orbit,
50% in other parameningeal sites, and 25% in nonorbital,
nonparameningeal locations, such as the scalp, face,
buccal mucosa, oropharynx, larynx, and neck. The
parameningeal sites include tumors arising from the
nasopharynx, nasal cavity, paranasal sinus, middle ear–
mastoid region, infratemporal fossa, and pterygopalatine
fossa. These sites exhibit a propensity for bony erosion
and contiguous intracranial spread hence, they have the
worst prognosis.
Genitourinary
Tumors arising from the prostate or bladder are
frequently large, so that it may not be possible to
determine the specific site of origin. Paratesticular RMS
arises from mesenchymal elements of the spermatic cord,
epididymis, or tunics.
RMS of the vagina and vulva occur in young children
and present with a nodule or protrusion of grape-like
mass from the introitus. Uterine corpus and cervix RMS
are less common compared with vaginal tumors.
Extremity
Extremity RMS is characterized by a higher incidence of
regional lymph nodes involvement (10–25%) which has
a negative impact on survival. Hence surgical evaluation
of lymph nodes, even when there are no clinically
involved nodes, is necessary to ensure accurate staging.
Other Locations
Paraspinal, abdominal wall, chest wall, perineum/
perianal, retroperitoneum/pelvis and biliary tract are
other sites for RMS.
Preoperative Workup
In addition to a complete history, physical examination
and standard investigations including complete blood
counts (CBC), electrolytes, and renal function tests, liver
function tests (LFTs) and urinalysis (UA) specific
investigations for evaluation of the primary tumor and
metastatic disease should be performed.
Computed tomography (CT) and magnetic resonance
imaging (MRI) of the primary site can help determine
the tumor size and extent as well as invasion to
surrounding structures. The draining lymph nodes are
also imaged to determine spread particularly in children
with extremity lesions or boys >10 years of age with
paratesticular RMS. CT is advantageous for the
evaluation of bone erosion and abdominal adenopathy.
MRI is preferable over CT for limb, pelvic, and paraspinal
lesions. Metastatic workup includes a bone marrow
aspirate and imaging of the chest and bones. For children
with parameningeal tumors, imaging of the neuraxis is
important to determine whether there is intracranial
extension and/or neuraxis spread; the cerebrospinal fluid
from a spinal tap is also analyzed for malignant cells as
parameningeal tumors can disseminate through this
route. Routine brain imaging for asymptomatic patients
with metastatic disease and non-head and neck primary
is not generally helpful.
Pretreatment Clinical Staging
Pretreatment clinical staging is based on physical
examination and preoperative imaging and determined
by the site, size, and invasiveness of the primary tumor,
nodal status, and distant spread (Table 16.7.1). Favorable

TABLE 16.7.1: IRS pretreatment staging
Stage Sites
1 Orbit, head, and neck (excluding
parameningeal), GU-non-
bladder/non-prostate, biliary
tract
2 Bladder/prostate, extremity,
parameningeal, other
(includes trunk,
retroperitoneum, etc.)
3 Bladder/prostate, extremity,
Parameningeal, other
(includes trunk,
retroperitoneum, etc.)
4 All
*T, tumor; T1, confined to anatomic site of origin; T2, extension and/or fixation to surrounding tissue.
†Size; a, < 5 cm; b, > 5 cm
‡N, regional nodes; NO, regional nodes not clinically involved; Nx, clinical status of regional nodes unknown; N1, regional nodes clinically
involved.
§M, metastasis; M0, no distant metastasis; M1, distant metastasis present.
sites of location include the orbit, nonparameningeal
head and neck, paratesticular, gynecological and biliary
tract tumors, whereas unfavorable sites include the
parameningeal, extremity, bladder, prostate, trunk, and
retroperitoneal tumors. The presence of positive cytology
from the cerebrospinal fluid, pleural or abdominal fluids,
as well as implants on pleural or peritoneal surfaces is
considered distant metastasis.
Surgical Principles
Biopsy
Biopsy incision should be planned in such a way that it
can be incorporated in future resection of the tumor.
Adequate tissue should be removed for pathologic and
biological studies. For deeper, less-accessible lesion core
needle biopsy is appropriate for diagnosis.
Resection of the Mass
If the initial surgical procedure was performed prior to
the diagnosis of RMS, more often than not, gross residual
disease or contaminated margins could be anticipated.
Under these circumstances re-excision is advisable.
Pretreatment re-excision (PRE) is a wide re-excision of
the previous operative site, including an adequate
margin of normal tissue before adjuvant therapy. PRE is
Pediatric Oncology 897
T* Size† N‡ M§
T1 or T2 a or b N0 or N1 or Nx M0
T1 or T2 a N0 or Nx M0
T1 or T2 a N1 M0
b N0 or N1 or Nx M0
T1 or T2 a or b N0 or N1 M1
particularly applicable to extremity and trunk lesions,
but should be applied whenever feasible as it impacts
the failure-free survival and overall survival.
The goal of surgery is wide and complete resection
of the primary tumor with a surrounding envelope of
normal tissue without disfiguring or compromising the
function. For unresectable tumors at initial diagnosis
neoadjuvant chemotherapy with or without RT may be
able to shrink the tumor with possibility of surgery.
Adequate margins of 0.5 cm should be obtained
circumferentially which is more easily obtained in the
extremities or trunk compared to head and neck tumors.
All margins should be marked and oriented at the
operative field to enable precise evaluation of margins.
Any microscopic or gross tumor should be marked with
small titanium clips in the tumor bed to aid radiotherapy
simulation and subsequent re-excision.
Lymph Node Sampling/Dissection
Clinically and radiologically positive nodes should be
biopsied to confirm tumor involvement thus ensuring
correct assessment of disease risk and assignment of
optimal therapy. The surgical evaluation of nodes that
are clinically uninvolved are specifically required in
extremity tumors and for children older than 10 years of
age with paratesticular tumors. Lymph node evaluation
898 IAP Textbook of Pediatrics

should not include a fervent lymphadenectomy as the
intent is not therapeutic and studies have shown that
there is no benefit from formal nodal dissection especially
if metastasis of RMS from the tumor site has occurred.
The concept of sentinel node mapping offers promise for
selective identification of nodes with subclinical disease.
If regional nodes are positive then nodes distal to the
regional nodes, should be harvested for pathologic study
since any tumor identified in these nodes would be
considered metastatic disease and would affect therapy.
Clinical Group
After pathologic examination from the definitive
operation, patients are assigned to a Clinical Group based
on the completeness of tumor excision and the evidence
of tumor metastasis to the lymph nodes or distant organs.
(Table 16.7.2). The extent of the disease after resection is
one of the most important prognostic factors to predict
which patients are likely to be cured. Decisions regarding
use of radiotherapy (RT) are often based on the Group
as patients with group 2, 3, and 4 tumors require RT.
Chemotherapy
RMS is a systemic disease hence even localized RMS may
be associated with distant micro metastasis. The gold
standard for chemotherapy includes a combination of
vincristine, dactinomycin, and cyclophosphamide
(VAC). Current IRS treatment recommendations are
based on risk group classification (Table 16.7.3). Low risk
children have a greater than 90% 5-year survival,
intermediate risk ranging from 55% to 70% 5-year
survival, and high risk less than 50% 5-year survival.
Combinations of VA + RT remain the standard
treatment for patients with low risk disease. The standard
TABLE 16.7.2: Clinical grouping system
Group I Localized disease, completely resected
A. Confirmed to organ or muscle of origin
B. Infiltration outside organ or muscle of origin;
regional nodes not involved
Group II Compromised or regional resection including
A. Grossly resected tumors with microscopic
residual tumor
B. Regional disease, completely resected, with
nodes involved and/or tumor extension into
an adjacent organ
C. Regional disease, with involved nodes,
grossly resected, but with evidence of
microscopic residual tumor
Group III Incomplete resection or biopsy with gross
residual disease remaining
Group IV Distant metastases present at onset
chemotherapy in patients with high-risk disease is
combination of VAC and RT.
Radiotherapy
RT is an important treatment modality for RMS especially
in the setting of residual (microscopic) disease or when
surgery is not feasible or very morbid. Children with
group 1 embryonal disease may not need RT. All patients
with group II to IV tumors receive RT as well as all group
I alveolar tumors. Doses from 36 Gy to 50.4 Gy are
commonly used. For patients with group III disease or
those with gross disease, a dose of 50.4 Gy given in 28
fractions (1.8 Gy/day) is used for all sites, with the
exception of orbital tumors which can be treated with 45
Gy in 25 fractions (1.8 Gy/day). Patients who had their
tumors resected with positive margins of resection (IRS
group IIa) receive 36 Gy in 20 fractions (1.8 Gy/day) to

TABLE 16.7.3: Risk based therapy in IRS-IV

Risk Stage Group Site Histology

Low 1 1 or 2 I or II Favorable or unfavorable EMB

1 III Orbit only EMB
Low 2 1 III Favorable EMB
3 I or II Unfavorable EMB
Intermediate 2 or 3 III Unfavorable EMB
1-3 I-III Favorable or unfavorable ALV
High 4 IV Favorable or unfavorable EMB
4 IV Favorable or unfavorable ALV

Definitions: Favorable—orbit/eyelid, head and neck (excluding parameningeal), genitourinary (not bladder or prostate).
Unfavorable—bladder, prostate, extremity, parameningeal, other (trunk, retroperitoneal, etc.).
EMB—embryonal, botryoid, or spindle variants or ectomesenchymomas with embryonal features.
ALV—alveolar or undifferentiated sarcomas, or ectomesenchymomas with alveolar features

the tumor bed. Patients who had regional node
involvement but completely resected (group IIb) receive
41.4 Gy in 23 fractions (1.8 Gy/day).
The late effects of RT are an area of concern and newer
techniques of RT delivery are being used which are
intended to minimize local toxicities without affecting
outcome. These techniques include three-dimensional
RT, intensity-modulated RT, proton therapy, and
brachytherapy.
Prognosis
The prognosis of patients with RMS is dependent on
many factors. Favorable prognostic factors include
embryonal/botryoid histology, primary tumor sites in
the orbit and nonparameningeal head/neck region and
genitourinary nonbladder/prostate regions, a lack of
distant metastases at diagnosis, complete gross removal
of tumor at the time of diagnosis, tumor size less than or
equal to 5 cm, and age less than 10 years at the time of
diagnosis. Clinical grouping was identified as one of the
most important predictor of failed treatment and tumor
relapse.
Relapse
Approximately 30% of patients with rhabdomyosarcoma
will relapse. The median survival from first recurrence
is 0.8 years with an estimated 5-year survival rate of 17%.8
Children with Stage 1 or group 1 disease and embryonal
or botryoid histology with local or regional relapse have
the best prognosis.
Nonrhabdmyosarcoma Soft Tissue Sarcomas
Nonrhabdmyosarcoma soft tissue sarcomas (NRSTS) are
a heterogeneous group of tumors accounting for 3–5%
of all childhood malignancies and around 60% of all
sarcomas in children. The relative infrequency of the
different histopathological subtypes precludes perfor-
mance of clinical trials on a single tumor type, and
consequently, NRSTS have to be analyzed as a group.
With contemporary treatment, more than 70% of
children and adolescents with surgically resected
nonmetastatic disease are expected to be cured. In
contrast, fewer than 10% of patients with metastatic
disease are expected to become long-term survivors.
Pathology
The NRSTS group encompasses several histological
variants, including synvovial sarcoma, malignant
peripheral nerve sheath tumor, alveolar soft part
sarcoma, angiosarcoma, clear cell sarcoma, fibrosarcoma,
Pediatric Oncology 899
ectomesenchymoma, epitheloid hemangioendothelioma,
GIST, hemangiopericytoma, myxoid chondrosarcoma,
spindle cell sarcoma, malignant fibrous histiocytoma
(MFH), leiomyosarcoma, epitheloid sarcoma, lipo-
sarcoma, dermatofibrosarcoma and poorly differentiated
or undifferentiated sarcoma, not otherwise specified.
Currently the WHO classification of soft tissue tumors:
intermediate (rarely metastasizing) and malignant
tumors, gives an exhaustive list of malignant NRSTS and
rhabdomyosarcoma.
With evolution of molecular studies, specific
chromosomal translocations have been identified in
certain sarcomas. Synovial sarcoma is associated with
t(x;18) (p11,q11) (SYT-SSX), alveolar soft parts sarcoma
associated with t(X;17) (p11;q25) (ASPLTFE3), and
myxoid liposarcoma with t(12;16) (q13;p11) (TLS-CHOP)
and t(12;22) (p13;q12) (EWS-CHOP). These chromosomal
translocations can be helpful in making the definitive
diagnosis and also for prognostication.
Clinical Presentation
They are more common in children above 5 years of age
but may occur in any age groups. Commonest presen-
tation includes mass lesions anywhere in the body. The
frequent anatomic sites are the extremities, most often
in the lower limbs, followed by the trunk, the thorax,
and the head/neck area. The lesions characteristically
impersonate a ‘benign-looking’, well-circumscribed
mass, which may mistakenly be observed or excised as a
shell-out procedure (‘Whoops procedure’). The extent of
the disease at presentation is usually local (70%),
locoregional (9%), or metastatic (21%). Metastatic disease
is most commonly seen in the lungs, followed by the brain
and bone marrow.
Evaluation and Diagnosis
Magnetic resonance imaging (MRI) is considered the
imaging modality of choice for the evaluation of local
and regional disease as it provides superior soft tissue
resolution, multiplanar image acquisition, and does not
require iodinated contrast agents or ionizing radiation.
Malignant lesions are usually larger and display
inhomogenous signal intensity on T2-weighted images.
A contrast-enhanced CT scan is useful for evaluation of
abdominal tumors and pulmonary metastases. Although
PET scans have become customary for investigations of
many tumors, the role in NRSTS is yet to be clearly
defined.
The utility of a biopsy in achieving a diagnosis
surpasses any other investigation. The prime consi-
900 IAP Textbook of Pediatrics
deration is to obtain adequate amount of tissue for
diagnosis with minimal disruption of tissue planes. Of
paramount importance is the correct placement of the
biopsy incision as an ill-conceived biopsy may adversely
affect the definitive surgical procedure. All incisions,
when possible, should be longitudinal on extremities,
parallel to the neurovascular structures, to allow easy
wide local excision. Fine-needle aspiration, trucut needle
biopsies or an open incisional biopsy are preferred
because they provide the least risk of local contamination.
Primary surgical resection is undertaken for small tumor
or when wide local resection can be done without risk or
functional deformity.
Treatment
Surgery
Surgery has remained the cornerstone of treatment as
many of the NRSTS are considered not very chemo-
sensitive. Wide local resection is the main objective of
surgery for NRSTS. The exact margin of resection that is
required to achieve a favorable outcome is unclear.
Historically, the standard margin of resection accepted
in adults was 2 cm, with recurrence rates of 10–15%. In
young children or adolescents with tumors in the head
and neck, mediastinum, or retroperitoneum, however, a
margin of 2 cm is not feasible as it would require
excessive mutilating surgical procedures. Previous
reports have recommended a tumor free margin or a
margin greater than 1 cm for adequate local control.11
Unplanned resections frequently (50%) have micro-
scopic residual disease which is associated with a higher
rate of local recurrence. Hence a pretreatment re-excision
or PRE should be undertaken when the initial operation
was not a cancer operation or when malignancy was not
suspected preoperatively. The main aim of PRE is to
achieve microscopic radicality prior to other treatment
and to avoid irradiation of the tumor bed. It appears to
have a positive effect on recurrences and survival. But a
delay of up to 107 days (median 29 days) to complete
surgical resection has been shown to have no adverse
effects.
Pulmonary metastatectomy is advocated as an
adjunct to combine modality therapy in children with
NRSTS as it has been shown to increase disease control
in pediatric NRSTS.
Radiotherapy
NRSTS are less responsive to radiotherapy than RMS and
ES. Adjuvant radiotherapy has been recommended for
high grade tumors, in tumors with positive margins of
resection or low grade unresectable tumor. Local control
with radiotherapy alone for unresected NRSTS has been
reported to be not higher than 25–30%. The use of
neoadjuvant RT with or without chemotherapy is being
investigated for achieving significant shrinkage of
initially unresectable tumor for facilitating resection.
However, the disadvantages include delay in surgical
resection, wound healing and loss of information on
tumor extent and pathology. In view of the distinct late
effects of radiotherapy in very young children, it can be
avoided in patients less than 2 years of age. Newer
techniques of radiation delivery like intensity-modulated
radiation therapy and proton beam therapy may reduce
the toxicity of radiation.
Chemotherapy
The role of adjuvant chemotherapy in the treatment of
pediatric NRSTS remains controversial. Chemotherapy
is recommended for initially unresectable or metastatic
disease. It is also been used in surgically-resected high-
grade and tumors more than 5 cm. The frequently used
drugs were a combination of vincristine, ifosfamide and
doxorubicin. Synovial sarcoma had higher response rates
than other patients with the ifosfamide based regimen.
BIBLIOGRAPHY
1. Blakely ML, Spurbeck WW, Pappo AS, et al. The impact
of margin of resection on outcome in pediatric non-
rhabdomyosarcoma soft tissue sarcoma. J Pediatr Surg
1999;34:672-5.
2. Chui CH, Spunt SL, Liu T, et al. Is reexcision in pediatric
nonrhabdomosarcoma soft tissue sarcoma necessary
after an initial unplanned resection? J Pediatr Surg
2002;37:1424-9.
3. Hays DM, Lawrence W Jr, Wharam M, et al. Primary
reexcision for patients with “microscopic residual” tumor
following initial excision of sarcomas of trunk and
extremity sites. J Pediatr Surg 1989;24:5-10.
4. Mandell L, Ghavimi F, LaQuaglia M, et al. Prognostic
significance of regional lymph node involvement in
childhood extremity rhabdomyosarcoma. Med Pediatr
Oncol 1990;18:466.
5. Meza JL, Anderson J, Pappo AS, Meyer WH. Analysis of
prognostic factors in patients with nonmetastatic
rhabdomyosarcoma treated on intergroup rhabdo-
myosarcoma studies III and IV: the Children’s Oncology
Group. J Clin Oncol 2006;24:3844-51.
6. Neville HL, Andrassy RJ, Lobe TE, et al. Preoperative
staging: prognostic factors and outcome for extremity
rhabdomyosarcoma: a preliminary report from the

Intergroup Rhabdomyosarcoma Study IV (1991-1997). J
Pediatr Surg 2000;35:317-21.
7. Pappo AS, Anderson JR, Crist WM, et al. Survival after
relapse in children and adolescents with rhabdo-
myosarcoma: a report from the Intergroup Rhabdo-
myosarcoma Study Group. J Clin Oncol 1999;17:
3487-93.
8. Pappo AS, Rao BN, Jenkins JJ, et al: Metastatic
nonrhabdomyosarcomatous soft-tissue sarcomas in
children and adolescents: The St Jude Children’s
Research Hospital experience. Med Pediatr Oncol
1999;33:76-82.
9. Paulino AC, Okcu MF. Rhabdomyosarcoma. Curr Probl
Cancer 2008;32:7-34.
16.8 Retinoblastoma
INTRODUCTION
Retinoblastoma (RB), a malignant tumor of the embryo-
nic neural retina, is the most common primary malignant
intraocular tumor of childhood. It occurs in approxi-
mately 1 in 18,000 infants. Hereditary and non-hereditary
patterns of transmission occur; there is no sex or race
predilection. The average age at diagnosis for bilateral
tumor is 12 months and for unilateral tumors it is 21
months. In trilateral RB syndrome, pineal tumors develop
in approximately 1 in 100 patients with bilateral ocular
disease. Characteristically, the diagnosis is made by
ophthalmoscopic, radiographic and ultrasonographic
appearance, without pathologic confirmation.
Pathology
This tumor which usually arises from the posterior
portion of the retina, consists of small round closely
packed malignant cells with scanty cytoplasm. Tumor
may grossly appear crumbly and friable with gelatinous
areas of degradation, patches of calcification or
pigmented hemorrhage. It may appear as a single tumor
in the retina, but typically has multiple foci. The growth
may be endophytic (forward into the vitreous cavity) or
exophytic (into the subretinal space). The tumor
fragments may break off and float free in the vitreous to
“seed” other parts of retina. The most frequent
extraocular sites of involvement are the optic nerve, orbit
and periorbital tissues, cranial tissue, bone and bone
marrow.
Pediatric Oncology 901
10. Puri DR, Wexler LH, Meyers PA, et al. The challenging
role of radiation therapy for very young children with
rhabdomyosarcoma. International Journal of Radiation
Oncology Biology Physics 2006;65:1177-84.
11. Spunt SL, Poquette CA, Hurt YS, et al: Prognostic factors
for children and adolescents with surgically resected non-
rhabdomyosarcoma soft tissue sarcoma: An analysis of
121 patients treated at St Jude Children’s Research
Hospital. J Clin Oncol 1999;17:3697-3705.
12. Wiener ES, Anderson JR, Ojimba JI, et al. Controversies
in the management of paratesticular rhabdomyosarcoma:
is staging retroperitoneal lymph node dissection
necessary for adolescents with resected paratesticular
rhabdomyosarcoma? Seminars in Pediatric Surgery
2001;10:146-52.
Sripad Banavali
Genetics and Molecular Biology
Retinoblastoma has served as the prototype and model
for understanding the heredity and genetics of childhood
cancer. In the 1970s' Knudson proposed that RB required
two mutations to develop the two hit theories. It occurs
either spontaneously or as an inherited disorder. RB
shows an autosomal dominant inheritance pattern with
high penetrance. Approximately 55% of tumor occur as
non-hereditary, unifocal, unilateral tumor. An additional
15% are unilateral, but are hereditary with a family
history. 30% occur as heritable bilateral unifocal or
multifocal tumors. The RB gene is a tumor suppressor
gene and RB tumors are homozygous for chromosome
13q 14 abnormalities with either deletions or alterations
of genetic material at that locus. Hereditary cases shows
a germ line abnormality in one gene at this locus. Some
affected children have other systemic features of the 13q
deletion syndrome.
Clinical Aspects
The most common sign of retinoblastoma is the white or
cat's eye reflex (leukokoria), the appearance of the yellow-
white tumor mass behind the lens. Other signs associated
with RB are visual impairment, strabismus, pseudo-
hypophyon, hyphema and vitreous hemorrhage.
Proptosis, signs of increased intracranial pressure of bone
pain may occur with very advanced or metastatic disease.
The findings of leukokoria must be followed by careful
fundoscopic examination under anesthesia. Ideally, an
902 IAP Textbook of Pediatrics
MRI scan of the orbit should be performed to evaluate
extent of tumor and to assess whether optic nerve, bony
structures or pineal gland are involved. Most intraocular
retinoblastomas show evidence of intratumoral calcifica-
tion. Ultrasound may aid in the differential diagnosis,
which include other causes of leukokoria such as retinal
detachment or dysplasia, retinopathy of prematurity,
persistent hyperplastic vitreous, nematode endophthal-
mitis, cataract, coloboma of the choroid. Radionuclide
bone scan and examination of bone marrow and CSF for
tumor cells are necessary only if there is evidence of trans-
scleral extension or extension beyond the cut end of optic
nerve. Second malignant neoplasms are a major concern
in RB survival. Approximately, 30% of individuals cured
of hereditary form of RB, will have a second malignancy
within 30-years. Osteosarcoma is the most frequent
second malignancy, although other tumors such as
rhabdomyosarcoma, melanoma, fibrosarcoma and
lymphoma have been reported.
Treatment
Although retinoblastoma is the most common primary
intraocular tumor in children, the treatment of this
disease is a complex topic. Therapeutic plans usually
require a multidisciplinary approach by a team consisting
of ocular oncologist, pediatric oncologist and radiation
oncologist. Treatment should be highly individualized.
Treatment strategies for retinoblastoma have gradually
evolved over the past few decades. The driving force
behind these new approaches is to avoid enucleation
and/or external beam radiation therapy and trend
towards focal “conservative” treatment. Every effort is
being made to save the child’s life with preservation of
eye and sight, if possible. The first goal is survival, with
maintenance of vision and salvage of the globe as
important secondary goals.
Retinoblastoma leads to metastatic disease and death
in 50% of children worldwide but in less than 5% of
children in the United States and other developed nations
with advanced medical care. Over the past decade, there
has been a trend away from enucleation and external
beam radiotherapy and towards chemoreduction
followed by focal therapies. This is largely due to more
effective chemotherapeutic regimens, improved focal
treatment modalities, and the desire to avoid loss of globe
and/or exposure to radiotherapy. External beam
radiotherapy (EBRT) has been a standard treatment for
medium and large, or visually threatening, intraocular
RB, but it markedly increases the risk of cosmetic
deformities and secondary cancer in children with
germline RB mutations.
Chemotherapy may be useful in all three clinical
settings: in intra-ocular retinoblastoma, in cases of
micrometastatic spread, and when there are overt
extraocular metastases. Tumor shrinkage with chemo-
reduction may allow treatment with less invasive
measures such as cryotherapy, laser photocoagulation,
thermotherapy or plaque radiotherapy, thereby, avoiding
enucleation and EBRT.
While chemotherapeutic agents vary according to the
preference of the pediatric oncologist, most of the current
studies have relied on carboplatin with or without
Etoposide, vincristine and cyclophosphamide. To
circumvent the multidrug resistance, cyclosporine has
been added to chemotherapy at some centers. Intra-
arterial melphalan has been recently used for salvaging
eyes with large intra-ocular disease, which otherwise
were destined to be enucleated.
Prognosis
The prognosis for patients with RB is directly related to
the size and extension of the tumor. Most tumors that
are confined to the eye can be cured. Cures are infrequent
when extensive orbital or optic nerve extension has
occurred or patient has CNS or distant metastasis.
Reported mortality with tumor invasion to the lamina
cribrosa is 29%, posterior to the lamina cribrosa is 42%
and to the cut end of the optic nerve is 78%. Orbital
recurrence, 2.5% in one series carries 66 to 94% mortality
with a mean survival of 15 months. The prognosis of
patients with CNS metastasis is still very poor nearing
0% even with aggressive therapy. However with the
advent of high dose chemotherapy with stem cell
transplantation, more and more patients with other (bone
and bone marrow) metastatic disease are now surviving.
Overall 5 years disease free survival with enucleation
and external beam irradiation has been reported as 88%
to 94%. Subsequent 10-year survival decreases in bilateral
cases secondary to second tumors.
BIBLIOGRAPHY
1. Abramson DH, Dunkel IJ, Brodie SE, et al. A phase I/II
study of direct intra arterial (ophthalmic artery)
chemotherapy with melphalan used for intra ocular
retinoblastoma. Opthalmology, 2008.
2. Deegan WF. Emerging strategies for the treatment of
retinoblastoma. Curr Opin Ophthalmol 2003;14:291-5.
3. Shields CL, Shields JA. Diagnosis and management of
retinoblastoma. Cancer control 2004;11:317-27.
4. Yanagisawa T. Systemic chemotherapy as a new
conservative treatment for intraocular retinoblastoma.
Int J Clin Oncol 2004;9:13-24.

16.9 Bone Marrow Transplantation
Brijesh Arora, Purvish M Parikh, MR Lokeshwar
INTRODUCTION
Bone marrow transplantation (BMT) is now called blood
and marrow transplantation or hematopoietic stem cell
transplantation (HSCT). HSCT is the term used to
describe the collection and transplantation of hema-
topoietic stem cells from bone marrow, peripheral blood
or umbilical cord blood. HSCT is established therapy for
congenital or acquired disorders of the hematopoietic
system and for hematological malignancies. This chapter
will deal with the principles, terminology and basic
applications of this transplantation. The biological
properties of hematopoietic stem cells that facilitate
transplantation include their capacity to proliferate and
differentiate into the entire lymphohematopoietic system,
their ability to migrate to the bone marrow space
following intravenous injection, and their maintained
viability despite cryopreservation, prolonged storage and
thawing for re-infusion. The mechanism by which BMT
is supposed to cure malignancy is by the anticancer effect
of drugs as well as by the immunological reaction
between graft and cancer cells known as graft versus
tumor effect. This second mechanism is important for
eradication of minimal residual disease in most cancers.
More than 50,000 transplants are performed each year
worldwide. In the last two decades, the number of HSCT
procedures has increased markedly due to expanding
indications, easy availability of donors for allogeneic
transplantation (including an increase in volunteer
unrelated donors of bone marrow/peripheral blood to
> 7.5 million worldwide and the establishment of
umbilical cord blood banks) and greater safety, allowing
HSCT in older and sicker patients (e.g. use of reduced-
intensity conditioning, improved prophylaxis, diagnosis
and treatment of infectious complications.
BMT in India
In India, there are at least twelve centres offering this
facility (including Tata Memorial Hospital, Mumbai;
Christian Medical college, Vellore; Institute Rotary
Center Hospital, New Delhi; Apollo Hospital, Chennai;
Army Hospital (R and R), New Delhi; Army Hospital,
Pediatric Oncology 903
Pune; Gujrat Cancer Research Institute, Ahmedabad;
Jaslok Hospital, Mumbai; Apollo Hospital, Hyderabad;
Sahyadri Hospital, Pune; Tata Rural Cancer Center,
Barshi; Adiyar Cancer Center, Chennai). Tata Memorial
Hospital was the first to start BMT in India on 20th March
1983. VK was then a nine year-old-girl with acute
myeloid leukemia. She went on to complete her studies
and currently is enjoying a happy married life while
being gainfully employed. A perfect example of cancer
cure! Tata Memorial Hospital was also the first center to
do umbilical cord blood transplantation, haploidentical
transplant (with the father as the donor) and allogeneic
transplant for chronic granulomatous disease. So far,
more than 500 transplants have been done in our country.
The various indications for BMT in children are shown
in Table 16.9.1.
Types of Hematopoietic Stem Cell Transplantation
HSCT can be classified according to:
1. Donor type (autologous – self, syngeneic – identical
twin, allogeneic non-identical donor)
2. Relationship between donor and recipient (related or
unrelated)
3. Degree of HLA matching between donor and
recipient (matched or mismatched); haplo-identical
HSCT may now be performed, often from a parent
donor to a child recipient
4. Anatomical source of the stem cells( Bone marrow ,
Peripheral blood,Umbilical cord blood)
5. Type of transplant conditioning (standard (myelo-
ablative) or reduced-intensity (non-myeloablative).
6. Type of graft manipulation (if any) (e.g. T-cell
depletion in allogeneic HSCT, tumor cell purging in
autologous HSCT)
Allogeneic HSCT occurs between a donor and a recipient
who are not immunogenically identical. It can lead to
graft-vs-host disease (GvHD – immune cells from the
donor react against antigens on host cells) and graft
rejection (immunocompetent host cells destroy the donor
stem cells before the graft is established). The risk of these
complications is determined largely by the degree of
904 IAP Textbook of Pediatrics

TABLE 16.9.1: Indications for hematopoietic stem cell matching between donor and recipient for antigens
transplantation encoded by genes of the MHC complex on chromosome
6. The most important genes are those encoding the
A. Allogenic HSCT human leukocyte antigen (HLA) molecules responsible
Malignant disorders
Leukemias for binding antigenic proteins and presenting them to
1. High-risk acute lymphoblastic leukemia (ALL) in first T- cells. Survival is not markedly affected following
remission or relapsed ALL in second remission HSCT involving one mismatched antigen, but is
2. Acute nonlymphoblastic leukemia (AML, ANLL) (after first significantly reduced by two or more mismatches.
remission)
3. Chronic myelogenous leukemia The risk of relapse of malignant disease is lower
4. Juvenile chronic myeloid leukemia (JCML) following allogeneic HSCT than after syngeneic or
5. Juvenile myelomonocytic leukemia (JMML) autologous HSCT, because of an immune-based graft-
Lymphomas vs-leukemia or graft-vs-tumor effect.
1. Hodgkin
2. Non-Hodgkin Autologous HSCT (ABMT) involves removal and
Myelodysplasia storage of the patients’ own stem cells, with subsequent
Myelofibrosis re-infusion following high-dose myeloablative therapy.
Familial hemophagocytic lymphohistiocytosis
Nonmalignant disorders The advantage of autologous HSCT is that higher doses
Congenital of myeloablative chemotherapy can be administered than
1. Immunodeficiency syndromes would otherwise be possible. There is no risk of graft
a. Severe combined immunodeficiency syndrome (SCID) rejection or GvHD, but there is also no graft-vs-leukemia
b. Congenital agammaglobulinemia (Bruton disease)
c. DiGeorge syndrome or graft-vs-tumor effect. In addition, there is a risk of
d. Wiskott–Aldrich syndrome contamination of the autologous stem cell product by
e. Chronic mucocutaneous candidiasis tumor. ‘Purging’ of the autologous cells by ‘negative
2. Hematologic disorders selection’ aimed at destroying tumor cells or ‘positive
a. Hemoglobinopathies( Sickle cell anemia, Thalassemia)
b. Fanconi anemia (progressive) selection’ of CD34+cells (CD34 is the surface antigen that
c. Shwachman–Diamond syndrome characterizes hematopoietic stem cells) has been shown
d. Kostmann agranulocytosis to reduce the number of contaminating tumour cells.
e. Diamond–Blackfan anemia ABMT was initially restricted to solid tumors where
f. Dyskeratosis congenita
g. Thrombocytopenia absent radii syndrome (TAR) the bone marrow was free of disease. The autologous
h. Chronic granulomatous disease reinfusion of hematopoietic cells helped in rescue from
i. Chédiak–Higashi syndrome the otherwise lethal myelosuppression by potentially
3. Storage diseases (Gaucher disease)
curative chemoradiotherapy given for the primary
4. Lysosomal diseases
5. Mucolipidosis tumor. ABMT has been successfully used in Neuro-
6. Mucopolysaccharidoses blastoma, Germ cell tumors, retinoblastoma and
7. Infantile osteopetrosis medulloblastoma. Subsequently this concept was also
Acquired
1. Severe aplastic anemia
expanded to include the hematological malignancies as
2. Paroxysmal nocturnal hemoglobinuria well such as lymphomas. The aim is to give benefits of
B. Autologous HSCT allo-BMT to patients who cannot undergo the procedure
Hematologic malignancies due to various reasons.
1. Non-Hodgkin lymphoma
2. Hodgkin disease Peripheral blood HSCT: Presence of circulating CD34
3. Relapsed AML
4. CML (investigational)
+ve stem cells in humans has been known since 1971.
Solid tumors However their number is too small to be of clinical use
1. High-risk Neuroblastoma stage of transplantation (being less than 0.5%). With the advent
2. Metastatic Ewing sarcoma of recombinant human hematopoietic growth factors, we
3. Metastatic Rhabdomyosarcoma
4. Germ cell tumor now have a method to mobilize them from the marrow
5. Brain tumor into circulation in sufficient number for clinical use. It is
6. Testicular cancer now well established that these circulating cells can
7. Wilms’ tumor
establish durable marrow engraftment. Most HSCT now
 Pediatric Oncology 905

use peripheral blood rather than bone marrow as a source status. The pretransplant evaluation includes cardiac,
of stem cells. The higher stem cell dose provides an pulmonary and renal function studies, hematological
engraftment advantage. In the allogeneic setting, studies including hemoglobin electrophoresis and tests
peripheral blood HSCT is associated with a higher for hemolytic anemia, serology for hepatitis virus,
incidence of chronic GvHD and fewer disease relapses. cytomegalovirus, HIV virus and toxoplasma, and
determination of blood groups, blood group antigens and
Umbilical cord Transplantation: Cord blood banks are
minor blood group antigens. Blood group mismatch
another source of stem cells. The graft composition and
between patient and donor is not a contraindication for
biological properties of umbilical cord stem cells and
transplant. Before the start of conditioning chemotherapy
immune effectors differ from those of adult bone marrow
secure venous access in established by using long-term
and peripheral blood donations, offering enhanced
siliconized central venous catheters (Hickman’s or
engraftment (despite a low CD34+ cell dose) and a
Groshong either single or multiple lumen). Patient
reduced incidence of GvHD, Even in the presence of two
prophylactically receives oral antibiotics, antifungal
or three HLA antigen mismatches. It is particularly useful
agents and Pneumocystis carinii prophylaxis depending
for transplantation in children.
upon the institutional policy.
Requirement and Limitations
Stem Cell Collection
The main requirement for performing allogenic BMT is
Traditionally, stem cell collection involves the aspiration
the availability of HLA matched sibling or unrelated
of 0.5-1.5 litres of bone marrow, mainly from the posterior
donor. HLA antigens mount response against the foreign
iliac crests, under general anesthesia. Hematopoietic stem
antigens. The HLA antigens are broadly divided into
cells circulate in very low concentrations in the peripheral
three groups Class I (HLA -A, -B and –C), class II (HLA-
blood, but increase markedly during recovery from
DR,-DP,-DQ) and class III group which include diverse
chemotherapy or with cytokines such as granulocyte
group of proteins (C2 and C4, TNF alpha and beta, etc.).
colony-stimulating factor (G-CSF). Adequate numbers
For allo BMT, typing of Class I and II group antigens is
of stem cells for transplantation can be harvested from
mandatory. The HLA phenotype of an individual is
donor peripheral blood after administration of G-CSF
determined using monoclonal antibodies (serological
for 4-5 days.
methods), homozygous typing of cells in mixed
In the autologous setting, peripheral blood stem cells
lymphocyte culture (MLC) and T-cell clones. Recently
can be harvested following chemotherapy and G-CSF.
typing for HLA-DR, -DP and –DQ loci is also done by
Harvesting involves an automated pheresis procedure
molecular methods like restriction fragment length
and is generally well tolerated. Umbilical cord blood
polymorphism (RFLP) and sequence specific oligo-
contains a high concentration of hematopoietic
nucleotide probes (SSOP). The discrepancy between host
progenitors with high proliferative capacity. Unrelated
and donor HLA type predisposes to development of
umbilical cord blood banks are now established.
GvHD.
For any individual there is a 25% chance of having Transplantation of Stem Cells
such a sibling donor. The reduction in family size over
Before transplantation, conditioning therapy is given to
the years has further decreased these chances. Though
eradicate the underlying disease and, in the allogeneic
the establishment of voluntary bone marrow registries
setting, immunosuppress the patient sufficiently to
has made it possible to get a HLA matched unrelated
prevent rejection of the transplant.
donor, the high incidence of treatment related compli-
Choice of conditioning therapy depends on many
cations and mortality with unrelated BMT has limited
factors, including the underlying disease, patient age,
its utility. Age is also a limitation as allo BMT cannot be
donor–recipient HLA matching and stem cell source.
done beyond the age of 55 years.
Standard (myeloablative) conditioning usually involves
high-dose chemotherapy, often with total-body irradia-
Methodology
tion. TBI is most commonly combined with cyclo-
Once a suitable patient is identified, he undergoes phosphamide (Cy/TBI). Since, use of TBI is associated
investigations to establish a baseline organ function with acute toxicity in the form of mucositis, enteritis,
906 IAP Textbook of Pediatrics
anorexia, etc and delayed complications life growth
retardation, pulmonary dysfunction and cataracts, TBI
can be replaced by combining busulphan with cyclo-
phosphamide or use of additional drugs like VP-16,
Cytosine arabinoside, Idarubicin , etc. The conditioning
treatment schedules used for ABMT have been more or
less similar to those used for allogeneic BMT. Anti-T cell
antibodies (e.g. antithymocyte globulin, alemtuzumab)
are often used in allogeneic HSCT to reduce the immune
complications of graft rejection and GvHD.
Following conditioning, stem cells are infused
through a large bore central venous catheter (e.g.
Hickman line) and migrate to the bone marrow. There is
a period of obligate neutropenia (usually about 2–3
weeks) before engraftment of mature, donor-derived
blood cells. During this time, the patient is nursed in an
isolation cubicle with air filtration to prevent inhalation
of fungal spores. Supportive care (e.g. anti-infection
drugs, blood and platelet transfusions) is important in
the early post-transplantation phase. Patients receiving
allogeneic HSCT receive cyclosporin A or tacrolimus for
the first few months to prevent GvHD.
Complications
Early Complications
Conditioning related: These include nausea, vomiting,
alopecia, hemorrhagic cystitis (cyclophosphamide),
mucositis and interstitial pneumonitis. Major organ
toxicity (e.g. cardiomyopathy, veno-occlusive disease of
the liver) may also occur.Neurologic side effects
especially convulsions are common with TBI and
Busulfan. Prophylactic use of phenytoin during the
chemotherapy has been recommended for this compli-
cation.
Infections: These are the most important cause of
morbidity and mortality posttransplant. The patients are
susceptible to infections with bacteria, viruses, fungi as
well as parasites. This is because of the various factors,
i.e. myelosuppression, immunosuppression, tissue
damage, indwelling venous access devices and use of
parenteral nutrients, etc. Development of graft versus
host disease depresses the host immunity further and
increases the chances of infections. The post-BMT period
characterized by three phases viz. 1. Phase of aplasia 2.
Early immune recovery and 3. Late immune recovery.
The phase of bone marrow aplasia lasts for 3 to 4 weeks
and in addition is associated with disruption of
mucocutaneous barriers. During this period bacterial
infections are common and after first 2 weeks incidence
of fungal infections is also high. During the phase of early
immune recovery which lasts for 3 to 4 months, the blood
counts are normal. This phase is modulated by develop-
ment of acute GvHD which delays immune recovery and
the treatment of the condition especially with steroids
further causes immune suppression. At this time patient
is susceptible to get infection with CMV and also fungal
infections like Aspergillus and Candida. The phase of
late immune recovery starts from 6 months and may not
be complete for 1 to 2 years. Development of chronic
GvHD during this period significantly delays the
immune recovery. During this time reactivation of
varicella zoster, infection with capsulated bacteria like
S. pneumoniae, Neisseria, H. influenzae, mucocutaneous
candidiasis is commonly encountered. In order to reduce
the incidence of infections, prophylactic use of anti-
bacterial, antifungal and antiviral agents has been tried.
Isolation of patient in HEPA filtered rooms with laminar
airflow and reverse barrier nursing helps in preventing
acquisition of new pathogens. Table 16.9.2 enlists the
infections seen during different phases after trans-
plantation.
TABLE 16.9.2: Infections most frequently seen at different
times post-transplantation
I. Infections in first 30 days post-transplantation
A. Bacteremia
Gram-positive organisms: Staphylococcus epidermidis
Gram-negative aerobes and anaerobes
B. Invasive fungal infections: Aspergillus, Candida
C. Reactivation of herpes simplex I
II. Infections 30–120 days post-transplantation
A. Protozoal infections
Pneumocystis carinii
Toxoplasma
B. Viral infections
Cytomegalovirus (CMV)
Adenovirus
Epstein–Barr virus (EBV)
Human herpesvirus 6 (HHV-6)
C. Fungal infections
Candida (C. albicans and C. tropicalis)
Aspergillus
Trichosporon
Fusarium
Candida krusei
III. Infections after 120 days post-transplantation
A. Sinopulmonary infections with encapsulated organisms
B. Viral infections (cutaneous herpes zoster)

Graft failure is rare in autologous HSCT, but can occur
following use of an inadequate stem cell dose. Causes of
graft failure following allogeneic HSCT include immune
rejection, infection with CMV, parvovirus or human
herpes virus 6, an inadequate stem cell dose, and use of
myelotoxic drugs in the post-transplantation period. A
second transplantation procedure may be required if
graft failure does not respond to appropriate measures
(e.g. treatment of viral infection, administration of G-
CSF).
GvHD occurs when allo-reactive T-cells from the donor
react with antigenic targets on host cells. Acute GvHD
develops within 3 months post-transplantation; chronic
GvHD develops or persists after this time.
Acute GvHD occurs in 30% of recipients of stem cells
from HLA-identical sibling donors and 50–60% of
recipients from unrelated donors. It is characterized by
an erythematous maculopapular rash, diarrhoea, and
liver disease with increased bilirubin and transaminase
levels. More severe acute GvHD (grade II–IV) is
associated with reduced survival and requires immuno-
suppressive therapy with corticosteroids and second-line
agents such as cyclosporin, tacrolimus, mycophenolate
mofetil and ATG. Preventive measures are important and
involve either post-transplantation immunosuppression
(generally cyclosporin and methotrexate) or removal of
T-cells from the stem cell inoculum (usually by T-cell
antibodies given in vivo or in vitro).
Chronic GvHD develops in 10–50% of transplant
recipients surviving beyond 6 months. It is characterized
by sicca syndrome, bile duct degeneration and choles-
tasis, bronchiolitis obliterans, mucocutaneous sclero-
derma and arthritis. Treatment of chronic GvHD is based
on prednisolone, immunosuppressive agents and
antibiotic prophylaxis, but is generally unsatisfactory.
Newer agents including thalidomide, antibodies to the
interleukin-2 receptor and tumor necrosis factor, and
extracorporeal photopheresis are also being increasingly
used.
Late complications—These include endocrine problems
(e.g. infertility, ovarian failure, osteoporosis, hypo-
thyroidism, growth hormone deficiency),cataracts
(particularly after total-body irradiation) and secondary
malignancies (e.g. AML, myelodysplasia, solid-organ
tumors, skin cancers).
Pediatric Oncology 907
BMT FOR HEMATOPOIETIC DISORDERS
Hematopoietic Malignancies
For certain leukemias and myelodysplastic diseases (for
example, those identified by unfavorable genetic
markers), HSCT is the only curative option available and
is considered a primary treatment modality. Otherwise,
HSCT for hematopoietic malignancies is widely used as
a salvage therapy for patients who fail primary
chemotherapy.
Acute Myeloid Leukemia
Acute myeloid leukemia (AML) has poor outcome if
treated with conventional chemotherapy alone. Tradi-
tionally the treatment has been the combination of
cytosine arabinoside and anthracycline. VP-16 has also
been used. With the current treatment regimens, 70 to
90% children achieve complete remission. In patients
achieving remission after conventional chemotherapy,
relapse remains the most important risk with more than
70% patients developing the complication. The median
time to relapse has been 1 year. Hence, only 30 to 40%
patients are long-term survivors. Second remission can
be achieved in 40% patients but the duration of response
is short. Hence allogenic-BMT is recommended after first
remission as a curative modality for all patients except
ones with favourable cytogenetics and good risk group
which includes acute promyelocytic leukemia with trans-
location t(15;17), t(8;21) and inv(16), or with chemo-
therapy-sensitive disease defined by a low minimal
residual disease (MRD) after the first induction course.
The results of transplant are best if it is done during first
remission. Results from various studies have shown that
almost 50 percent patients can be cured of their disease
if the transplant is done during first remission. The results
of transplant done in first relapse or second remission
are same with 30 percent leukemia free survival and
relapse probability of 40 to 45%.
The results of ABMT are better than conventional
therapy for AML. In patients achieving second or
subsequent CR, the chances of cure are less than 5% with
conventional therapy. ABMT has shown consistently
better results in these patients with 30–35% probability
of DFS and relapse risk of 50%.
908 IAP Textbook of Pediatrics

Acute Lymphoblastic Leukemia remission in more than 70%, only a minority of patients
achieves a molecular remission. Currently, there is no
ALL in pediatric population has been a success story of
data to guide the duration of imatinib therapy and to
modern day combination chemotherapy. With current
suggest that imatinib is curative. All of this has created
regimens, it is possible to cure 70 to 80% children with
uncertainty regarding the role and timing for HSCT. At
standard risk ALL and 60 to 70% with high- risk ALL.
present, the optimal management of newly diagnosed
Nevertheless there remain some ALL subtypes which
CML is unclear. Matched-sibling HSCT for patients in
are not cured by conventional chemotherapy alone. These
chronic phase of CML results in cure rates of 70% and
include Ph positive, hypodiploid and t(4:11) positive
86%. For children with a donor, HSCT can be curative
ALL, biphenotypic leukemia and patients with high
and delay in HSCT beyond a year may diminish the
MRD (>1%) after induction. In these patients, BMT offers
potential for cure. Current data do not indicate an adverse
a better chance of cure. BMT is considered for such high
influence of prior Imatinib therapy on HSCT. Up to 30%
risk ALL patients after its remission and as a salvage
of patients fail to achieve a satisfactory cytogenetic
procedure for resistant disease or after second and
response to imatinib. In this circumstance, HSCT should
subsequent remissions.
be considered even if this requires HSCT from alternative
In children with high-risk ALL transplanted in first
donors. There may be a role for imatinib as adjuvant
remission, disease free survival in the range of 80% can
therapy to prevent disease relapse following HSCT and
be obtained. Allo BMT can cure 35% of relapsed patients
along with donor lymphocyte infusions to control
in second remission, which is not possible with
reappearance or persistence of BCR/ABL cells after
conventional chemotherapy. In patients with induction
HSCT.
failures, it can achieve long-term disease free status in
almost 40% patients. Compared to AML, the role of
HODGKIN’S DISEASE AND NON-HODGKIN’S
ABMT is unproven in ALL and is investigational.
LYMPHOMA
MYELODYSPLASTIC SYNDROME Pediatric patients with lymphoma who do not enter
remission or who subsequently relapse are rarely cured
MDS in children must be distinguished from AML
using therapy at conventional doses. These children
presenting with a low blast count; the latter shows
benefit with ABMT. Lymphoma patients with favorable
minimal hematopoietic dysplasia and often manifests
characteristics have a DFS of up to 60% after ABMT,
cytogenetic abnormalities associated with AML.
whereas fewer than 20% of poor-risk patients achieve
Allogeneic HSCT remains the principal curative
durable remissions. In NHL, progressive disease or lack
modality. DFS rates between 36% and 87% have been
of response to salvage chemotherapy before ABMT is a
reported for children with primary MDS who are
negative prognostic factor associated with DFS of less
undergoing allogeneic transplantation from matched
than 10%. For patients with relapsed HD, bulky disease
alternative donors. Because of higher relapse rates,
and poor response to prior chemotherapy at the time of
patients with JMML and refractory anemia with excess
ABMT adversely affects outcome.
blasts in transformation (RAEBt) generally fare worse
than patients with the other MDS types. However, more
TRANSPLANTATION FOR SOLID TUMORS
recent trials have reported improved DFS up to 55% for
matched HSCT and 49% for unrelated donor HSCT in Brain Tumors
these disorders.
The prognosis is dismal for those children with brain
tumors failing surgery, radiation therapy, and/or
CHRONIC MYELOGENOUS LEUKEMIA
conventional chemotherapy. Several groups have
CML is rare among children. Prior to the development explored the use of autologous BMT. The results for
of the specific BCR/ABL tyrosine kinase inhibitor, patients with primitive neuroectodermal tumor or
imatinib, HSCT was the only recognized curative medulloblastoma and high-grade gliomas outside the
therapy. Although imatinib induces hematologic brainstem are closely correlated with tumor burden at
remission in more than 90% patients and cytogenetic the time of HSCT, ranging from less than 10% in children

with bulky disease to 50% for those with minimal or no
disease. HSCT has also been used with encouraging
preliminary results in infants and young children to
avoid or reduce neuroaxis radiation. However, good
outcome depended on the ability of surgery or chemo-
therapy, or both, to produce a state of minimal disease
before HSCT.
Neuroblastoma
Conventional treatment of children with high-risk
neuroblastoma has generally resulted in a DFS of less
than 20%. Newly diagnosed high-risk patients treated
with regimens culminating in ABMT have been reported
to have a 3-year DFS of 43% after conditioning with
myeloablative chemotherapy and TBI. Purged BM is used
as the SC source in most studies. Post-HSCT therapy with
oral cis-retinoic acid, which decreases proliferation and
induces differentiation in neuroblastoma cells, further
improves survival in this cohort. Use of iodine-131–
metaiodobenzylguanidine (131I-MIBG), a targeted
radiotherapeutic agent , monoclonal antibodies [e.g., anti-
ganglioside G(D2)] as adjuvant therapy after autologous
SCT, use of genetically modified tumor vaccines, and the
use of autologous tumor-specific T-cell therapy after
transplant are novel strategies being used to further
improve the outcome for this poor prognosis disease.
Sarcomas and Other Solid Tumors
Results of autologous ABMT for children with high-risk
Ewing’s sarcoma and Rhabdomyosarcoma including
those with metastatic disease at presentation or those
with recurrent disease have been discouraging. This poor
response after autografting may be related to contami-
nation of SC harvests with tumor cells, which appears
associated with relapse. An EFS of 21% at 5 years for
new patients with metastatic disease and 32% for those
transplanted in CR2 has been reported. Some children
with metastatic Wilms’ tumor have a poor likelihood of
cure with conventional therapy. Autologous HSCT leads
to EFSs ranging from 36% to 48.2% in this group, with
improved outcomes seen in patients who were in CR at
the time of HSCT. In conclusion, curing children with
recurrent or refractory solid tumors remains difficult and
can result in appreciable toxicity.
Non-Malignant Disorders
Congenital immunodeficiency disorders including
severe combined immunodeficiency, Wiskott–Aldrich
Pediatric Oncology 909
syndrome and Chediak–Higashi syndrome can generally
be cured with HSCT. Cure rates are 90% with HLA-
identical sibling donors and 50–70% with unrelated or
haplo-identical related donors.
Severe aplastic anemia— HSCT is generally regarded
as the optimal treatment for patients less than 40-years
of age; cure rates of up to 90% are expected. Results are
less favourable in older patients and in those without an
HLA-identical donor, and a trial of immunosuppression
is often recommended.
Hemoglobinopathies— HSCT from an HLA-identical
sibling donor achieves a cure in 70–90% of patients with
conditions such as thalassemia and sickle cell anemia,
particularly if transplantation is undertaken before
development of end-organ disease.
Other non-malignant conditions— HSCT has been used
successfully in storage disorders (Gaucher’s disease,
Hurler’s syndrome, leucodystrophy), congenital
leucocyte disorders (Kostmann’s syndrome, chronic
granulomatous disease) and congenital anemia
(Blackfan–Diamond syndrome, Fanconi’s anemia), and
is under investigation in severe autoimmune disorders
such as scleroderma and rheumatoid arthritis.
Recent Developments and Future Advances
Reduced-intensity conditioning In reduced-intensity
conditioning allogeneic HSCT (‘mini-transplants’), total-
body irradiation is avoided and conditioning comprises
of chemotherapy that is nonmyeloablative but immuno-
suppressive. Fludarabine is widely used with other
agents (e.g. melphalan, busulfan, cyclophosphamide),
and some protocols include T-cell antibodies (e.g.
alemtuzumab, ATG) given in vivo. Peripheral blood stem
cells are preferred over bone marrow to enhance
engraftment. This approach is particularly promising in
patients with lymphoma and myelodysplasia.
Alternative donor transplants Overall likelihood of
identifying an HLA-identical sibling donor is about 30%.
A suitable unrelated donor (matched or one antigen
mismatched) is found in 50–80% of cases, depending on
the patient’s HLA type and ethnicity. Thus, many
patients have no allogeneic donor. Haplo-identical
transplantation (often a parent donor matched for only
one haplotype with a child patient) has recently become
possible. Engraftment is promoted by a high stem cell
dose and very immunosuppressive conditioning
regimens. GvHD is prevented by stringent T-cell
depletion of the infused graft.
910 IAP Textbook of Pediatrics
Graft engineering Many groups are investigating the
possibility of selecting subpopulations of cells from
peripheral blood stem cell collections, for infusion at the
time of or following HSCT. Examples include T-cell
subset depletion to reduce GvHD, selection and culture
of virus-specific cytotoxic T-cells to induce enhanced
immune responses (e.g. to CMV and EBV), and a similar
approach involving leukemia-specific antigens (e.g. Bcr/
Abl in CML) to augment the graft-vs-leukemia effect.
CONCLUSION
HSCT is one of the most challenging and a promising
therapeutic modality for treatment of a wide variety of
disorders. Its results and applications are likely to expand
further with easier donor availability for unrelated
transplantation, use of alternative stem cell sources
including umbilical cord, reduced-intensity conditioning
and graft engineering. In the future, gene therapy and
stem cell research is further expected to dramatically
change the landscape of stem cell transplantation.
BIBLIOGRAPHY
1. Blume KG, Forman SF, Appelbaum F. Thomas’ hemo-
poietic cell transplantation book. Oxford: Blackwell, 2004.
2. Bodmer JG, Marsh SG, Albert ED, et al. Nomenclature
for factors of the HLA system,1998. Hum Immunol
1999;60(4):361-95.
3. Gluckman E. Umbilical cord blood hematopoietic stem
cells; biology and transplantation.Curr Opin Hematol
1995;2(6)413-16.
4. Gratwohl A, Baldomero H, Horisberger B, et al. Current
trends in hematopoietic stem cell transplantation in
Europe. Blood 2002;100:2374-86.
5. Gupta S, Kumar L, Raju GM, Kochupillai V, Shukla DK.
Autologous bone marrow/Stem cell transplantation;
initial experience at a north Indian referral center. Nat1
Med J India 2000;13(2):61-66.
6. Hongeng S, Krance RA, Bowman LC, et al. Outcomes of
transplantation with matched-sibling and unrelated-
donor bone marrow in children with leukemia. Lancer
1997;350(9080):767-71.
7. Levine JE, Harris RE, Fausto R, et al. A comparison of
allogeneic and autologous bone marrow transplantation
for symptomatic lymphoma. Blood 2003;101(7):2476-82.
8. Matthay KK, Villablanca JG, Seeger RC, et al. Treatment
of high-risk neuroblastoma with intensive chemo-
therapy, radiotherapy, autologous bone marrow
transplantation, and 13-cis-retinoic acid. Children’s
Cancer Group. N Engl J Med 1999;341(16):1165-73.
9. Morrison VA, Peterson BA. High-dose therapy and
transplantation in non- Hodgkin’s lymphoma. Semin
Oncol 1999;26(1):84-98.
 17.1 Disorders of Growth: PSN Menon ....................................................................................................................................................... 912
17.2 Disorders of Pituitary: PSN Menon ..................................................................................................................................................... 919
17.3 Obesity: Anju Virmani ........................................................................................................................................................................... 925
17.4 Disorders of Thyroid Gland: Meena P Desai ..................................................................................................................................... 931
17.5 Disorders of Bone and Mineral Homeostasis: Vijayalakshmi Bhatia ............................................................................................... 935
17.6 Disorders of Puberty: Prisca Colaco ................................................................................................................................................... 941
17.7 Disorders of Sexual Differentiation: P Raghupathy .......................................................................................................................... 947
17.8 Disorders of Adrenocortical Biosynthesis: P Raghupathy .............................................................................................................. 951
17.9 Disorders of Adrenal Glands: PSN Menon ........................................................................................................................................ 955
17.10 Diabetes Mellitus: Vijayalakshmi Bhatia .............................................................................................................................................. 962
912 IAP Textbook of Pediatrics
17.1 Disorders of Growth
SHORT STATURE
A child is diagnosed to have short stature when his or
her height is below the 3rd percentile or below 2 SD of
the mean height for that age and sex. Even when the
actual height measurements are within normal ranges,
the child should be regarded as short, if the height
velocity is less than the 25th percentile for age over 6 to
12 months of observation or the child is very short for
midparental or target height.
Rationale of Clinical Evaluation
Measurement of Growth
Supine length is measured by an infantometer in infants
and children less than 2 years and standing height by a
stadiometer in older children. The techniques for
measuring height are detailed in Chapter 2. In addition
to height, measurements of weight, midarm
circumference, skin fold thickness and head
circumference are often helpful in diagnosis. The height
and weight can be expressed as standard deviation scores
(SDS or Z score). Z score is calculated using the formula:
(The child’s height – mean height for age from a reference
chart) ÷ 1 SD of height for that age in the reference data.
Height Velocity
Estimation of height velocity is essential for optimal
decision making. On an average most infants measure
50 cm in length at birth, and gain approximately 25 cm
in the first year of life, 12.5 cm in the second year, 6-7 cm
each in the third and fourth years, and subsequently 5
cm every year until pubertal growth spurt. The peak
height velocity during adolescence is about 9-11 cm per
year for boys and about 7-9 cm per year for girls.
Retardation of height is very significant if height velocity
is low or decreasing. On the other hand, if the child has
a normal height velocity and is growing along his
percentiles, the parents can be reassured. Height velocity
can also be expressed in Z scores.
PSN Menon
Growth Charts
The growth pattern of child should be recorded both
numerically as well as graphically using appropriate
growth charts.
Predicting Adult Height
A crude way to assess the genetic potential is to plot the
heights of the parents on the adult equivalent (e.g. at 18-
20 years) on a standard growth chart. The target height
or midparental height (MPH) is calculated by the formula
— for boys: average of father’s height and mother’s height
+ 6.5 cm; for girls: average of mother’s and father’s
heights – 6.5 cm. MPH should be plotted on the adult
equivalent on the growth chart. It provides the target
height for the child and the percentile he/she is likely to
follow (Fig. 17.1.1).
Body Proportions
The body proportions employed in clinical decision
making are upper:lower segment ratio (US:LS ratio) and
arm span:height ratio. They vary with age. The US:LS
ratio is approximately 1.7 at birth, 1.3 at 3 years, 1.1 by 6
years and 1 by 10 years. Arm span is less than length at
birth by 2.5 cm and equals height at about 11 years and
thereafter it is greater than height. An abnormal US:LS
ratio or arm span:height ratio indicates disproportionate
short stature. Children with achondroplasia have a
normal sized trunk with short limbs, while
spondyloepiphyseal dysplasia gives rise to short trunk
and normal limbs.
Pubertal Assessment
Pubertal assessment has an important role in the
diagnosis and prognosis of short stature. Onset of puberty
is associated with the height spurt seen during
adolescence. Delayed or precocious puberty thus has an
important role in stature. The stage of puberty is assessed
by the Tanner’s method of sexual maturity rating.
Testicular volume is measured by comparing testis with
an orchidometer.
 Endocrinology 913

Figure 17.1.1: Growth chart showing how to record a child's height. The actual height of a 9 years old girl is recorded as 120 cm
as 'measured height'. The father's height, mother's height and the target or midparental height is recorded at 20 years on the
growth chart. She is expected to follow the 25th centile according to the target height but is short for her target height for age. The
mean height for the age is recorded at the 50th centile. Bone age, recorded as a triangle is further behind her chronological age,
but equal to her 'height age', the point where the actual height crosses the 50th centile
914 IAP Textbook of Pediatrics
Bone Age Assessment
An essential investigative tool for evaluating short stature
is bone age measurement. This is conventionally done
from X-rays of wrist and elbow. The bone age is
computed from the appearance of epiphyseal centers and
fusion of epiphysis with metaphysis using Greulich-Pyle
atlas or Tanner-Whitehouse method. A child with
delayed bone age has a better prognosis for future height
gain than those with appropriate or advanced bone age.
Children with familial genetic short stature have bone
age appropriate for chronologic age, whereas those with
an endocrine cause for such as growth hormone
deficiency or hypothyroidism have delayed bone age.
Adult height can be predicted by computing chronologic
age and bone age using the Bayley-Pinneau charts.
Etiology of Short Stature
Short stature may be due to a variety of disorders (Table
17.1.1). Endocrine causes include hypothyroidism,
hypopituitarism, diabetes mellitus, Cushing syndrome,
pseudohypoparathyroidism and hypogonadism. A
significant number of children who turn-up for
evaluation of short stature have no pathological cause.
Most have a physiological cause for their short stature.
Clinical and Laboratory Evaluation
An algorithmic approach to diagnosis of short stature is
given in Figure 17.1.2.
Clinical History
The time of onset of short stature has great relevance in
the differential diagnosis. Hence antenatal and birth
history (including maternal illness during pregnancy,
birth weight, length, gestational age, signs of congenital
anomalies), development, puberty, psychosocial
behavior and nutrition are essential. Details of
consanguinity, family history of short stature and
pubertal development are indispensable.
Short stature with normal height velocity with growth
curve following a line parallel to 3rd centile and positive
family history suggest familial short stature (FSS). Children
with constitutional delay in growth and puberty (CDGP)
have growth failure from the age of 2-3 years with
delayed onset of puberty, positive family history in
parents or siblings. When the growth failure is noted
postnatally, environmental causes such as malnutrition,
chronic infections, and emotional disturbances in family
should be probed. Social history is important to detect
psychosocial short stature. All systems including
endocrine, renal and gastrointestinal, should be reviewed
carefully to identify the likely cause for deceleration of
growth.
Physical Examination
The presence of characteristic physical signs of an
endocrine disease or dysmorphic syndrome greatly
facilitates the diagnostic work-up. Children with
endocrine disorders generally have a weight percentile
better than that of height, whereas those with systemic
disorders usually lose weight first and are thin by the
time they are short. Disproportions of body are seen in
skeletal dysplasia, rickets, hypothyroidism and some
dysmorphic syndromes. Pallor and signs of vitamin
deficiencies are frequent in many nutritional disorders,
TABLE 17.1.1: Differential diagnosis of short stature
A. Normal variants
1. Familial genetic short stature
2. Constitutional delay in growth and puberty
B. Disproportionate short stature
1. Skeletal dysplasias: Achondroplasia, hypochondroplasia,
spondyloepiphyseal dysplasia
2. Rickets: Nutritional, metabolic
3. Untreated hypothyroidism
C. Proportionate short stature of prenatal onset
1. Intrauterine growth retardation
• Placental insufficiency disorders: Maternal toxemia,
diabetes mellitus
• Intrauterine infections: TORCH complex
• Teratogens: Alcohol, nicotine, drugs
2. Dysmorphic syndromes: Russell-Silver syndrome, Seckel
syndrome
3. Chromosomal anomalies: Down syndrome, Turner’s
syndrome
D. Proportionate short stature of postnatal onset
1. Nutritional disorders: Malnutrition
2. Chronic infections: Tuberculosis
3. Gastrointestinal disorders: Celiac disease, chronic
diarrhea, malabsorption syndromes, chronic liver disease
4. Hematological disorders: Hemolytic anemia
5. Renal disorders: Chronic renal failure, tubular disorders
6. Cardiac disorders: Congenital cyanotic heart disease,
chronic congestive failure
7. Pulmonary disorders: Cystic fibrosis, chronic asthma
8. Endocrine disorders: Hypothyroidism, growth hormone
deficiency and insensitivity, Cushing syndrome,
hypogonadism, pseudohypoparathyroidism, diabetes
mellitus
9. Psychosocial short stature
 Endocrinology 915

Figure 17.1.2: An algorithmic approach to diagnosis of short stature.

LFT – Liver function tests, RFT – Renal function tests
916 IAP Textbook of Pediatrics
malabsorption, chronic anemia, hypothyroidism and
renal failure. It is also important to evaluate the genitalia
and grade the pubertal development.
Constitutional delay in growth and puberty (CDGP) is
defined as a delay of growth and puberty in an otherwise
healthy child, usually an adolescent, with a standing
height below the expected for chronological age, but not
for his bone age. It tends to affect more boys than girls. It
should be a diagnosis of exclusion. The final adult height
will be within the normal range. These children are short
from around 2-3 years of age. Growth is just below but
parallel to 3rd centile initially with a further deviation
as the adolescent pubertal spurt is delayed. Bone age is
delayed. There is a familial tendency for short stature
and delayed catch up. The spine length may be relatively
short compared to limb length.
Children with familial short stature are short with a
height appropriate for the parent’s height with normal
height velocity. The growth curve is below but parallel
to the 3rd centile. Body proportions are normal and
pubertal development is appropriate for age. Bone age
is appropriate for his/her age. Again this is a diagnosis
of exclusion.
Children with congenital growth hormone deficiency
(GHD) are short with a cherubic appearance, doll-like
face and microphallus. Presence of midline anomalies
such as cleft lip, cleft palate or single central incisor tooth,
suggests the possibility of hypopituitarism. Visual field
defects, optic atrophy, optic nerve hypoplasia and
papilledema are often associated with septo-optic
dysplasia and tumors of the pituitary-hypothalamic
region.
Acquired hypothyroidism often manifests as short
stature. Coarse facies, myxedema, dry rough skin,
macroglossia and developmental retardation with
delayed relaxation of deep tendon reflexes characterize
hypothyroidism. Growth retardation may sometimes be
the only presenting feature of Cushing syndrome in
childhood. Pseudohypoparathyroidism manifests with short
stature, round facies, central obesity, short fourth
metacarpals and mental subnormality, hypocalcemic
tetany or seizures, cataract and calcification in the basal
ganglia.
Turner syndrome may present in girls with short
stature alone. It is characterized by the presence of short
webbed neck, shield chest, widely placed nipples with
characteristic cardiac, renal and skeletal defects. Down
syndrome, a common cause of mental retardation, has
short stature with characteristic facies with mongoloid
slant of eyes. Russell-Silver syndrome is characterized by
IUGR, small triangular facies, hemihypertrophy,
clinodactyly, occasionally a large penis and precocious
puberty, and sometimes GH deficiency.
Investigations
If the clinical work up suggests a cause for short stature,
the appropriate confirmatory test should be performed.
Many a time children with short stature present with no
other abnormality on history and examination. Thus in
all cases of significant short stature with a low growth
velocity and/or delayed bone age, it is advisable to
perform screening investigations to diagnose some of the
important causes (Table 17.1.2).
Estimation of bone age is the first vital step in the
diagnosis of short stature. Most children with CDGP,
nutritional disorders, chronic diseases have mild delay
and endocrinopathies such as GH deficiency and
hypothyroidism have significantly delayed bone age.
Cushing syndrome and precocious puberty cause an
advancement of bone age. If the screening tests are
normal, tests to exclude relatively silent causes of short
stature should be performed. These include tests to
exclude hypothyroidism, GH deficiency, renal tubular
acidosis, Turner syndrome, and celiac disease. It is a
policy in some pediatric endocrine centers to do thyroid
function in all children and chromosome studies (for
Turner syndrome) in all girls referred for short stature.
Elevated gonadotropins, especially FSH, also point
towards the diagnosis of Turner syndrome. Those with
TABLE 17.1.2: Laboratory evaluation for short stature
A. Radiology: X-ray for bone age
B. Hematological tests: Hemoglobin, hematocrit, total and
differential leukocyte counts, blood cell morphology, ESR
C. Urinalysis: pH, specific gravity, osmolality, microscopy,
protein, glucose estimations
D. Stool examination: Microscopy for parasitic infections, fat
for malabsorption, glucose
E. Blood chemistry: fasting blood sugar, urea, creatinine,
sodium, potassium, calcium, phosphate, alkaline phosphatase,
cholesterol, albumin and transaminases, venous CO2
F. Special tests: Tuberculin test and chest X-ray, thyroid
hormones (T4 and TSH), tests for celiac disease (anti-
endomysial and transglutaminase antibodies), FSH and
karyotype (Turner syndrome)
G. Tests for hypothalamic-pituitary axis: IGF-I, IGFBP-3 and
GH stimulation tests, X-ray skull for suprasellar calcification,
MRI brain.

disproportionate short stature require skeletal survey,
and evaluation for hypothyroidism and RTA. Low
bicarbonate levels suggest RTA.
A measurement of insulin like growth factor–I (IGF–
I) is useful when the cause of short stature is uncertain.
In some centers IGF binding protein, IGFBP–3 is also
estimated as a screening tool. Low levels (below 2 SD of
the mean) of IGF-1 and IGFBP-3 suggest the probability
of growth hormone deficiency. Measurement of GH in a
random blood sample is not a reliable test for GH
deficiency, as GH levels are usually low during day and
spontaneous peaks are brief and unpredictable. The most
practical method is a pharmacological GH stimulation
test using clonidine, insulin or other agents. A GH level
less than 10 μg/ml following stimulation indicates
impaired pituitary secretion. Details of GH deficiency
and insufficiency are given in Chapter 17.2.
Management
After the initial visit, the family should be advised
regarding the need for a balanced diet with adequate
calories and proteins, coupled with regular physical
exercises. Supplemental hematinics may be prescribed
if indicated. Height and weight should be recorded and
height gain assessed regularly. Counseling of the child
and the family is essential in conditions such as familial
short stature, CDGP, skeletal dysplasia and IUGR. The
importance of regular follow-up and monitoring of
therapy should be stressed.
Treatment of short stature essentially depends on the
cause. There is no specific treatment for familial short
stature and most cases of IUGR. CDGP can cause
enormous anxiety, and peer-group pressure may lead to
psychological distress. They may benefit from a short
course of low dose testosterone (50 mg testosterone
intramuscularly every 3-4 weeks) or estrogen (2.5 μg of
ethinyl estradiol daily) given for 3-6 months. This will
trigger the secondary sexual characteristics and the
pubertal growth spurt.
Hypothyroidism should be managed with
replacement by levothyroxine. Low dose estrogens are
useful in girls with Turner’s syndrome and delayed
puberty. Anabolic steroids (oxandrolone) have been tried
with some success in Turner syndrome and a few
children with CDGP. They act by increasing GH
secretion. A low-dose daily regimen will induce growth
spurt, which continues even after the steroids are
stopped. Specific therapy for chronic systemic disorders,
Endocrinology 917
e.g. renal tubular acidosis and celiac disease is associated
with good catch-up growth. For most skeletal dysplasias,
there is no medical treatment, even though GH has been
shown to benefit some selected groups. Limb lengthening
surgery is an option for some skeletal dysplasias.
Growth hormone (GH) is indicated in children with
GH deficiency. The recombinant GH is given in a dose
of 0.23-0.3 mg/kg/week (1 mg = 3 IU) divided in 6-7
doses subcutaneously, preferably at night, till adult
height is reached. There are very few side effects reported
in children who have received GH for GH deficiency.
Contrary to earlier suggestions, there is no report of
increased susceptibility to tumors or leukemia in treated
children. Children gain on an average 10-12 cm in the
first year of therapy and 6-8 cm/year thereafter every
year. However, the high cost of therapy has limited its
use in the subcontinent.
GH has been used to increase height in a number of
other disorders with limited success. These include
Turner syndrome, end stage chronic renal failure, and a
group of children with IUGR with poor catch up growth.
It is also used in children with Russell-Silver syndrome.
It has been shown to be effective in some groups of
children with constitutional delay and idiopathic short
stature. The dose used is higher than that used in GH
deficiency. In Turner syndrome, a combination of GH
with low dose estrogen and/or oxandrolone has been
shown to produce excellent height gain. The chances for
development of side effects are higher in these children.
Hence, regular monitoring of therapy with recording of
height is essential to obtain good results. Recently
aromatase inhibitors such as anastrozole and letrozole
have been tried with some success in adolescent boys
with short stature. These aromatase inhibitors delay the
tempo of bone age acceleration by estrogen blockade.
TALL STATURE
Compared to short stature, referrals for tall stature are
rather uncommon. A list of common causes for tall
stature is given in Table 17.1.3.
Some children have constitutional tall stature with tall
parents. Tall stature is usually evident early in childhood.
They have a high growth velocity and often a slightly
advanced bone age. If the tall stature is a matter of
psychological concern, sex steroids appropriate for sex
may be given at the onset of puberty to achieve early
epiphyseal fusion.
918 IAP Textbook of Pediatrics
TABLE 17.1.3: Etiology of tall stature in children
• Constitutional tall stature
• Exogenous obesity
• Precocious puberty
• Hyperthyroidism
• Growth hormone excess – Gigantism
• Sotos syndrome
• Marfan syndrome
• Homocystinuria
• Beckwith–Wiedemann’s syndrome
• Klinefelter syndrome
• Fragile X-syndrome
Many children with exogenous obesity appear tall, but
the adult height is normal. Children with precocious
puberty appear to be taller than peers due to the growth
enhancing action of gonadal steroids. However, early
epiphyseal fusion makes them short as adults, unless
treated early.
Gigantism is due to excessive production of GH by an
acidophil adenoma of the pituitary gland. It is
characterized by tall stature with prognathism, increased
soft tissue of hands and feet, broad root of nose, increased
sweating, hypertension and glucose intolerance. The
diagnosis is confirmed by detection of raised IGF–I levels
and lack of suppression of GH (levels <1 μg/ml)
following administration of oral glucose, 1.75 gm/kg.
Treatment is by trans-sphenoidal pituitary surgery.
Recurrence can be managed by octreotide, a somatostatin
analogue.
Sotos syndrome (cerebral gigantism) is characterized
by increased birth weight and length, macrocephaly and
dolichocephaly, hypertelorism and mental retardation.
Marfan syndrome is characterized by tall stature,
arachnodactyly (long thin fingers) and long thin limbs
with an abnormally long lower segment resulting in arm
span more than height. In addition there may be
hypotonia, hyperextensible joints, scoliosis, flexion
contractures, dislocation of the lens, and cardiac
anomalies. Klinefelter syndrome is associated with tall
stature, abnormally long legs, gynecomastia, mental
retardation and behavioral abnormalities with a
karyotype of 47, XXY.
BIBLIOGRAPHY
1. Allen DB. Growth hormone therapy for short stature: Is
the benefit worth the burden? Pediatrics 2006;118:343-
48.
2. Bajpai A, Sharma J, Menon PSN: Practical Pediatric
Endocrinology. 1st edition. Jaypee Brothers Medical
Publishers (P) Ltd: New Delhi, 2003.
3. Consensus guidelines for the diagnosis and treatment
of growth hormone (GH) deficiency in childhood and
adolescence: summary statement of the GH Research
Society. J Clin Endocrinol Metab 2000;85:3990-93.
4. Desai MP, Menon PSN, Bhatia V. Pediatric Endocrine
Disorders, 2nd edition. Orient Longman Ltd, Hyderabad.
2008;60-179.
5. Drop SL, Greggio N, Cappa M, Bernasconi S;
International workshop on management of puberty for
optimum axiological results. Current concepts in tall
stature and overgrowth syndromes. J Pediatr Endocrinol
Metab 2001; 14 (Suppl 2):975-84.
6. Farber RS, Kerrigan JR. The multiple indications for
growth hormone treatment of pediatric patients.
Pediatric Annals 2006;35(12):926-32.
7. Khadilkar VV, Khadilkar AV, Choudhury P, et al. IAP
growth monitoring guidelines for children from birth to
18 years. Indian Pediatr 2007;44:187-97.
8. Menon PSN. Use of growth hormone (GH) in non-GH
deficient short stature. Indian J Pediatr 2008 75(Suppl):
S14-S19.
9. Ranke MB, Lindberg A, Chatelain P, et al. Prediction of
long-term response to recombinant human growth
hormone in Turner syndrome: development and
validation of mathematical models. KIGS International
Board. Kabi International Growth Study. J Clin
Endocrinol Metab 2000;85:4212-18.
10. Rosenthal S, Cohen P, Clayton P, et al. Treatment
perspectives in idiopathic short stature with a focus on
IGF-I deficiency. Pediatr Endocrinol Rev 2007;4(Suppl.
2):252-71.
11. Tanner JM: Normal growth and techniques of growth
assessment. Clin Endocrinol Metab 1986;15:411-51.

17.2 Disorders of Pituitary
PHYSIOLOGY
The anterior pituitary develops from the Rathke’s pouch
and the posterior pituitary from the infundibulum, which
is a downgrowth from the floor of the diencephalon. The
principal hormones produced by the anterior pituitary
are:
• Thyroid stimulating hormone (TSH),
• Adrenocorticotropic hormone (ACTH),
• Follicle stimulating hormone (FSH),
• Luteinizing hormone (LH),
• Growth hormone (GH), and
• Prolactin (PRL).
These hormones act on target glands and a variety of
tissues in the body. The hypothalamus produces a
number of hormones which regulate pituitary function.
These include:
• Growth hormone releasing hormone (GHRH) —
regulates GH release.
• Gonadotropin releasing hormone (GnRH) —
regulates LH and FSH release.
• Thyrotropin releasing hormone (TRH) — regulates
TSH and PRL release.
• Corticotropin releasing hormone (CRH) — regulates
ACTH release.
• Somatostatin (SS) or growth hormone release
inhibiting hormone (GHRIH) —inhibits GH release.
• Prolactin inhibiting factor (PIF) — inhibits release of
PRL, TSH and GH.
• Ghrelin — regulates GH release.
• Vasopressin (AVP) — has a role in ACTH release.
GH has specific growth promoting actions on protein
synthesis, skeletal growth and intermediary metabolism.
A number of regulatory proteins or transcription factors
are important for the development and function of the
pituitary. They act at different stages of pituitary
development and trigger the expression of specific genes
involved in hormone release and action. These
transcription factors include HESX1, POU1F1 (PIT-1),
PROP-1, LHX3, LHX4, GLI2 and SOX3.
The growth hormone binding proteins (GHBP) act
as a reservoir for circulating GH. Their levels reflect the
GH receptor concentration, with the GHBP constituting
Endocrinology 919
PSN Menon
the extracellular domain of the GH receptor. A single
molecule of GH released from circulation binds to two
GH receptors to form a dimer complex. The actions of
GH are mediated through synthesis of insulin–like
growth factor–I (IGF–I). IGF–I in turn circulates bound
to binding proteins called IGFBP; the major one being
IGFBP–3. The GH–IGF–1 axis plays a key role in
regulating growth and the growth promoting effects of
IGF–I can be both GH–dependent and GH–independent.
GROWTH HORMONE DEFICIENCY (GHD)
Growth hormone deficiency is characterized by short
stature. The growth impairment starts within a few
months after birth, but a clinical diagnosis is usually not
obvious till the child is about 1 or 2 years old.
Etiology
The spectrum of GHD varies from complete to milder
grades of insufficiency. Incidence varies from 1 in 3500
to 4000 in USA and UK. The common causes of GHD are
given in Table 17.2.1. The most common form however
is idiopathic.
Clinical Features
The height is usually less than the 3rd percentile for the
age and the height gain is often as low as 1 cm/year.
These children have normal body proportions and are
somewhat overweight for their height with increased
subcutaneous fat, truncal obesity and normal body
proportions. Bone age is delayed to a variable extent. The
height age is less than the bone age and both are less
than chronological age.
The typical child with GHD is very short and plump
with immature facies and prominent forehead (Fig
17.2.1). They look much younger than their actual age.
Some of the features of congenital hypopituitarism
include midline facial abnormalities such as cleft palate
and lip, single central upper incisor tooth and prominent
philtrum. The eyes appear very prominent with a
depressed nasal bridge with a saddle shaped nose. In
addition there may be underdeveloped mandible and
920 IAP Textbook of Pediatrics
TABLE 17.2.1: Causes of growth hormone deficiency
• Congenital–Developmental defects of the hypothalamus
and/or pituitary
– Anencephaly, holoprosencephaly
– Septo-optic dysplasia, Hall-Pallister syndrome
– Midline brain and facial abnormalities: Single central
incisor tooth, cleft lip/palate
– Associated with abnormal pituitary morphology on MRI:
Hypoplasia of anterior lobe, interruption or hypoplasia of
stalk, ectopic posterior pituitary
• Defects in genes necessary for pituitary development
and function
– Isolated GHD: Autosomal recessive, autosomal
dominant, X–linked — (mutations of GH–1, GHRHR,
SOX3, HESX1)
– Combined pituitary hormone deficiencies: autosomal
recessive (mutations of PIT–1 (POUF1), PROP 1,
LHX3, LHX4, HESX1); autosomal dominant (mutations
of PIT–1 (POUF1), PROP 1); and X–linked, Rieger’s
syndrome
• Acquired
– Tumors within the hypothalamic–pituitary axis:
Craniopharyngioma, germinoma, teratoma
– Cranial irradiation: Leukemia, meduloblastoma,
astrocytoma/glioma, ependymoma, rhabdomyosarcoma
– Trauma to the hypothalamic–pituitary region: Perinatal
(breech, forceps) or postnatal
– Infiltration: Langerhans cell histiocytosis, thalassemia
major
– CNS infections: Tuberculosis
Figure 17.2.1: Nine-year-old boy with growth hormone
deficiency. Note immature facies, hypoplastic scrotum and
micropenis
chin, crowding of teeth, nystagmus with impaired vision
and a high pitched voice. The hands and feet are small
with slowly growing nails and hair. The skin is thin, with
a tendency for premature wrinkling.
Most children with GHD have normal length at birth.
Only 2–5% of children with GHD have suggestive clinical
signs in early infancy and present by the age of 2 years.
Thus regular height monitoring may help in early
detection. Hypoglycemia and prolonged jaundice in
neonatal period are early pointers to the diagnosis of
GHD. Neonatal hypoglycemia and convulsions are often
associated with ACTH deficiency. Hypogonadism may
be evident in boys as small sized genitalia (Fig 17.2.2).
Pubertal growth spurt is less than normal. Mental
development and intelligence are normal.
Diagnosis
Children with a height below 3rd percentile and height
gain less than 4 cm per year over a period of observation
for at least 6 months, with a bone age below the
chronologic age needs evaluation for GHD. The diagnosis
of GHD depends on demonstration of absent or low levels of
GH in response to stimulation. Since GH levels are
fluctuating because of its pulsatile nature, random or
fasting blood GH level measurements are not helpful in
diagnosis.
Pharmacological stimuli are preferred to
physiological stimuli. Tests which are based on the
physiological stimuli include physical exercise and deep
Figure 17.2.2: Ten-year-old boy with GHD—please note
micropenis and hypoplastic scrotum

sleep. Standard provocation tests use insulin, clonidine,
arginine, L–dopa, glucagon or GHRH. Of these insulin
(0.05–0.1 IU/kg IV) and clonidine (0.15 μg/m2 orally) are
the most preferred stimuli. Blood samples are collected
before and at 15 to 30 minute intervals for 2 hours.
Diagnosis of GHD is suspected when the peak GH level
is < 10 ng/ml following stimulation. The tests are not
foolproof and there is often an overlap between normal
short children and children with GHD. Hence two
standard provocative tests are usually suggested before
recommending GH therapy. Insulin administration
carries the risk of hypoglycemia and seizures. Hence in
infancy glucagon test is preferred. Priming with sex
steroids is required in short children with delayed
puberty and a bone age of 10 years or more (Boys: Depot
testosterone 100 mg IM 3–5 days before the test; Girls:
Premarin 5 mg orally the night before and morning of
the test). Euthyroid state is essential before GH testing.
The spontaneous secretion of GH can be evaluated
by measuring GH levels every 15 to 20 minutes during a
12 or 24–hour period. However this is not a practice in
India.
IGF–I and IGFBP–3 are increasingly used for initial
testing in the diagnosis of GHD. There are technical
limitations to IGF–I assays. Their levels vary with age,
nutritional status and certain disease states. IGF–I is low
in infancy and less dependable in young children (< 5
years of age) and there may be an overlap with GHD. It
is not dependable in GHD associated with brain tumors
and/or cranial irradiation. IGFBP–3, not IGF–I, is helpful
for diagnosis during infancy and can be used in suspected
neonatal GHD. The IGFBP–3 assay is technically simple,
and plasma concentrations vary much less with age and
nutritional status. It is a good predictor of GHD in a child
with short stature.
GHD may be associated with deficiencies of other
anterior pituitary hormones. Hence a complete
evaluation of anterior pituitary function is undertaken
in each patient with GHD.
CT or MRI of brain is useful in the evaluation of GHD
to rule out organic causes and study pituitary
morphology—ectopic posterior pituitary, anterior
pituitary hypoplasia, interruption or absence of pituitary
stalk, midline anomalies and tumors. Approximately
15% of children with GHD have an abnormality of
pituitary on imaging.
Molecular genetic testing provides an additional
useful diagnostic tool. Inherited forms of genetic
Endocrinology 921
abnormality may be the probable underlying cause of
GHD in 10–15% of all patients.
Increased serum concentrations of GH, both basal and
stimulated, together with low IGF–I and low IGFBP–3
levels, suggest growth hormone insensitivity. Estimation
of GH binding proteins (GHBP) is helpful in the diagnosis
of GH insensitivity.
Treatment
It is important to observe the child with regular growth
records for 6 months to one year—a child who gains more
than 4 cm/year is unlikely to have hypopituitarism. If
GH levels are low, the child may be given recombinant
GH in a dose of 0.23–0.3 mg/kg/week (1 mg = 3 IU)
subcutaneously, till adequate growth is achieved. Dosage
is titrated with the growth rate, pubertal stage, bone age
and serum IGF–I levels. Depot GH preparations are
under investigation.
GH therapy in children with GHD induces rapid
catch up growth during the first 2 to 3 years of treatment,
increasing the height gain 2 to 4 fold above the
pretreatment rate. The child on an average gains a height
of 10–12 cm in the first year of therapy and 6-8 cm/yr
thereafter every year. In subsequent years, the height gain
typically declines and follows normal patterns of growth.
Younger children and those receiving a higher dose show
a better response than older children with conventional
dose.
GH is administered daily by subcutaneous injection
in the evening 6 to 7 times a week, varying the site of
injection. Pen devices and prefilled syringes are available
which simplify daily administration. Many centers start
GH therapy at half the normal replacement dose and
increase the dose during the first month to avoid the
possible adverse effects of fluid retention. In addition to
growth, serum IGF–I levels should act as a guide during
GH dose titration. If IGF–I levels are low, an assessment
of injection technique and compliance might be necessary
before dose adjustment. If IGF–I levels are above the
normal range and height gain is adequate, a reduction
in dose should be considered.
The cessation of GH therapy at the end of linear
growth is guided by the following criteria:
• Height gain decreasing to 1 cm/year,
• Attainment of an acceptable height close to target
height,
• Bone age is greater than 16 years in boys and 14 years
in girls.
922 IAP Textbook of Pediatrics
After final height has been achieved, GH therapy
should be discontinued and GH status reassessed to
identify those with persistent severe GHD (peak GH < 5
ng/ml). Discontinuation of GH therapy is recommended
for a period of 1 to 3 months or longer before retesting.
GH therapy is relatively safe. Contrary to earlier
suggestions, there is no report of increased susceptibility
to tumors or leukemia in treated children. Salt and water
retention occurs within the first few months of initiation.
Treatment with GH increases the risk for slipped capital
femoral epiphysis, pseudotumor cerebri and worsening
of scoliosis. Impaired glucose tolerance may develop in
a few, hence blood glucose and HbA1c estimation is
recommended periodically.
There is also need for regular monitoring of thyroid
function during therapy with GH, as some patients
develop reversible hypothyroidism. Pituitary thyroid
axis should be checked annually. The dose required to
maintain euthyroid status is lower than in children with
primary hypothyroidism. Supplementation of other
pituitary/hypothalamic hormones along with GH
depending upon concomitant pituitary deficiencies is
important. Care should be taken while replacing steroid
replacement in children with ACTH deficiency as
hydrocortisone dose should usually not exceed 10 mg/
m2/24 hour. Sex steroid replacement should be at the
normal age around 11–12 years in girls and 12–13 years
in boys. Concurrent treatment with GH and a GnRH
analogue or aromatase inhibitor (anastrozole or letrozole)
has been recommended in some children presuming that
interruption of puberty will delay epiphyseal fusion and
prolong growth to give a better final height.
GH for Non–GH–Deficient Short Stature
Growth hormone enhances growth of many non–
GH–deficient short children and is recommended in the
following situations:
• Turner syndrome — A number of early studies
demonstrated that GH therapy with or without
anabolic steroids accelerated growth velocity and led
to an improved final height. The current practice is
to use approximately 0.35 mg/kg/week. In clinical
practice, it may be useful to add oxandrolone as a
synergistic agent if response to GH becomes
attenuated in late childhood.
• Chronic renal insufficiency prior to undergoing renal
transplantation — FDA has approved GH (0.3 mg/
kg/week) in children with chronic renal insufficiency
with poor height gain over 6 months, prior to
undergoing renal transplantation.
• Small–for–gestational age (SGA) — SGA children aged
4 years or older with failure to catch-up, height below
–2.5 SD, and height SDS more than 1 SD below
midparental height SDS are eligible for GH treatment
in US since 2001 and in Europe since 2003. The
recommended dose is 0.23–0.35 mg/kg/week.
• Prader–Willi syndrome — The indications for GH
therapy in Prader–Willi syndrome are for the
improvement of both growth and body composition.
The recommended dose is 0.16–0.23 mg/kg/week.
• Idiopathic short stature (ISS) — ISS is a heterogeneous
group of disorders with two common features—short
stature (height less than 2 SD or below the third
percentile for age and gender) and normal GH
response to stimulation tests. The tempo of growth
may be slow or normal. It is a diagnosis of exclusion.
Long–term GH therapy (0.24–0.37 mg/kg/week) can
lead to increased adult height in children with ISS,
but the degree and predictability is uncertain.
IGF–I DEFICIENCY AND GROWTH HORMONE
INSENSITIVITY (GHI)
IGF–I deficiency can result from genetic or non–genetic
effects and has been found to be an important underlying
cause of short stature in children. One of the first
examples of insensitivity to GH was reported by Laron
and colleagues in 1966 in three Israeli Jewish siblings
presenting with hypoglycemia, and a clinical phenotype
of GHD, but with marked elevation of immunoreactive
serum GH. Similar cases have been reported from India.
This is a hereditary disorder with primary resistance to
actions of GH due to a molecular defect in the growth
hormone receptor.
The primary genetic form of GHI is associated with
abnormalities of the GH receptor, required to mediate
actions of GH. It may also follow post–GH receptor
defects or molecular defects in IGF–I. Children with
primary GH insensitivity have the classic clinical
phenotype of severe isolated GH deficiency in its most
severe form. The craniofacial features may be more
prominent with characteristic midfacial hypoplasia,
depressed nasal bridge and protruding forehead. Height
age is more severely retarded in relation to bone age.
Basal serum GH concentration may be normal or
elevated, with excessive GH response to provocative
stimuli. Typically these children have low levels of

IGF–I, IGFBP–3, and very low or absent growth hormone
binding protein, GHBP. Administration of GH does not
bring about a rise in IGF–I levels, which forms the basis
of the IGF–I generation test. The final diagnosis of GHI
is based on the demonstration of the specific molecular
defect in GH receptor gene, in the presence of clinical
phenotype and laboratory criteria.
Initial results of treatment with IGF–I appear to be
promising, but there are a number of limitations.
ACROMEGALY AND GIGANTISM
Excess secretion of GH in children, usually due to a
pituitary adenoma, results in somatic overgrowth or
gigantism. When hypersecretion of the hormone occurs
after the fusion of skeletal epiphyses, it causes
acromegaly which is seen in adults.
Clinical Features
There is rapid linear growth and the child is taller than
his/her peers. Peripheral parts of the body, the hands,
feet, nose and mandible are large. The head circum-
ference is increased. Facial features are coarse with
prominent jaw, broad nose, enlarged tongue, bushy
eyebrows, thick skin and subcutaneous tissue, with
dorsal kyphosis. Muscle weakness, bony and
cartilaginous overgrowth, cardiomyopathies and
pigmentation of skin may be present. Diffuse or nodular
goiter or hyperthyroidism may be present. Involvement
of other endocrine organs may lead to hypogonadism,
hypocortisolism or diabetes mellitus. Headaches, visual
field defects including bitemporal hemianopsia,
papilledema followed by optic atrophy and external
ophthalmoplegia are common. Behavioural problems are
common. A GH-secreting adenoma may occur in
association with McCune–Albright syndrome or multiple
endocrine neoplasia (MEN 1).
Diagnosis
The diagnosis is based on clinical examination, periodic
growth assessment and investigations. Enlarged sella
turcica with erosion of margins is seen on X-rays. Tufting
of phalanges and increased heel-pad thickness may be
present. Skeletal maturation is normal. CT or MRI scan
should be done to determine the extent of the tumor.
The diagnosis is confirmed by detection of raised IGF–I
levels and lack of suppression of GH (levels <1 ng/ml)
Endocrinology 923
following administration of oral glucose, 1.75 g/kg.
Secretion of ACTH, TSH, LH and FSH may be impaired.
Treatment
Treatment of adenoma includes surgery, irradiation and
medical therapy. The pituitary microadenoma is resected
by trans-sphenoidal route if there is evidence for raised
intracranial tension. Larger tumours can be removed by
transcranial route. Conventional or high voltage
radiotherapy may halt the progress of the disease but
may not cause clinical improvement. Pituitary radiation
can also be carried out by implanting radioactive
isotopes. A long acting somatostatin analogue, octreotide
has been found to be better than bromocriptine in
suppressing the levels of GH, IGF–I and IGFBP–3
concentrations and reducing the size of tumor mass.
DIABETES INSIPIDUS
Diabetes insipidus results from lack of antidiuretic
hormone (ADH) or arginine vasopressin (AVP). AVP is
secreted from the supraoptic and paraventricular nuclei
of the hypothalamus. It is transported through axons to
posterior pituitary where it is stored until release. It acts
on receptors (V1 and V2) especially in the collecting ducts
of kidney. Binding of AVP to the V2 receptor leads to a
cascade of actions through the G–protein-adenyl cyclase
system and release of a second messenger known as
aquaporin 2, which allows transport of water. AVP
release is primarily controlled by alterations in plasma
osmolality.
Etiology
The deficiency may be partial, complete or transient.
Central or neurogenic diabetes insipidus results from
various abnormalities of AVP synthesis and/or action
due to lesions of neurohypophysis, such as suprasellar
tumors (craniopharyngioma, optic glioma), histiocytosis,
reticuloendotheliosis, encephalitis, tuberculosis,
granulomas and trauma. Diabetes insipidus can occur
in the newborn following asphyxia, intracranial bleeding,
and meningitis. Diabetes insipidus with diabetes
mellitus, optic atrophy and deafness is known as
Wolfram syndrome.
Nephrogenic diabetes insipidus is due to the inability of
the kidney tubules to respond to AVP—failure to increase
renal water reabsorption in the presence of adequate
924 IAP Textbook of Pediatrics
AVP. It is often due to abnormalities in kidney function
and structure affecting collecting duct or mutations that
affect the V2 receptors.
There is a psychogenic form of polydipsia with
associated polyuria due to compulsive water drinking.
In central and nephrogenic diabetes insipidus,
diffusion of water from the distal tubules and collecting
ducts is reduced due to lack of AVP. Since sodium and
water transport from the loop of Henle and distal tubule
remains unchanged, urine becomes hypotonic and
cannot be concentrated beyond 150 mOsm/kg.
Clinical Features
These children are thirsty and pass large quantities of
urine and often report with nocturnal enuresis. The
symptoms are often not recognized by the parents.
Infants with diabetes insipidus thus may present with
intermittent high fevers, irritability, loss of weight, poor
feeding, dehydration and collapse. Abnormal behavior
and hyperactivity are common. In children who have
acquired bladder control, enuresis may be the first
symptom. Signs and symptoms of causative lesions may
be present and include growth retardation, cachexia,
obesity, sleep disturbances, precocious puberty, visual
disturbances and emotional disorders.
Diagnosis
Polyuria and polydipsia should be confirmed by 24 hour
intake and output records. Urinary specific gravity varies
from 1.001–1.005 and osmolality 50–200 mOsm/kg.
Serum osmolality may vary depending on the degree of
dehydration. Other renal function studies are normal.
Often DI is suspected in the presence of life-threatening
hypernatremia. Serum AVP levels are helpful in
establishing the diagnosis with the child in a
hyperosmolar state with voiding hypo–osmotic urine.
Often the distinction between central and
nephrogenic DI requires a water deprivation test or
DDAVP test. During water deprivation test for a
minimum of 3–6 hours, children with central and
nephrogenic diabetes insipidus fail to concentrate urine
and plasma more than > 300 mOsm/kg, whereas, there
is urinary concentration in children with compulsory
water drinking. The interpretation of water deprivation
test is given in Table 17.2.2. If there is concentration of
urine following DDAVP, (5 μg intranasal), the cause is
primary AVP deficiency. Failure to concentrate urine and
TABLE 17.2.2: Interpretation of Water Deprivation Test
Initial evaluation
• Serum sodium
• Plasma osmolality
• Urine osmolality
• Weight (calculate 5% weight)
Test not required if urine osmolality > 750 mOsm/kg or
plasma osmolality > 300 mOsm/kg
Monitoring
• Urine osmolality and plasma osmolality hourly
• Urine output and weight hourly
• Look for features of dehydration
Termination of test
• Weight loss > 5% or
• Urine osmolality > 750 mOsm/kg or
• Plasma osmolality > 300 mOsm/kg
Vasopressin response test
• Aqueous vasopressin (0.1–0.5 unit/kg, intramuscularly)
• DDAVP (1–2 mg subcutaneously)
• Avoid intranasal DDAVP
Classification
Increase in urine osmolality
• < 50% of baseline – Nephrogenic DI
• > 50% of baseline – Central DI
Conversion of urine osmolality to urine specific gravity:300
mOsm/kg ≅ 1.005; 750 mOsm/kg ≅ 1.010
absence of response to DDAVP indicates nephrogenic
diabetes insipidus.
Radiologic studies including MRI may reveal
evidence for intracranial tumor such as calcification,
enlargement of sella, erosion of clinoid process and
increased width of suture lines or evidence of
reticuloendotheliosis such as rarefaction. MRI also can
demonstrate the absence of the bright hyperintense spot
in hypothalamic-pituitary lesions.
Treatment
Central diabetes insipidus can be treated by
administration of desmopressin (DDAVP), an analogue
of AVP given as a nasal spray, solution or tablets. The
usual dose is 5–10 μg daily either as a single dose or
divided into two doses. Children under two years require
lesser doses (0.15–0.50 μg/kg). Oral administration of
chlorpropamide 20 mg/kg/24 hours in 2 divided doses
may reduce polyuria and polydipsia in partial deficiency.
Hydrochlorothiazide and indomethacin may offer some
relief in nephrogenic diabetes insipidus.

BIBLIOGRAPHY
1. Bajpai A, Kabra M, Gupta AK, Menon PS. Growth Pattern
and Skeletal Maturation Following Growth Hormone
Therapy in Growth Hormone Deficiency: Factors
Influencing Outcome. Indian Pediatr 2006;43:593-599.
2. Bajpai A, Menon PS. Growth hormone therapy. Indian J
Pediatr 2005;72;139-144.
3. Bajpai A, Menon PS. Insulin like growth factors axis and
growth disorders. Indian J Pediatr 2006;73:67-71
4. Carr M, Gill D. Polyuria, polydipsia, polypopsia:
“Mummy I want a drink”. Arch Dis Child Educ Pract
Ed 2007;92:ep139-43.
5. Consensus guidelines for the diagnosis and treatment
of growth hormone (GH) deficiency in childhood and
adolescence: summary statement of the GH Research
Society. J Clin Endocrinol Metab 2000;85:3990-3993.
6. Desai MP, Menon PS, Bhatia V (Eds). Pediatric Endocrine
Disorders. Orient Longman, Hyderabad. 2008;2:
60-179.
17.3 Obesity
Obesity is becoming an increasing problem in children
and adolescents, with an estimated 30% or more
overweight in the West. In urban and semi-urban India
too, obesity in childhood is increasing rapidly, and
recently the prevalence of obesity crossed the prevalence
of malnutrition. Obesity is now recognized as a disease,
which decreases longevity, not just a cosmetic problem.
Apart from impaired mobility and interference with daily
living activities, it also has several health consequences
— hyperinsulinemia, hypertension, diabetes, polycystic
ovarian syndrome (PCOS), dyslipidemia, intertriginous
infections, sleep apnea with all its consequences, renal
alterations, hyperuricemia, psychosocial problems and
eating disorders. Obese children may suffer from feelings
of inadequacy and being different, and being stereotyped
as clumsy, lazy, stupid, or worthless. Almost half of
overweight children are overweight adolescents, and
almost 80% overweight adolescents are obese adults.
They in turn, in addition to all these problems, have more
coronary heart disease, osteoarthritis, cholecystitis and
fatty liver disease, higher risk of certain malignancies,
and worsening of asthma and renal disease. These
consequences are likely to be more severe in the coming
decades, as the duration of obesity will be longer with
childhood onset compared to adult onset.
Endocrinology 925
7. Desai MP, Upadhye PS, Kamijo T, et al. Growth Hormone
Releasing Hormone Receptor (GHRH-R) gene mutation
in Indian children with familial isolated GH deficiency:
A study from western India. J Pediatr Endocrinol Metab
2005;18:955–73.
8. Laron Z. Laron Syndrome (Primary growth hormone
resistance or insensitivity): The personal experience
1958–2003. J Clin Endocrinol Metab 2004;89:1031–44.
9. Rivkees SA, Dunbar N, Wilson TA. The management of
central diabetes insipidus in infancy. Desmopressin, low
renal solute load formula, thiazide diuretics. J Pediatr
Endocrinol Metab 2007;20:459-69.
10. Rosenfeld RG. Molecular mechanisms of IGF-1
deficiency. Horm Res 2006;65(suppl 1):15-20.
11. Rosenthal S, et al. Pediatr Endocrinol Rev 2007;4(Suppl.
2):252-271.
12. Scott R, Hedley-Whyte E. N Eng J Med. 2002;347(20):1604-
1611.
Anju Virmani
The problem is worse in South Asians, as we tend to
have more body fat for the same body mass index (BMI)
and more adverse body fat patterning including
abdominal adiposity. Individuals with low birth weight
and subsequent obesity are at a very high-risk for
impaired glucose tolerance. Many of these problems can
be reversed with weight loss, but established obesity is
one of the most frustrating disorders to manage, as
sustained weight loss is difficult to achieve, and lost
weight returns rapidly. Currently, the goals of
management are not attainment of ideal body weight
(IBW), which may be near-impossible, but achieving and
maintaining a 10-20% weight profile. Because weight
reduction is so difficult, prevention is crucial, and
pediatricians today must be vigilant in preventing
obesity, while reducing the health impact in those who
are already obese.
In clinical practice, obesity and overweight are often
used interchangeably, though overweight refers to a
situation where the person is upto 20% more than the
IBW, while obesity is when the weight is > 20% above
IBW. The term most commonly used to quantify obesity
is body mass index or BMI, calculated as weight in kg ÷
(height in m2). Adult obesity is defined as BMI > 25kg/
m2, though it has been recommended that for south
926 IAP Textbook of Pediatrics
Asians, the cut-off should be 23 kg/m2. Morbid obesity
is BMI > 40, and super-obesity a BMI > 60. In children,
Poskitt suggests using percentage of BMI, i.e. actual BMI/
ideal BMI for age. Alternatively, weight for height can
be calculated, and if it is upto 120% to ideal, considered
overweight, and >120% obese.
PATHOGENESIS
Several hormones (e.g. insulin and leptin) and nutrients
(glucose and fatty acids) link the brain, GI tract and
adipose tissue, influencing appetite, energy expenditure,
and growth. A number of orexicants (including Ghrelin,
cholecystokinin, cortisol, agouti-related protein,
neuropeptide-Y, GABA, melanin con H and
endocannabinoids) and anorexicants (leptin, α-MSH,
pro-opiomelanocortin, insulin, serotonin, dopamine,
glucagon-like peptide 1 and glucose dependent
insulinotropic peptide) are involved in the complex
processes of energy intake and expenditure and
maintenance of body weight. Many of them act via the
melanocortin 4 receptor (MC4R) in the arcuate nucleus
of the hypothalamus. Loss of function mutations of the
melanocortin 4 receptor (MC4R) cause severe obesity by
disrupting hypothalamic appetite control centers, and
promoting binge eating. Leptin, produced by adipose
tissue, suppresses food intake and increases energy
expenditure, but early hopes of its use in therapy were
belied as obese individuals are in a relatively leptin
resistant state. Other compounds are being explored for
possible therapeutic use.
The adipose tissue itself has been found to be an active
endocrine organ. It metabolizes sex steroids (e.g. converts
androstenedione to testosterone, and estrone to
estradiol), which in turn may play a role in fat
distribution. Thus increased fat deposits are seen in
hypogonadal states like Turner and Klinefelter
syndromes. Adipose tissue also secretes inflammatory
cytokines like TNF-α, interleukin-6, plasma activator
inhibitor type 1, adiponectin, visfatin, etc. which link
central/ visceral obesity with cardiovascular disease.
CAUSES
Obesity is, simplistically, caused by an imbalance of
energy intake and output, but the exact mechanisms are
unclear. Genetic influences are very strong, as shown by
several studies on adopted children and twins.
Environmental factors are equally important —
contributing factors are differences in food choices, levels
of physical activity, attitudes to food, activity, body
image, etc. A consistently strong correlation has been seen
with TV viewing, which reduces activity, and increases
calorie intake. In general, obesity runs in families, as they
share both genes and environment, and parental obesity
is a strong risk factor, with 80% of children of both obese
parents, and 40% of one obese parent being overweight.
Maternal weight, weight gain during the prenatal period,
and diabetes are important predictors of overweight at
birth and in infancy. These facts must be kept in mind
by the pediatrician, who can start delivering appropriate
messages from an early date.
Pathologic causes account for less than 1% of all cases
(Table 17.3.1). Corticosteroid or other drug therapy is the
commonest. Others include hypothyroidism, Cushing
syndrome, growth hormone deficiency (GHD) and
hypothalamic disorders. In Cushing syndrome, obesity
has a truncal distribution, but in infants the distribution
can be generalized (Fig. 17.3.1). A number of single gene
mutations can result in marked obesity. These include
syndromes like Prader-Willi, Laurence-Moon-Biedl,
pseudohypoparathyroidism type 1A, Alstrom,
Carpenter, Cohen, and POMC deficiency. The degree of
obesity is variable, ranging from very marked and
difficult to control, to mild. In craniopharyngioma,
obesity is multifactorial, and tends to worsen after
surgery.
CLINICAL EVALUATION
The most important clinical feature which distinguishes
pathological or endogenous from exogenous obesity is
the height. Children with endogenous obesity tend to be
taller than expected for age and genetic background,
while those with pathological states are shorter than
expected. History should include past growth
measurements (if available), any central nervous system
illnesses, drugs (e.g. corticosteroids, anticonvulsants and
antipsychotics), details of activity patterns, diet intake
(including total fat intake in cooking, milk and snacks),
mental development and school performance. Parents
may describe that during sleep the child snores loudly,
and sometimes appears to stop breathing — this should
be taken seriously.
Examination should include accurate measurements
of height, weight, BP, waist and hip circumference, and
pattern of fat distribution. Parents’ heights (for
calculating mid-parental/ target height) and weights
should be measured, rather than just asked for. The
 Endocrinology 927

Figure 17.3.2: Acanthosis nigricans seen in

the neck in an obese boy

evaluation and mental assessment must be done. In boys,

stretched penile length (SPL) must be measured, since
the penis is usually buried in abdominal fat. Even though
Figure 17.3.1: An infant with Cushing syndrome
the penis looks small in exogenous obesity, and may
bring the child to medical attention with concerns about
small genitalia and “hypogonadism”, the SPL is normal,
TABLE 17.3.1: Causes of pathological obesity while true micropenis may be found in GHD and some
Endocrine: syndromes. Adolescent boys may also be brought with
• Hypothyroidism concerns about enlarged breasts, which could be due to
• Growth hormone deficiency gynecomastia, lipomastia, or both. Orthopedic
• Cushing syndrome complications of a mechanical nature (genu valgum,
Hypothalamic: slipped capital femoral epiphyses, Legg-Calve-Perthes
• Laurence-Moon-Biedl syndrome disease) are more common, and healing after ankle
• Prader-Willi syndrome
sprains is slower. The child’s behavior and level of self-
• Craniopharyngioma
esteem should be assessed, as those who are
Drugs:
• Corticosteroids
embarrassed, withdrawn or depressed are less likely to
• Sodium valproate exercise and may be more prone to binge eating. Past
Miscellaneous: attempts at dieting, and parents’ attitudes should also
• Achondroplasia be assessed — dieting to control weight and high degrees
• Muscular dystrophy of parental control have been shown to promote fatness.
• Severe mental retardation
LABORATORY EVALUATION
child’s facies (dysmorphic features, Cushingoid, Investigations are guided by the clinical presentation, but
hypothyroid, etc.) and skin (white or red striae; may include thyroid hormones (T4 and TSH), blood
acanthosis nigricans, hirsutism score) provide valuable glucose, lipids and insulin, and if necessary serum
clues. Acanthosis is best seen in the neck and axillae, but cortisol. Fasting insulin level >20 IU/mL denotes
knuckles are also often pigmented (Fig. 17.3.2). Rashes hyperinsulinemia (normal <15 IU/mL). Changes of
in skin folds and inner thighs should be looked for, as PCOS may be seen in the adolescent girl (raised
these might interfere with exercise programs unless testosterone and/or DHEAS, altered LH/ FSH ratio, and
treated. Genital examination, pubertal staging, fundus polycystic changes in the ovaries). Sleep studies, if
928 IAP Textbook of Pediatrics
available, may reveal sleep apnea, which may be
obstructive, central, or combined. Bone age tends to be
advanced in exogenous obesity, usually being close to
the advanced height age. Bone age is usually retarded in
pathologic causes, e.g. hypothyroidism, GHD, and
Cushing syndrome. Further workup is hardly ever
required.
In exogenous obesity, levels of serum cortisol and
urinary metabolites of cortisol may be somewhat raised,
but are easily suppressible; urinary free cortisol levels
are normal. GH stimulation tests show a lowered
response, but IGF-1 and IGF-BP3 levels are normal. Other
findings in obese adolescents include proteinuria, fatty
changes in the liver, raised serum T3, decreased sex-
hormone binding globulin (SHBG), and pubertal levels
of FSH in 7-9 years old girls (with no increase in LH). In
adults, serum PTH has been found to be raised and an
independent predictor of obesity; high dairy calcium
intake has been shown to accelerate weight loss.
PREVENTION
All children and adolescents should have their weights
and heights measured periodically and plotted on a growth
chart throughout the growing years. All those at risk (one
or both obese parents, obese sibling(s), maternal age over
35 years at birth, single child, single parent, on certain
medications), and specially those showing rapid weight
gain (crossing percentile lines), must be focused upon
early as a family. Similarly, children with obesity-related
comorbidities should have early intervention.
All families must be given ongoing education to
breastfeed, avoid force feeding, keep fat and
carbohydrate intake moderate, encourage all forms of
physical activity, limit TV viewing (and in the Indian
context, limit/avoid home tuitions), and express affection
and approval through ways other than food. This should
be specially done if the birth weight was low, or high.
Schools should be encouraged to ensure that canteens
and vendors do not sell sugary drinks and fried snacks,
but offer attractive healthy food choices like fruit and
low fat dairy drinks. Some exercise should be mandatory
during school time for all children. The community in
general should be encouraged to make sure there is
enough space for children to cycle and to play — an
unhealthy trend in cities has been to forbid games in
parks, and discourage cycling. Pediatricians involved
with school health programs must pay attention to
children with rapid weight gain. Such children should
not be dismissed with the label of “simple” obesity. Older
children and adolescents can be advised in the school
setting and also with parents, about sensible diets and
active life styles. The tendency to follow popular and
unbalanced diets should be discouraged. Pediatricians
are quick to pay attention to and refer a child with failure
to thrive, but usually intervene or refer the obese child
very late. Studies have shown that treatments started
many years after obesity onset, are usually ineffective.
MANAGEMENT
Management of pathological obesity depends on the
underlying cause, e.g. replacement of the relevant
hormone in hypothyroidism, GHD, etc. While treating
endogenous obesity, what is critical is not only to lose
weight, but to maintain the loss. Hence, efforts should
be made with those patients who are motivated to make
long-term diet and activity changes as a family. In terms
of health benefits, a small but long-term change is more
important than drastic, short-lived changes. Similarly,
changes made only for the child, not by the rest of the
family are doomed to fail. Rapid weight loss (e.g. very
low calorie diets) should be planned under careful
supervision, only if it is life-saving (extreme obesity,
severe sleep apnea or cardiopulmonary manifestations,
as in the Pickwickian syndrome). Management consists
of a combination of dietary measures and increased
activity, supported by behavioral modification
techniques. Diet change alone, or exercise alone, is
unlikely to give sustained benefit. Drug therapy and
surgery are less frequently advised in childhood and
adolescence.
Diet Therapy
Diet changes are critical for weight loss attempts.
Standard diet therapy restricts calories to a variable
extent, while utilizing the same nutritional principles as
for healthy people — fat intake less than 30% of total
calories, protein 15%, and rest 55% as carbohydrates in
the form of complex carbohydrates, with adequate fiber
and micronutrients and plenty of liquids. In a child with
moderate to severe obesity, calorie restriction should be
moderate, aiming for a weight loss of up to 0.5 kg/week,
while ensuring adequate protein intake of 0.8 to 1 gm/
kg/day. Before initiating diet therapy, nutritional
deficiencies, e.g. iron, calcium, vitamin D, etc. (which are
quite common) should be corrected.

Intake of foods with little or no processing and low
glycemic index (GI) such as fruits, salads, whole wheat
products, whole legumes, low fat dairy products, etc.
should be encouraged. The entire family is advised to
reduce intake of high calorie foods with high fat and/or
simple sugars (fried foods and snacks, rich desserts, full
fat milk and its products, aerated drinks, and nutritive
sweeteners). Diet foods may have higher rather than
lower calorie content, and may be over-consumed, and
so are best avoided. Large meals with long gaps, and
missed meals should also be avoided — a “grazing”
eating pattern is better than a “gorging” pattern. Small
changes are made initially to ensure compliance. Care
must be taken not to over-restrict fat intake — low fat
diets with a compensatory increase in sugary and starchy,
high GI foods (e.g. polished rice, potatoes, ready to eat
cereals, bread and other maida products) result in sharp
rises in insulin levels. Such diets may actually promote
weight gain. At no time should diet restrictions be viewed
as punishments.
Very low calorie diets (400-800 calories per day) for 2
to 6 weeks result in rapid weight loss and marked
improvement in BP and levels of blood glucose, insulin,
leptin, and lipids. However, they can be dangerous unless
they are done under close monitoring and supplemented
with adequate minerals and vitamins. Long-term results
are poor, with weight loss returning within 1-5 years.
Stringent dieting can cause poor height gain, slowed
pubertal development, osteopenia, irritability, behavioral
problems, and a weight loss plateau because of a slower
metabolic rate.
Exercise
All forms of physical activity increase energy
expenditure, and are essential for healthy weight loss.
Increased purposeful exercise, and non-exercise activity
thermogenesis (NEAT) help with weight control. Aerobic
exercise increases energy expenditure directly, while
anaerobic exercise helps build muscle mass and thus
energy expenditure. Physical activity has other benefits
— psychological well-being, lesser irritability, lesser acne
and hirsutism, more regular menstrual cycles, better lipid
profiles, lower BP, and lower insulin levels. It also reduces
appetite while increasing metabolic rate (while calorie
restriction alone causes decreased metabolic rate).
In order to ensure compliance, it is important to make
sure active games are viewed as fun (walking with
friends, swimming, dancing, and sports). Initially low
Endocrinology 929
impact, moderate-intensity exercise (30 min × 5 days/
week) should be advised, as this level of exercise has been
shown to improve health-related outcomes. Later, the
time and intensity of exercise should be increased to
about 300 minutes per week (60 min × 5 days/week), as
higher levels of activity are needed for long-term weight
loss and maintenance.
Behavior Modification and Social Support
These are absolutely critical in achieving and sustaining
weight loss, as long-term changes in eating and activity
patterns are necessary. Techniques include monitoring,
goal setting, contracting, stimulus control, social
reinforcement, reward and punishment, aversion
therapy, managing high-risk situations, and relapse
prevention. Reasonable, clear goals must be set by the
family and health care provider working together.
Maintaining food, activity and screen-time (TV,
computer, and videogames) diaries is crucial. Giving
small rewards (especially zero calorie, e.g. a hug or a
stationery item) and other motivational techniques
ensure better and longer compliance. Occasional treats
should be given so that frustration does not build up.
Too much denial can push the child into stealing food
and other dysfunctional behavior patterns. For best
results, the entire family must be convinced of the need
for weight loss, and be keen to participate whole-
heartedly.
It is very important to avoid yo-yo weight patterns,
because each cycle of weight loss and gain causes
metabolic and psychological changes which make
subsequent attempts at weight control more difficult.
Treatment of Comorbidities
Associated problems — hypertension, type 2 diabetes,
dyslipidemia, PCOS, psychological, orthopedic and skin
problems, sleep apnea — are often not paid adequate
attention by health care givers. All these need proper
care in their own right.
Medications
A large number of anorexic agents, including amphe-
tamines, non-amphetamine appetite suppressants, and
antidepressants are available, but are not recommended
for use in children. Medication should be considered only
after significant efforts at diet, exercise and behavior
control have failed, and only as an add-on to these efforts.
930 IAP Textbook of Pediatrics
Insulin sensitizers, primarily metformin, have been
shown to safely achieve weight loss, decrease body fat,
and decrease plasma leptin, insulin and lipids, in PCOS
and other hyperinsulinemic adolescents, with or without
diabetes. Drugs approved for adult obesity include
sibutramine, orlistat and rimonabant. Sibutramine,
approved by the US FDA in adolescents (>16 years of
age), is a selective serotonin and noradrenaline re-uptake
inhibitor, which primarily increases satiety and thus
decreases food intake. It has been shown to cause weight
loss of 5 to 15% from baseline, with improvement in
metabolic parameters. The dose is 5 mg/day, going up
to 15 mg/day. Side effects include mild hypertension,
anxiety, headaches, and depression. Orlistat, approved
by the FDA for use in children over 12 years of age, is a
potent reversible inhibitor of gastrointestinal lipases,
which given with meals can decrease fat absorption by
30%, and thus causes significant weight loss, and
improves lipid and glycemic profile. The dose is 120 mg
three times per day. It causes oil spotting, flatulence and
frequent stools, and may lead to deficiency of fat soluble
vitamins like A and D. Rimonabant was not approved
by the FDA; it was approved in Europe but this approval
has since been suspended. Its side effects include
depression.
Surgery
Surgical treatment for morbid obesity is relatively
contraindicated in patients less than 18 years of age.
However, extreme obesity with severe sleep apnea or
other complications, not responding to nonsurgical
treatment, may call for bariatric surgery, after suitable
psychological preparation. Side effects can be significant
— pulmonary embolism, wound infection, micro- and
macronutrient malabsorption, diarrhea, anemia,
cholecystitis, and dumping syndrome. Some patients
may regain lost weight within 1-5 years.
BIBLIOGRAPHY
1. Bhargava SK, Sachdev HS, Fall CH, et al. Relation of serial
changes in childhood body-mass index to impaired
glucose tolerance in young adulthood. N Engl J Med
2004;350:865-75.
2. Bhatia V; IAP National Task Force for Childhood
Prevention of Adult Diseases. IAP National Task Force
for Childhood Prevention of Adult Diseases: insulin
resistance and Type 2 diabetes mellitus in childhood.
Indian Pediatr 2004;41:443-57.
3. Boney CM, Verma A, Tucker R, Vohr BR. Metabolic
syndrome in childhood: association with birth weight,
maternal obesity, and gestational diabetes mellitus.
Pediatrics 2005;115:e290-6.
4. Dennison BA, Erb TA, Jenkins PL. Television viewing
and television in bedroom associated with overweight
risk among low-income preschool children. Pediatrics
2002;109:1028-1035.
5. Dubey S, Kabra M, Bajpai A, Pandey RM, Hasan M,
Gautam RK, Menon PS. Serum leptin levels in obese
Indian children: relation to clinical and biochemical
parameters. Indian Pediatr 2007;44:257-62.
6. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T,
O’Rahilly S. Clinical spectrum of obesity and mutations
in the melanocortin 4 receptor gene. N Engl J Med 2003;
348:1085-95.
7. Hood MY, Moore LL, Sundararajan-Ramamurti A,
Singer M, Cupples LA, Ellison RC. Parental eating
attitudes and the development of obesity in children. The
Framingham Children’s Study. Int J Obes 2000;24:1319-
25.
8. Laxmaiah A, Nagalla B, Vijayaraghavan K, Nair M.
Factors affecting prevalence of overweight among 12- to
17-year-old urban adolescents in Hyderabad, India.
Obesity (Silver Spring) 2007;15:1384-90.
9. Marwaha RK, Tandon N, Singh Y, Aggarwal R, Grewal
K, Mani K. A study of growth parameters and prevalence
of overweight and obesity in school children from Delhi.
Indian Pediatr 2006;43:943-52.
10. Periera MA, Jacobs DR Jr, Van Horn L, Slattery ML,
Kartashov AI, Ludwig DS. Dairy consumption, obesity,
and insulin resistance syndrome in young adults: the
CARDIA study. JAMA 2002;287:2081-89.
11. Quattrin T, Liu E, Shaw N, Shine B, Chiang E. Obese
children who are referred to the pediatric
endocrinologist: characteristics and outcome. Pediatrics
2005;115:348-51.
12. Raj M, Sundaram KR, Paul M, Deepa AS, Kumar RK.
Obesity in Indian children: time trends and relationship
with hypertension. Natl Med J India 2007;20:288-93.
13. Ravussin E. Physiology. A NEAT way to control weight?
Science 2005;307:530-31.
14. Sachdev HS, Fall CH, Osmond C, Lakshmy R, Dey
Biswas SK, et al. Anthropometric indicators of body
composition in young adults: relation to size at birth and
serial measurements of body mass index in childhood
in the New Delhi birth cohort. Am J Clin Nutr
2005;82:456-66.
15. Singh R, Bhansali A, Sialy R, Aggarwal A. Prevalence of
metabolic syndrome in adolescents from a north Indian
population. Diabet Med 2007;24:195-99.
16. Warren JM, Henry CJ, Simonite V. Low glycemic index
breakfasts and reduced food intake in preadolescent
children. Pediatrics 2003;112:e414.

17.4 Disorders of Thyroid Gland
INTRODUCTION
Disorders of the thyroid gland are frequently
encountered in childhood and adolescence and are
amongst the most common endocrine problems seen in
these age groups. These disorders manifest with
qualitative or quantitative alterations in hormone
secretion, thyromegaly (goiter) or both. Insufficient
hormone secretion results in hypothyroidism and
excessive secretion causes hyperthyroidism or
thyrotoxicosis. Thyroid dysfunction causes disturbance
of metabolic functions in children as well as adults, but
the effects on growth and development and brain
functions are unique to the pediatric age group.
Undiagnosed and untreated or suboptimally treated
congenital hypothyroidism in infancy can lead to
permanent subnormal intellectual/neurological
function. This emphasizes the crucial role of thyroid
hormones on developing brain during fetal and early
postnatal life.
PHYSIOLOGY
The human thyroid gland originates embryologically
from an evagination of the pharyngeal epithelium with
cellular contributions from the lateral pharyngeal
pouches, followed by a process of descent to the neck
with occasional persistence of the remnants along the
tract as ‘lingual thyroid’, ectopic thyroid, thyroglossal
cyst or nodules. Less commonly, lingual thyroid may be
the sole functioning thyroid tissue which may not be
adequate to maintain a euthyroid status. Three
transcription factors, TTF-1, TTF-2 and PAX8, are
important for thyroid gland morphogenesis and
differentiation. A transcription factor, Pit-1 is important
for growth and differentiation of pituitary thyrotrophs.
The thyroid gland concentrates iodide from blood and
synthesizes and secretes thyroxine (T4) along with
smaller amount of 3,3’5-tri-iodothyronine (T3). The
synthesis and secretion of thyroid hormones occurs
through a series of enzyme dependant steps. The
thyroglobin so formed is stored in colloid, functioning
as a thyroid hormone precursor releasing thyroid
hormones in circulation as required and also permitting
Endocrinology 931
Meena P Desai
storage of iodine. T4 and T3 circulate bound to transport
proteins – the thyroxine binding globulin (TBG) and
thyroxine-binding prealbumin (TBPA) and albumin.
Seventy-five percent of circulating T3 in blood is derived
by monodeiodination of T4 in liver, kidney and other
peripheral tissues with the simultaneous formation of
reverse T3 (rT3), which is metabolically inactive. There
is a certain amount of tissue autonomy in the production
of T3 from T4. The concentrations of free T4 and free T3,
active at the cellular level approximate 0.03 and 0.30
percent respectively, of the total hormone concentration.
T3 is almost four times more potent than T4 and 85
percent of the bioactivity of T4 is attributed to T3.
The thyroid gland is under the regulatory control of
the pituitary thyrotropin or thyroid-stimulating hormone
(TSH) which in turn is regulated by the hypothalamic,
thyrotropin-releasing hormone (TRH). The fetal thyroid
gland and the hypothalamic-pituitary-thyroid axis
function largely independently of that of the mother.
Maternal TRH, not TSH, can cross the placenta. The
placenta is also relatively impervious to the passage of
maternal thyroid hormones under normal circumstances.
However, during first half of pregnancy, maternal
euthyroid status and optimal levels of maternal thyroid
hormones seem to be neuroprotective for the fetus.
Simultaneous presence of maternal and fetal
hypothyroidism is detrimental to neuro-intellectual
outcome as in endemic iodine deficiency or in presence
of genetic abnormalities of thyroid function.
There are physiological variations in the levels of TSH
and circulating thyroid hormones after birth, with an
acute surge in the TSH level within 30 minutes of birth
in response to relative hypothermia. This is followed by
rise in serum T3 and T4 levels by 24 hours, with a gradual
decline in their levels as well as of TSH by end of 1st
week. TSH surge in the premature infant is of a lesser
magnitude with a greater decline in T4 concentration in
the following 2 weeks. Hence, appropriate interpretation
of TSH, T3, T4 values obtained in neonatal period is
extremely important in arriving at the correct diagnosis
when newborns are screened for congenital hypothy-
roidism. Subsequently circulating levels of T3 and T4 are
higher during infancy and childhood. TSH level may
remain upto 10 μIU/ml during infancy beyond which it
declines below 5 μIU/ml.
932 IAP Textbook of Pediatrics
As stated earlier thyroid hormone actions also vary
with age, with maximal effects on somatic and skeletal
growth and maturation, brain growth and development
in infancy and childhood. Metabolic effects are more
pronounced in adulthood. The thyroid hormones
increase oxygen consumption, stimulate protein
synthesis, affect carbohydrate, lipid and vitamin
metabolism and promote growth and differentiation.
Approximately 100 μg of thyroxine (T4) is secreted by
the thyroid gland daily and about 90 mg of iodide
(15 mg/kg) is the recommended daily intake during
infancy and childhood with higher requirements in
preterms.
HYPOTHYROIDISM
Etiology and Epidemiology
Amongst disorders of thyroid gland in pediatric age
group congenital form of primary hypothyroidism due
to thyroid dysgenesis is most common. Hypothyroidism
may be acquired little later in childhood when it is most
commonly due to autoimmune disease of the thyroid
gland. Pituitary or hypothalamic disease can cause
secondary or tertiary forms of hypothyroidism which
may be congenital or acquired, is less common and is
usually associated with deficiency of other pituitary
hormones (Table 17.4.1). The term thyroid dysgenesis
denotes developmental abnormalities of the thyroid
gland ranging from agenesis, and hypoplasia to ectopic
or lingual thyroid gland. The worldwide prevalence of
congenital hypothyroidism (CH) approximates 1:3500 to
4000 newborns as revealed by neonatal screening
programs implemented in several parts of the world.
Though there are some racial differences, it is twice as
common in females. Most of these infants detected on
screening are asymptomatic in the first few weeks of life,
but the main objective of screening is to detect and treat
them very early so as to prevent or minimize the
neuropsychologic damage which can be irreversible if
the treatment is delayed beyond the first few weeks of
life. Hereditary biosynthetic defects leading to
dyshormonogenesis as well as autoimmune thyroid
disease are some of the other causes of hypothyroidism
in children and adolescents. A variety of biosynthetic
defects causing dyshormonogenesis leading to
hypothyroidism usually associated with varying degrees
of goitrous enlargement of thyroid gland have been
identified. Autoimmune thyroid disease is a common
TABLE 17.4.1: Causes of hypothyroidism in childhood and
adolescence
A. Primary Hypothyroidism
I. Thyroid dysgenesis
• Aplasia, hypoplasia
• Ectopic or lingual thyroid gland.
II. Inborn errors of thyroid hormone synthesis, secretion or
utilization
III. Endemic iodine deficiency
IV. Autoimmune thyroiditis
V. Iatrogenic
• Antithyroid drugs and goitrogens
• Irradiation
• Post-thyroidectomy
B. Secondary/tertiary Hypothyroidism
(Pituitary/hypothalamic)
I. Congenital
• Isolated or Panhypopituitarism
II. Acquired
• Trauma
• Infection
• Neoplastic / postsurgical
• Irradiation
cause of hypothyroidism beyond midchildhood and in
adolescents. Endemic iodine deficiency still remains an
important cause of endemic cretinism and hypo-
thyroidism in some parts of the world and in northern
regions of India.
Clinical Manifestations
The symptoms and signs of congenital hypothyroidism
in the neonatal period are nonspecific and vague, leading
to difficulties in clinical diagnosis. Less than 10 percent
of newborns detected on screening as having biochemical
hypothyroidism, can be recognized clinically. In the
newborns and in early infancy, symptoms predominate
over signs. Growth retardation which is so characteristic
of this disorder in postnatal life is not seen at birth. These
infants may be large at birth and may be postmature.
Some of the early manifestations like prolonged
physiological jaundice, constipation, feeding difficulties,
inactivity, macroglossia, constipation, wide fontanels,
mottling, hypothermia, and hoarse cry should arouse
suspicion. Clinical signs become more obvious over the
following weeks. Coarse hypothyroid facies often
associated with puffiness of eyes, protruding tongue,
pallor, lethargy, fullness in supraclavicular regions,
altered skin and hair texture, hypotonia, distended
abdomen with umbilical hernia, low pitched irritable

Figure 17.4.1: Five months old male child with congenital
hypothyroidism presented for constipation, feeding difficulty,
and failure to grow. Not the protruding tongue, little puffiness
of eyes, distended abdomen and small umbilical hernia
prolonged cry, are features which combine to give a
characteristic appearance to these infants (Fig. 17.4.1).
Failure to grow and delayed milestones become
increasingly obvious. Bradycardia, muffled heart sounds,
delayed relaxation while eliciting deep tendon reflexes
are helpful signs. Children with dyshormonogenesis may
present with goiter at birth or during infancy. The
incidence of other associated congenital abnormalities
with CH is around 8 percent.
Hypothyroidism in older children is usually caused
by autoimmune thyroiditis but occasionally children
with thyroid dysgenesis having hypoplastic or ectopic
thyroid tissue or dyshormonogenesis may present late.
They may present with usual symptoms and signs of
hypothyroidism with lethargy, failure to grow or short
stature of insidious onset. Presence of a small goiter
which is firm in consistency with a pebbly surface favours
the possibility of thyroiditis as opposed to
dyshormonogenesis where the goiters may be small or
large but the consistency tends to be soft to firm with
occasional presence of a bruit (Fig.17.4.2). Obesity,
goiters, scholastic problems, delayed sexual maturation
or uncommonly sexual precocity or muscular
hypertrophy, are the other modes of presentation.
Diagnosis
The diagnosis of primary hypothyroidism is confirmed
by the presence of low serum T4 and T3 concentrations
Endocrinology 933
Figure 17.4.2: Eight years old girl with goitrous hypothyroidism
due to dyshormonogenesis. Note hypothyroid facies, puffiness
of eyes, and goiter. (Had two more siblings with similar clinical
picture)
and elevated serum TSH values. Estimation of free T4
and free T3 is also available now. TSH is an extremely
sensitive index of primary hypothyroidism. Radio-
graphic studies demonstrate significant delay in skeletal
maturation and occasionally epiphyseal dysgenesis. The
skeletal age may also suggest the approximate age at
which the disorder was initiated. Imaging studies like
ultrasonography and radioisotope scans in particular,
help in delineating the anatomical and functional status
of the gland but are not mandatory. Thyroid antibody
studies are helpful in identifying autoimmune basis of
the disease in the older age group. In secondary and
tertiary forms of disease, the TSH concentration may be
low or undetectable with subnormal levels of T3 and T4
as well as free T4 and T3. Usually associated deficiency
of other pituitary hormones is also present.
Treatment
Once the diagnosis is established, the need for life long
therapy in congenital hypothyroidism should be
adequately stressed. The goal of therapy is to maintain
the circulating serum T4 level in the upper normal range
934 IAP Textbook of Pediatrics

and normalize the elevated TSH. The preferred Clinical Manifestations

preparation is sodium-levothyroxine because of its
About 5 to 10 percent of all patients with hyper-
uniform potency, reliable absorption and increased
thyroidism are under 15 years of age with a peak
bioavailability. In newborns detected on screening and
incidence in adolescent. The incidence is nearly five times
in early infancy, 10 μg/kg has been recommended. In
higher in girls. The clinical course is variable but less
the newborn period, full replacement therapy can be
severe than in adults. The onset of symptoms is often
initiated promptly. In longstanding thyroid deprivation
insidious with the interval between the onset of the
where the diagnosis is delayed for months or occasionally
disorder and diagnosis ranging between 3 to 12 months.
for years, ¼ of the daily dose can be administered initially
Emotional disturbances, behavioral changes
and stepped up gradually to full replacement dose, in 3
characterized by excitability, irritability and tendency to
to 6 weeks. The daily requirement is about 100 μg/m2.
emotional outbursts may herald the onset of the disease.
The required dose is administered as one single dose,
Motor hyperactivity and restlessness may be
preferably at a convenient fixed time during the day and
misdiagnosed as chorea. Increased appetite with no
on empty stomach to maximize absorption. Regular
increase in weight or actual loss of weight, diarrhoea,
therapy is extremely important. Individualization of
heat intolerance and excessive sweating and mild fever
therapy by monitoring serum thyroid levels and TSH is
are some of the other findings. Tremors of the hands
ideal and necessary. Therapeutic monitoring is
become evident with further progression. Exophthalmos
recommended with blood samples obtained at periodic
may be present but not severe. Lid lag on looking
intervals for TSH, T3 and T4 estimations. Clinical
downward, impairment of convergence, retraction of
evaluation and growth monitoring during therapy are
upper eyelids with infrequent blinking may be
important.
noticeable. The degree of thyroid enlargement is variable
but never marked and may escape detection. Goiter is
Prognosis
present in almost 90% of cases. Bruit may be heard. Palms
The final outcome in CH is closely related to the nature may be warm and moist. Muscular weakness is
and severity of the underlying thyroid abnormality, the uncommon. Patient may complain of feeling of weakness,
age at diagnosis and onset of treatment, the adequacy tiredness and palpitations. Tachycardia is appreciable
and regularity of therapy with the required degree of and a wide pulse pressure is often noted. Dyspnea,
clinical and laboratory follow-up. Worldwide neonatal cardiac decompensation and rarely atrial fibrillation may
screening programs for CH have had a significant impact occur. Thyroid ‘crisis’ or ‘storm’ and the apathetic,
on reducing intellectual deficits in hypothyroid infants cachectic type of hyperthyroidism are uncommon in
diagnosed and treated early. childhood.
HYPERTHYROIDISM
Laboratory Data
Hyperthyroidism (thyrotoxicosis) is an uncommon
Serum levels of T4, T3, free T4 and free T3 are elevated.
disorder of childhood and adolescence. It results from
excessive secretion of thyroid hormones and is usually In some patients, T3 may be higher with T4 levels in the
upper normal range or minimally elevated. TSH is
the result of diffuse toxic goiter (Graves disease) in
suppressed below normal and thyroid antibodies are
children. Other uncommon causes are thyrotoxicosis
present. Radioiodine uptake and assay for TSH receptor
factitia (ingestion of thyroid hormones), thyroid
antibodies are not essential for diagnosis. Advanced
neoplasia or very rarely due to TSH producing pituitary
skeletal maturation may be noted. Craniostenosis may
tumors. In infants born of mothers with Graves disease,
hyperthyroidism may occur as a transitory phenomenon occur in infants.
during neonatal period due to transplacental passage of
Treatment
thyroid stimulating immunoglobulin. Germ line
mutations of the TSH receptor known as gain of function The therapy is directed toward reducing the production
mutations can cause familial or sporadic hyper- of thyroid hormones and blunting their effects. Medical
thyroidism, and may cause persistent hyperthyroidism therapy is the preferred modality of treatment in children
during infancy. rather than subtotal thyroidectomy or radioiodine

therapy. The thionamide drugs in use are pro-
pylthiouracil (PTU), methimazole, and carbimazole. The
therapy has to be continued for long to prevent relapses.
Toxic reactions like agranulocytosis, hepatic dysfunction
and lupus like syndrome do occur. Transient urticarial
rashes are most common. Propranolol helps in
controlling symptoms due to hyperactivity of the
sympathetic nervous system. Other modalities of therapy
such as radioiodine thyroid ablation or subtotal surgical
excision are indicated, if medical therapy fails after
adequate trial.
GOITER
Presence of goiter may be the initial complaint for which
children and adolescents may seek medical attention. In
these patients underlying cause of the thyromegaly needs
to be determined and the functional status of the thyroid
gland whether euthyroid, hypothyroid or hyperthyroid
needs to be ascertained. Common causes which lead to
goitrous enlargement in this age group are simple goiter
or physiological enlargement. Often this may be related
to iodine deficiency or other causes such as chronic
lymphocytic thyroiditis, dyshormonogenesis or rarely
malignancy. WHO has defined a goiter as a thyroid gland
where the size of the lateral lobes exceed the size of the
terminal phalanx of the subject examined. Prevalence of
small asymptomatic goiters in school children to the
extent of 6% have been noted though the incidence is
higher in regions of endemic iodine deficiency. Based
on the functional status of the thyroid gland and the
underlying cause of goiter further strategies for
17.5 Disorders of Bone and Mineral Homeostasis
INTRODUCTION
The role of the skeleton in maintaining mechanical
stability of the body and aiding locomotion is easily
appreciable. Its role as an important metabolic organ is
more subtle but equally important. The skeleton is the
largest reservoir of calcium and phosphorus. It is vital
for extracellular concentrations of calcium to be
Endocrinology 935
management need to be planned. Nodular goiter or
single nodule need careful evaluation for the presence
of thyroid malignancy.
BIBLIOGRAPHY
1. Brown RS, Huang S. The thyroid and its disorders. (Eds.)
CGD Brooke P.E. Clayton, RS Brown, MO Savage.
Blackwell 5th ed. 2005; publishing 218-53.
2. Delang F. Iodine deficiency as a cause of brain damage.
Postgrad Med J 2001;77:217-20.
3. Delang F. Neonatal screening for congenital hypo-
thyroidism results and perspectives. Horm Res
1997;48:51.
4. Desai MP. Disorders of the Thyroid Gland. In Pediatric
Endocrine Disorders ed. Meena Desai, PSN Menon, V
Bhatia. 2nd ed. Orient Longman Pvt. Ltd., 2008;282-310.
5. Fisher DA. Disorders of the thyroid in the newborn and
infants. In Pediatric Endocrinology ed. M.A. Sperling,
Philadelphia: WB Saunders 2002; 161-86.
6. Fisher DA. Thyroid disorders in childhood and
adolescence. In Pediatric Endocrinology ed. M.A.
Sperling, Philadelphia; WB Saunders 2002; 187-204.
7. Gruters A, Krude H, Beibermann H, et al. Alterations of
neonatal thyroid function. ACTA Paediatr. 1999;428:17-
22.
8. Halac I, Zimmermann D. Thyroid nodules and cancers
in children. Endocrinol Metab Clin N Am. 2005;34:
725-44.
9. Koch CA, Sarlis NJ. The spectrum of thyroid diseases in
childhood and its evolution during transition to
adulthood: Natural history, diagnosis, differential
diagnosis and management. J Endocrinol Invest. 2001;
24 : 659.
10. Kraeim Z, Newfield RS. Graves disease in children.
J Pediatr Endocrinol Metab. 2001;14:229.
Vijayalakshmi Bhatia
maintained within a narrow range. This is brought about
via the actions of hormones such as parathyroid hormone
(PTH), 1,25-dihydroxy-cholecalciferol (1,25(OH)2D or
calcitriol) and calcitonin on bone, kidney and gut. In bone,
the osteoblast cells are responsible for bone formation,
the osteocytes are the mature bone cells and the
osteoclasts bring about bone resorption to restore serum
calcium as well as to enable bone remodelling.
936 IAP Textbook of Pediatrics
MINERALS
Calcium
Ninety nine percent of total body calcium resides in bone.
The plasma levels range from 9 to 10.5 mg/dl in children.
Approximately half the plasma calcium is present bound
to plasma proteins and half in the free ionized form.
Intestinal absorption of calcium is vitamin D-dependent
when present in the gut in smaller quantities. Urinary
calcium excretion is of the order of 4 mg/kg/day. Dietary
sources of calcium are mainly milk products and fish;
smaller amounts are available from green vegetables, ragi
and til. The daily requirement of calcium ranges from
about 300 mg in infants to 600 to 800 mg in childhood
and 1000 mg in adolescence, pregnancy and lactation.
Phosphorus
About 85 percent of the total body content of phosphate
is in the bone, in the form of the calcium salt,
hydroxyapatite. Serum phosphorus is higher in infancy
(4.5 to 7.5 mg/dl) and falls gradually during childhood
to adult levels of 2.5 to 4.5 mg/dl. Serum phosphorus
concentration is largely maintained by variable renal
reabsorption. Normally about 85 percent of the filtered
load is reabsorbed — 75 percent in the proximal tubules
and 10 percent in distal tubules. Both proximal and distal
reabsorption of phosphate is decreased by PTH and
calcium. Phosphorus deficiency results in effective and
complete reabsorption. Phosphorus is available in
commonly eaten staple foods such as cereals and lentils.
Its deficiency is encountered only in special circum-
stances such as prematurity or parenteral nutrition.
Magnesium
Magnesium is an important component of the adenylate
cyclase system. Its deficiency leads to hypocalcemia, both
by inhibiting PTH release and inducing resistance to its
action. Hypomagnesemia may be seen in the setting of
diarrhea, malnutrition, malabsorption, and parenteral
nutrition. Normal serum magnesium level is 1.8 to 3.0
mg/dl.
THE CALCIOTROPIC HORMONES
Parathyroid Hormone (PTH)
PTH is an 84-amino acid chain, but its biologic activity
resides in the first 34 residues. The major stimulus to the
secretion of PTH is a fall in the ionized fraction of plasma
calcium, detected by the calcium-sensing receptor on the
parathyroid gland. The biological actions of PTH at a
variety of target organs serve to increase plasma calcium.
PTH stimulates activity of 1α-hydroxylase in the kidney,
enhancing production of calcitriol. The increased level
of calcitriol induces synthesis of a calcium-binding
protein in the intestinal mucosa with resultant absorption
of calcium. PTH also mobilizes calcium by directly
enhancing bone resorption. The effects of PTH on bone
and kidney are mediated through binding to specific
receptors on the membranes of target cells and through
activation of a transduction pathway involving a “G”
protein, coupled to the adenylate cyclase system.
Vitamin D
Vitamin D (cholecalciferol) is produced in the dermis,
by conversion from cholesterol, under the influence of
ultraviolet rays from sun exposure. Latitude, season,
cloud cover, pollution, skin pigment, clothing and
sunscreen affect dermal vitamin D. Cholecalciferol is
hydroxylated to form 25 hydroxyvitamin D (25-OHD)
in the liver. In the next step, 25-OHD is further
hydroxylated in the kidney to produce the active form
of the hormone 1,25(OH)2D (calcitriol). The production
of 1,25(OH)2D is directly related to body needs. Its
formation is enhanced by PTH, vitamin D and dietary
calcium depletion, hypocalcemia and hypophos-
phatemia. 25-OHD (calcidiol) is the major transport form
of vitamin D and its circulating concentration reflects an
individual’s vitamin D nutritional status. Serum 25-OHD
below 20 ng/ml indicates vitamin D deficiency. Diet is a
poor source of vitamin D except in communities who
consume large quantities of fatty fish (such as the
Eskimos). Therefore in many temperate countries, where
sunshine is poorly available during winter, food is
fortified with vitamin D.
Calcitonin
Calcitonin is a 32-amino acid polypeptide secreted by
the parafollicular or C cells of the thyroid. It is the only
hormone in humans capable of actively lowering plasma
calcium. The hypocalcemic action results from inhibition
of bone resorption and increased bone mineral
deposition.
 Endocrinology 937

HYPOCALCEMIA day of life are included in this category (Table 17.5.1).

Presentation
Hypocalcemia in the older child presents with tetanic
spasms of the fingers and wrist or toes and foot, perioral
numbness, tingling, or seizures. Mental changes include
irritability, impairment of memory, paranoia, depression,
and frank psychosis. Papilledema may be present.
Subclinical hypocalcemia may be elicited by the Chvostek
or Trousseau signs. Chronic hypocalcemia leads to
cataracts and basal ganglia calcification. However, in
neonates, hypocalcemia may present quite differently,
with jitteriness, apneic spells or laryngeal stridor, in
addition to seizures.
Etiology
The causes of hypocalcemia are highlighted in Table
17.5.1. They can be categorized into “early” (typical
neonatal) causes occurring in the first 4-5 days of life and
“late” causes occurring thereafter. A brief discussion of
some of the etiologies follows below.
Early neonatal hypocalcemia: The fetus is supplied with
calcium via active transport across the placenta.
Interruption of this enriched supply at birth,
compounded by a relatively poor PTH response to
hypocalcemia, makes the newborn baby vulnerable to
hypocalcemia. Various neonatal situations such as
prematurity, birth asphyxia, infant of a diabetic mother,
IUGR, polycythemia, alkali therapy, and sepsis, among
others, enhance the risk.
Late neonatal hypocalcemia: Conditions which
generally present with hypocalcemia after the 4th or 5th
Precipitation of hypocalcemia by the high phosphorus
content of cow milk (six times the concentration in breast
milk) is commonly encountered. An increasingly
diagnosed cause for late neonatal hypocalcemia is
maternal (and hence neonatal) vitamin D deficiency. This
may present as late as 1 or 2 months of age, and is often
characterized by resistance to the phosphaturic action of
PTH, exhibiting hyperphosphatemia instead of low
phosphorus as expected. Renal failure is another
condition associated with high serum phosphorus.
Various causes of hypoparathyroidism are respon-
sible for hypocalcemia in childhood (Table 17.5.1). Mani-
festations of mucocutaneous candidiasis, Addison
disease, alopecia, lymphocytic thyroiditis, pernicious
anemia, hepatitis and primary gonadal insufficiency may
be associated with that of hypoparathyroidism as part
of the APECED (autoimmune polyendocrinopathy
candidiasis ectodermal dysplasia) syndrome. Dental
enamel hypoplasia may be seen as part of hypocalcemia
(Figure 17.5.1). Pseudohypoparathyroidism (PHP) des-
cribes a group of disorders characterized by biochemical
hypoparathyroidism (i.e. hypocalcemia and hyper-
phosphatemia), increased secretion of PTH, and target
tissue unresponsiveness to the biological actions of PTH
due to mutations in the alpha subunit of G proteins. There
is an association between PHP and somatic abnorma-
lities. These include short stature, round face, short neck,
and shortening of the metacarpals and metatarsals.

TABLE 17.5.1: Etiology of hypocalcemia

Early neonatal hypocalcemia

• Prematurity
• IUGR
• Infant of diabetic mother
• Birth asphyxia
Late neonatal and childhood hypocalcemia
• Cow milk ingestion
• Hypoparathyroidism
• Familial hypercalciuric hypocalcemia
• Secondary to maternal hyperparathyroidism.
• Pseudohypoparathyroidism
• Severe vitamin D deficiency
• Hypomagnesemia
Figure 17.5.1: Enamel hypoplasia (highlighted with arrows) in
a child with hypoparathyroidism. The same could be seen in
• Critical illness
children with calcipenic rickets of any etiology.
938 IAP Textbook of Pediatrics
Characteristic radiographic findings include shortening
of the fourth, fifth or all metacarpals and metatarsal
bones. Resistance to other hormones with G protein
mediated actions may coexist.
Diagnosis
Besides confirmation by serum total and ionized calcium,
an ECG is useful as it may reveal a prolonged QT interval.
Serum magnesium should be performed in all cases of
hypocalcemia. CT head may show calcification of the
basal ganglia. Serum creatinine, albumin (every gm/dl
of serum albumin below normal decreases total calcium
by 0.8 mg/dl), blood gases, 25-OHD, PTH, and 24 hour
urinary calcium or calcium/creatinine ratio, complete the
armamentarium for investigation.
Treatment
Calcium gluconate (10 % solution) 0.2 ml/kg slow
intravenous injection (over 10 minutes at least), corrects
hypocalcemia initially. Maintenance doses are about
50 to 75 mg of elemental calcium/kg/day.
Hypoparathyroidism is treated with oral calcium and
calcitriol in a dose of 30–70 ng/kg/day. Calcitriol has a
short half-life and hence should be given in two equal
divided doses. It has a rapid onset of effect (1-4 days)
and rapid reversal of hypercalcemia after discontinua-
tion, in the event of over-dosage.
Hypovitaminosis D must be treated with calcium and
vitamin D. While there is no objective evidence at this
time for recommendation of doses of vitamin D for
nutritional rickets, about 10,000 to 60,000 units orally
weekly for a month (the lower end dose to be used in
infancy to avoid any risk of hypercalcemia), followed by
1 sachet (60,000 units) every 2 months approximately for
another 3 to 6 doses should suffice. During this time the
importance of sun exposure is reinforced.
Hypomagnesemia is treated with 0.2 ml/kg/dose of
a 50 % solution of magnesium sulphate. The oral
maintenance dose of elemental magnesium is 12 -20 mg/
kg/day, best provided as gluconate, lactate or chloride
to minimize the side effect of diarrhea.
HYPERCALCEMIA
Presentation
The symptoms of hypercalcemia may be nonspecific and
include anorexia, constipation, vomiting, failure to thrive,
polyuria, muscular weakness, dehydration.
Etiology
Table 17.5.2 highlights the causes of hypercalcemia.
Inactivating mutations of the calcium sensing receptor,
which cause mild asymptomatic hypercalcemia when
inherited heterozygously, result in severe neonatal
hypercalcemia when inherited homozygously. PTH is
low or inappropriately normal for the state of
hypercalcemia. This condition is a mirror image of the
hypocalcemic disease, which is due to activating
mutations of the same receptor. Primary hyperparathy-
roidism, due to an adenoma or hyperplasia of the
parathyroid glands, in India is still dominated by the
manifestations that are characteristic of advanced
disease, bones (fractures and brown tumours due to
osteitis fibrosa cystica, stones (renal), groans (bone pain),
and psychic overtones, though in developed countries it
is often diagnosed incidentally by routine serum
chemistry. William syndrome is characterized by
hypercalcemia, elfin facies and supravalvular aortic
stenosis. A deletion of part of the long arm of
chromosome 7 is seen in a majority of the patients.
Hypercalcemia subsides after 2 to 3 years of age. Till then,
low calcium diet and sunscreen are used to minimize
calcium absorption.
Diagnosis
Serum calcium, phosphorus, potassium, urinary calcium
or calcium/creatinine ratio, PTH, and 25-OHD are
relevant investigations. Plain radiology of the hand
shows subperiosteal resorption and endosteal and
intracortical tunneling. There may be tufting of the
terminal phalanges. The skull is characterized by salt and
pepper erosions. Hyperparathyroidism in growing
children causes appearances which radiologically
resemble rickets but which are quite different histolo-
gically. This is due to resorption of metaphyseal bone
which may give rise to crippling, skeletal deformities.
TABLE 17.5.2: Etiology of hypercalcemia
• Transient neonatal hyperparathyroidism (secondary to
maternal hypoparathyroidism)
• William syndrome
• Granulomatous disease e.g. sarcoidosis
• Vitamin D toxicity
• Primary hyperparathyroidism
• Multiple endocrine neoplasia
• Familial hypocalciuric hypercalcemia and neonatal severe
hyperparathyroidism
• Tertiary hyperparathyroidism
• Non-endocrine malignancies. (PTHrP excess)
 Endocrinology 939

Treatment TABLE 17.5.3: Causes of rickets

Hydration and forced diuresis with a loop diuretic are Calcipenic rickets Phosphopenic rickets
the cornerstones of treatment of hypercalcemia. Vitamin D/calcium deficiency Prematurity (calcium plus
Reduction of calcium absorption by corticosteroid phosphorus deficiency)
administration is useful in vitamin D intoxication, Anticonvulsant induced Fanconi syndrome (proximal
William syndrome and sarcoidosis. Inhibition of bone RTA)
resorption can be brought about by calcitonin or Malabsorption Congenital hypophosphatemic
Distal renal tubular acidosis rickets X-linked/autosomal
bisphosphonate (pamidronate) administration. Life
dominant
threatening hypercalcemia can be reversed by dialysis. Chronic renal failure Hypophosphatemic rickets with
Surgery is the treatment for primary hyperparath- hypercalciuria
yroidism. 1 hydroxylase defect Tumor induced (mesenchymal
tumor, epidermal nevus)
Calcitriol receptor defect
RICKETS

Nutritional Rickets
Rickets occurs due to deficiency of vitamin D or calcium
or both. Deficiency of phosphorus leading to rickets is
found only in special circumstances such as prematurity
or parenteral nutrition where adequate care has not been
given to supplementation of all minerals, as dietary
sources of phosphorus are common. In India, vitamin D
deficiency is particularly encountered in the neonate or
infant, due to poor maternal stores. Thereafter, it is
prominent during adolescence, especially in girls, who
cannot take advantage of sunshine due to modest
clothing and poor outdoor activity. In toddlers and mid-
childhood (and also in older age groups), dietary calcium
deficiency plays a predominant role. Nutritional rickets
is discussed in detail in the chapter on vitamins.

Non-nutritional Rickets

When vitamin D and calcium supplementation has been

given in adequate doses for at least 2 months without
onset of radiological healing or improvement in serum
alkaline phosphatase, non-nutritional or resistant rickets
should be suspected. Alternatively, in the presence of
clues to a non-nutritional cause, it may be investigated
for without waiting. Such clues include alopecia, features
of malabsorption, hypokalemia, nephrocalcinosis,
polyuria, or dense bones, among others (Figure 17.5.2).
Resistant rickets may be categorized into calcium
deficiency or phosphorus deficiency rickets for ease of
differential diagnosis and investigative pathway
(Table 17.5.3).
Figure 17.5.2: Skeletal radiograph of a child with calcitriol
receptor abnormality (vitamin D resistant rickets type 2),
showing alopecia, rachitic rosary and widened malleoli at the
ankles (highlighted by arrows) (reproduced with permission
from Pediatric Endocrine Disorders, Desai M, Menon PSN,
Bhatia V eds, 2nd edition, Orient Blackswan, Chennai)
Etiology and Presentation
Children with renal tubular acidosis (RTA) may present
with polyuria, failure to thrive, hypokalemia, and in the
case of distal RTA, with dental enamel hypoplasia,
nephrocalcinosis or nephrolithiasis. Anemia, abdominal
940 IAP Textbook of Pediatrics

pain, diarrhea, Bitot’s spots or night blindness, or xylose test and endoscopic duodenal biopsy. If these are
hypoalbuminemia may alert the pediatrician to the negative, serum 25OHD and 1,25(OH)2D can throw light
presence of malabsorption. Hypophosphatemic rickets on 1-hydroxylase defect and calcitriol receptor defect
typically presents at the end of the first year of life. (VDRR 1 and 2). Low PTH type of resistant rickets should
Ricketic features predominantly affect the skull and be worked up for phosphate clearance (phosphate
lower limbs, with relative sparing of upper limbs and clearance/creatinine clearance) and TmP/GFR
chest. measurement. Proximal RTA is tested by bicarbonate
loading test and documenting amino aciduria, glycosuria
Diagnosis and uric aciduria in addition to phosphaturia. Plain
Typical clinical differentiating features of calcium versus radiology reveals coarse trabecular pattern in RTA and
renal failure, and dense bone in hypophosphatemic
phosphorus deficiency rickets are highlighted in Table
rickets.
17.5.4. If a good clinical examination does not provide a
clue to etiology, then PTH should guide further work
Treatment
up. Primary and secondary hyperparathyroidism result
in increased phosphorus leak from the proximal tubule. RTA is treated with alkali, the distal variety requiring 3-
Thus a child with any cause of calcipenic rickets, such as 5 mmol/kg/day and proximal RTA a greater amount
malabsorption or distal renal tubular acidosis, due to such as 10-15 mmol/kg/day of bicarbonate. Citrate as
concomitant secondary hyperparathyroidism, may the source of alkali is useful in distal RTA, to diminish
appear to have hypophosphatemic rickets. Serum PTH renal calcium deposition. Potassium replenishment is
is useful investigation at this juncture, being only provided as necessary. Investigation and treatment of
marginally elevated in hypophosphatemic rickets, and the primary disease, if any, producing RTA, must be
significantly raised in calcipenic rickets. performed. Anticonvulsant therapy should be
Cases with high PTH should be investigated for distal accompanied by 500 to 1000 units daily of vitamin D
RTA by serum potassium, blood and urine pH, supplementation. VDRR 1 is treated with calcitriol in
ammonium chloride loading test if necessary, and physiological or minimally higher doses, and VDRR 2
ultrasound of kidneys for nephrocalcinosis. Malabsorp- with very high doses of calcitriol or with intravenous
tion tests include ESR, anti-endomyseal antibodies, D- calcium. Hypophosphatemic rickets requires phosphorus
supplementation to produce healing of bone and
TABLE 17.5.4: Features of calcipenic versus calcitriol to suppress the secondary hyperparathyroidism
phosphopenic rickets which is invariably produced. Deformity often
Calcipenic Phosphopenic normalizes with years of growth and remodeling, in all
rickets rickets etiologies of rickets. Therefore, one need not rush for
Hypotonia Present Absent corrective osteotomy unless deformities come in the way
Bone pain Present Absent of locomotion.
Tetany/seizure Present Absent
Dental enamel Present Absent
Metabolic Bone Disease of Prematurity
hypoplasia The preterm baby is deprived of the large supply of
Dental caries Absent Present calcium normally accrued during the third trimester of
Serum calcium Low Normal pregnancy via active transport across the placenta. Breast
Serum phosphorus Low Low milk is not adequate to supply similar amounts of calcium
Alkaline phosphatase Markedly raised Moderately raised and phosphorus. The resulting bone disease presents
Parathyroid hormone Raised Normal / minimally with fractures upon minimal handling, and X-ray picture
raised showing lucent bones. It can be prevented by using
Plain radiology Lucent bone, Dense bone commercially available human milk fortifiers providing
osteitis fibrosa the required 200 mg/kg/day of calcium and 100 mg/
cystica kg/day of phosphorus.

Conditions of Increased Bone Fragility
While the prototype disease of fragile bones in children
is osteogenesis imperfecta, the most common condition
in this category encountered by pediatricians is
glucocorticoid induced osteoporosis (GIO). Since
pediatricians care for children on pharmacological doses
of glucocorticoids for diverse conditions, they must be
familiar with the precautions to be taken for preventing
or minimizing GIO. These include adequate calcium,
protein and vitamin D nutrition, institution of gonadal
steroids in a timely manner in adolescents, in whom
pubertal delay has occurred due to the basic systemic
disease, avoiding immobilization and encouraging
regular appropriate weight bearing exercise. Needless
to say, the minimum effective dose of glucocorticoid
should be used, to minimize bone fragility as well as
diverse other side effects of systemic glucocorticoid
therapy.
A discussion on osteogenesis imperfecta, fibrous
dysplasia and osteopetrosis is beyond the scope of this
book. A few useful bibliographies are mentioned below.
BIBLIOGRAPHY
1. Chesney RW. Metabolic bone disease. In: Behrman RE,
Kliegman RM, Jenson HB (Eds). Nelson Textbook of
Pediatrics, WB Saunders Co 2004;17:2341-48.
17.6 Disorders of Puberty
Puberty marks the transition of a child into an adult. The
age of onset of puberty is variable but usually occurs at
about 10.5 years in girls and between 11 and 12 years in
boys. In girls, puberty usually begins with breast
development (thelarche) but occasionally with the
appearance of pubic hair (pubarche). Menarche usually
occurs about 2 years after breast development begins. In
boys, testicular enlargement (more than 3 ml) marks the
onset of puberty and is followed by the appearance of
pubic hair and development of the external genitalia. The
pubertal growth spurt is an early event in girls usually
at Tanner stage B2, while in boys the growth occurs late,
usually at the time when a testicular volume of 10 ml is
achieved. What triggers the onset of puberty is still
Endocrinology 941
2. Doyle DA and DiGeorge AM, Disorders of the
parathyroid glands. In: Behrman RE, Klaus G, Watson
A, Edefonti A, Fischbach M, Ronnholm K, Schaefer F, et
al. Prevention and treatment of renal osteodystrophy in
children on chronic renal failure: European guidelines.
Pediatr Nephrol 2006;21(2):151-9.
3. Kliegman RM, Jenson HB (Eds). Nelson Textbook of
Pediatrics, 17th ed, WB Saunders Co 2004; Pp 1890-97.
4. Mughal Z. Rickets in childhood. Semin Musculoskelet
Radiol 2002;6:183-190.
5. Rauch F, Schöenau E. Skeletal development in premature
infants: a review of bone physiology beyond nutritional
aspects. Arch Dis Child Fetal Neonatal Ed 2002;86:F82-
F85.
6. Seibel MJ. Biochemical markers of bone remodeling.
Endocrinol Metab Clin N Am 2003;32:83-113.
7. Teotia M, Teotia SPS, Nath M. Metabolic studies incon-
genital vitamin D deficiency rickets. Indian J Pediatr
1995;62:55-61.
8. Thornton J, Ashcroft DM, Mughal MZ, Elliot R, O’Neill
TW, Symmons D. Systematic review of effectiveness of
bisphosphonates in treatment of low bone mineral
density and fragility fractures in juvenile idiopathic
arthritis. Arch Dis Child 2006;91(9):753-61
9. Van Staa TP, Cooper C, Leufkens HGM, Bishop N.
Children and the risk of fractures caused by oral
corticosteroids. J Bone Miner Res 2003;18:913-918.
10. Yamamoto T. Clinical approach to clarifying the
mechanism of abnormal bone metabolism in McCune
Albright syndrome. J Bone Miner Metab 2006;24(1):7-10.
Prisca Colaco
hypothetical. The first neuroendocrine event is an
increase in the frequency and amplitude of GnRH pulses.
Loss of tonic CNS inhibition and decreasing sensitivity
to the negative feedback of gonadal steroids occur at the
time of puberty. The age at onset of puberty is controlled
by both genetic and extrinsic factors, and therefore, may
sometimes occur earlier or later than normal.
PRECOCIOUS PUBERTY
Puberty is considered precocious if its onset occurs before
the lower limits of normal. This was considered to be 8
years in girls and 9 years in boys. However a large study
in the US showed that puberty is being achieved about a
year earlier in white girls and 2 years earlier in African
942 IAP Textbook of Pediatrics
American girls. New guidelines recommended that
puberty be considered precocious only when breast
development or pubic hair appears before the age of 7
years in white girls and 6 years in black girls. However
rapid progression of puberty in children below the age
of 8 years or the occurrence of menarche before the age
of 9 years merits evaluation. For boys, the onset of
puberty before the age of 9 years is considered precocious.
Classification
Sexual precocity can be classified as:
i. Central or true precocious puberty – which is due to
the premature activation of the hypothalmic-
pituitary-gonadal (HPG) axis and is therefore
isosexual.
ii. Peripheral or pseudoprecocity – This results from the
production of sex steroids independent of the HPG
axis and may be isosexual or heterosexual.
iii. Incomplete forms or pubertal variants – premature
thelarche, premature pubarche and premature
menarche.
Etiology
The common causes of precocious puberty are given in
Table 17.6.1.
Central Precocious Puberty
Central precocious puberty (CPP) is the most common
form of precocious puberty and is about five times more
common in girls than in boys. CPP in girls is most often
idiopathic (about 75%). But, the younger the child the
greater is the likelihood of underlying pathology. In
idiopathic CPP the appearance of sexual characteristics
is merely a normal event occurring early and puberty
progresses normally. In contrast to girls, in about two-
thirds of boys, CPP is secondary to CNS pathology.
Hypothalamic hamartomas are the most common
tumors causing precocious puberty. These are benign
tumors which contain measurable GnRH and act as
ectopic GnRH pulse generators. In India CNS infections,
particularly tubercular meningitis, are important causes
of neurogenic CPP (Fig. 17.6.1). Hypothyroidism,
untreated or inadequately treated, is sometimes
associated with precocious puberty. The cause is not clear
but it is thought to be due to the effect of markedly
elevated TSH levels on the FSH receptor (Fig. 17.6.2).
TABLE 17.6.1: Causes of Sexual Precocity
A. Central Isosexual Precocious Puberty
• Idiopathic
• Neurogenic:
1. Intracranial tumors— Hypothalamic hamartoma,
glioma, pineal tumor
2. Post-infectious— Meningitis, encephalitis
3. Congenital malformations— Hydrocephalus,
porencephaly, microcephaly
4. Traumatic— Perinatal, accidental
• Other diseases:
1. Neurofibromatosis
2. Tuberous sclerosis
3. Russell-Silver syndrome
4. Hypothyroidism
5. Advanced somatic maturation due to androgen
exposure
6. Idiopathic epilepsy
B. Peripheral Isosexual Precocious Puberty
• Girls:
1. Ovarian — McCune Albright syndrome, follicular cysts,
tumors
2. Adrenal —Feminizing adrenal adenoma
3. Exogenous estrogens
• Boys:
1. Testes — Leydig cell tumor, familial testotoxicosis
2. Adrenal — Congenital adrenal hyperplasia, adenoma,
carcinoma, Cushing syndrome
3. hCG secreting tumors
4. Exogenous androgens
C. Contrasexual development
• Virilization in girls — CAH, virilizing ovarian and adrenal
neoplasms
• Feminization in boys — Adrenal neoplasms, extraglandular
conversion of circulating steroids to estrogens
D. Variations of Pubertal Development
• Premature thelarche
• Premature pubarche
• Premature menarche
Peripheral Precocious Puberty
Peripheral precocious puberty is only about one-fifth as
common as CPP. Virilizing conditions in boys and
feminizing conditions is girls may be due to adrenal or
gonadal causes. Adrenal disorders, most commonly
congenital adrenal hyperplasia (CAH), are the most
common causes of peripheral precocity in boys. PPP is
therefore much more common in boys as compared to
girls. The prepubertal size of the testes suggests the
diagnosis. Ovarian disorders are much more likely in
girls with PPP. McCune Albright syndrome (MAS)

Figure 17.6.1: A five-year-old girl with central precocious
puberty following tuberculous meningitis at 2 years of age. Note:
Breast development and 3rd nerve palsy on the left side
Figure 17.6.2: A seven-year old girl with hypothyroidism
and precocious puberty
Endocrinology 943
consists of fibrous bony dysplasia, skin pigmen-tation
and precocious puberty, and predominantly affects girls.
Autonomous secreting follicular cysts of the ovary
without any evidence of MAS may also result in sexual
precocity. These cysts are often more than 2 cm in
diameter in contrast to the smaller cysts which may be
normally present in the prepubertal ovary or in true
precocious puberty. Pubertal signs often develop rapidly.
Subsequent atresia of the cysts results in withdrawal
bleeding.
Pubertal Variants
The incomplete forms of sexual precocity can be
differentiated from precocious puberty by the absence
of other signs of puberty and a normal growth rate.
Premature thelarche: In premature thelarche breast
development persists for more than 6 months or occurs
anew. It usually occurs before 3 years of age and rarely
after 4 years. There is no other evidence of estrogen effects
such as increase in uterine size, changes in external
genitalia, growth acceleration or bone age advancement.
The cause is unknown. It could be caused by transient
estrogen secretion by follicular cysts of the ovary.
Exogenous estrogens in food or environmental exposure
could also lead to breast development.
Premature pubarche: It is due to increased adrenal
DHEAS secretion (adrenarche) which results in the
appearance of pubic hair. It is more commonly seen in
girls in the 3 to 8 years age group. Pubarche is not
progressive. Occasionally these children may develop
slight acne, axillary hair, and adult type body odor but
no other secondary sexual characteristics. Skeletal matu-
ration and linear growth are at upper normal limits. Signs
of severe androgen excess should prompt a search for a
virilizing condition such as an adrenal tumor or CAH.
Premature menarche: This is a rare condition and local
lesions must be ruled out. It is due to transient ovarian
activity resulting in an isolated follicular cyst. It may
occasionally be the first sign of puberty.
Evaluation
A detailed history and clinical evaluation is helpful in
arriving at a diagnosis and directing investigations.
History
• Age at onset: Idiopathic CPP usually presents between
6 and 7 years of age. The earlier the onset of puberty
the greater the likelihood of there being an underlying
944 IAP Textbook of Pediatrics
organic cause. Hypothalamic hamartomas and
familial testotoxicosis present very early in the first 3
to 4 years of life.
• Pubertal progression: In idiopathic CPP the rate of
progression may sometimes be very slow with
menarche occurring upto 5 years after breast
development. Very rapid progression of puberty is
seen in androgen-producing tumors, ovarian cysts
and some CNS tumors such as hypothalamic
hamartomas.
• Accelerated growth is a feature of both central and
peripheral precocious puberty but is not seen in
pubertal variants.
• Irregular vaginal bleeding is more common in
functioning ovarian tumors and hypothalamic
hamartomas.
• History of past CNS infection, headaches, visual
disturbances, personality changes, seizures and
developmental delay would suggest a neurologic
disorder.
• Drug exposure should be enquired into.
• Symptoms suggestive of hypothyroidism should be
looked for.
• A family history of precocious puberty would suggest
constitutional precocious puberty or familial
testotoxicosis. A history of precocious puberty in boys
and genital ambiguity in girls of the same family
would suggest CAH.
Clinical Examination
• Evaluate (a) androgen effects – acne, hirsutism,
increased muscle mass and clitoromegaly and (b)
estrogen effects – breast development and changes in
vaginal mucosa.
• Pubertal staging according to Tanner’s staging.
• Abdominal and rectal examination for uterine size,
ovarian masses and adrenal tumors.
• Testicular palpation: A testicular volume of more than
3 ml indicates the onset of true precocious puberty.
Scrotal masses suggest testicular tumors or adrenal
rests.
• Inspection of the skin is helpful in McCune Albright
syndrome, neurofibromatosis and tuberous sclerosis.
• Neurologic examination should include fundus
examination and perimetry.
• Examination for signs of hypothyroidism.
Investigations
Hormonal Evaluation
• Sex steroids: In girls serum estradiol levels are not very
helpful in determining the stage of puberty. Levels
overlap between normal pre-puberty, early puberty,
precocious puberty and premature thelarche. Levels
> 20 pg/mL suggest that puberty has started.
Markedly elevated levels (>100 pg/mL) are seen in
estrogen secreting ovarian tumors and sometimes in
follicular cysts.
• In boys, serum testosterone levels <30 ng/mL are
generally prepubertal, though in some laboratories
levels of 10-30 ng/mL by may indicate early puberty.
Testosterone levels may be very high related to the
stage of puberty in boys with primary gonadotropin
excess.
• Serum gonadotropins and the response to GnRH
stimulation: Gonadotropin levels are elevated in CPP
and suppressed in PPP. Basal serum FSH and LH
were of limited value in early puberty. But with the
availability of sensitive third-generation assays the
random LH is a good screening test for central
precocious puberty. An LH level of <0.1 IU/L is
prepubertal and levels of 0.3 IU/L or more are
pubertal. Random FSH levels are not helpful in
discriminating between prepubertal and pubertal
children.
• GnRH stimulation test is more helpful in distinguishing
central from peripheral precocity. In CPP, an LH
predominant response is seen with GnRH stimula-
tion. An increase in FSH levels much more than LH
indicates that the child is prepubertal. In PPP,
gonadotropin levels do not rise in response to GnRH
stimulation.
• Serum dehydroepiandrosterone sulfate (DHEAS) levels
are elevated in premature adrenarche. and can be
very high in virilizing adrenal problems.
• Serum17-hydroxyprogesterone (17OHP) and the response
to ACTH or serum 11-deoxycortisol may be required to
rule out CAH.
• hCG levels in the serum, if an hCG secreting tumor is
suspected.
• Thyroid hormone studies in suspected hypothyroidism.
Radiology
• Bone age: Skeletal maturation is advanced in all cases
of precocious puberty except if associated with
 Endocrinology 945

hypothyroidism, but remains normal in the
incomplete forms. It is also helpful in predicting adult
height.
• CT or MRI brain to determine the etiology of CPP.
• Pelvic and abdominal sonography: To evaluate the size
and morphology of the uterus, ovaries and adrenals.
This is essential in PPP to find the cause. In CPP the
size of the uterus is increased and an endometrial
shadow seen. The ovaries will also be enlarged
bilaterally, and may show multiple small follicular
cysts.
• Testicular sonography: if a tumor is suspected.
• Skeletal survey: In suspected cases of MAS.
Treatment
child’s psychological development corresponds with the
chronologic age. No major psychopathology is associated
with precocious puberty. Future fertility is maintained.
DELAYED PUBERTY
Delayed puberty is defined as the absence of any sign of
puberty in a girl by the age of 13 years or by 14 years of
age in a boy. It also includes incomplete pubertal
development such as no menarche at 15 years or no
progression from an intermediate stage for 2 years.
Classification
Delayed puberty can be classified as (i) temporary and
(ii) permanent (Table 17.6.2).

Surgery Evaluation
Tumors of the ovary, testis and adrenals require surgical History
removal. Ovarian cysts more than 3 cm in size should be
• Medical history should focus on a review of symptoms
explored surgically. Smaller cysts require repeated
which may indicate a chronic systemic disease,
evaluation. Surgery of hypothalamic hamartomas is
hazardous and is not recommended, because they do not
grow or become malignant. Germ cell, pineal tumors and TABLE 17.6.2: Etiology of delayed puberty
hCG-producing suprasellar tumors can be treated by Temporary causes:
radiotherapy. 1. Constitutional delay in growth and puberty (CDGP) –
sporadic or familial.
Medical Treatment 2. Nutritional disorders
3. Chronic systemic disease
Treatment of precocious puberty is indicated if: 4. Hormonal disturbances e.g. hypothyroidism, isolated
• There is evidence that adult height may be significan- GH deficiency and excess glucocorticoids
tly compromised. Permanent causes:
• Menarche occurs before 6 years of age. A. Hypogonadotropic:
• Pubertal development is psychologically distressing Congenital:
1. Isolated gonadotropin deficiency
to the child.
2. LH deficiency
• Pubertal development progresses rapidly over an 3. Associated with syndromes e.g. Kallmann, Prader-Willi,
observation period of about 6 months. Laurence-Moon- Biedl
Therapy aims at reversing the development of sexual 4. Panhypopituitarism
characteristics and decreasing the acceleration of growth Acquired: Tumors, surgery, trauma, hyperprolactinemia
and bone age by using GnRH analogue therapy. B. Hypergonadotropic: (Primary gonadal failure)
Antigonadotropic and antiandrogen drugs such as Congenital:
1. Sex chromosome anomalies e.g. Turner syndrome, XO/
medroxyprogesterone and cyproterone acetate cause a
XY, Klinefelter
regression of pubertal signs but have no effect on growth 2. Anomalies of testosterone synthesis or action
acceleration and bone age progression. Other drugs 3. Pure gonadal dysgenesis
which may be used in PPP include ketoconazole, 4. Associated with other syndromes, e.g. Noonan’s,
spironolactone and testolactone. Alstrom, Smith-Lemli-Opitz
Acquired:
1. Surgical or traumatic castration
Psychological Support
2. Orchitis/oophoritis
Psychological support for the child and parents is an 3. Chemotherapy, radiotherapy
4. Idiopathic
essential part of the general management scheme. The
946 IAP Textbook of Pediatrics
prolonged drug therapy or drug abuse, poor
nutrition, head trauma and anosmia.
• Family history of delayed puberty or hypogonadism
and a history of parental consanguinity should be
enquired into. In CDGP, a history of delayed puberty
is often obtained in either a parent or sibling.
• Drawing a growth curve and calculation of the growth
velocity may help in distinguishing between CDGP
and growth hormone deficiency (GHD). In CDGP the
growth velocity is appropriate for the child’s
bone age while in GHD it is subnormal. In
hypogonadotropic hypogonadism, height is usually
normal and the growth curve shows a deceleration
only at the time of puberty.
• Rate of pubertal progression: In CDGP, the rate of
pubertal progression is normal. Slow progression
suggests a partial gonadotropin deficiency.
Examination
• System review: Search for the presence of chronic
disease, malnutrition, anosmia, midline defects,
endocrine disorders, and dysmorphic syndromes.
Neurological assessment should include fundus
examination and evaluation of visual fields.
• Signs of puberty should be noted and staged according
to Tanner’s staging.
• Height measurement: Children with temporary delay
are commonly short. In hypogonadotropic hypo-
gonadism associated with GH deficiency the height
is markedly short, while in those with isolated
gonadotropin deficiency the height is normal, but the
pubertal growth spurt is absent. The height of those
with primary gonadal failure is usually normal unless
associated with syndromes.
• Body proportions: Eunuchoid proportions are a feature
of the prepubertal child with Klinefelter syndrome
and of hypogonadotropic hypogonadism due to the
absence of the pubertal spurt. Weight related to height
is decreased in malnutrition and chronic disease and
increased in most hormonal disorders, e.g.
hypothyroidism, GHD and cortisol excess. Obesity
is also a feature of many syndromes associated with
hypogonadism.
Investigations
Hormonal Evaluation
• Serum gonadotropin levels, FSH and LH, distinguish
between hypogonadotropic and hypergonadotropic
hypogonadism.
• Serum gonadotropin response to GnRH stimulation may
show a pubertal response in CDGP but is not usually
helpful in distinguishing it from isolated gonado-
tropin deficiency.
• Serum testosterone/estradiol.
• Serum DHEAS levels are usually normal for
chronologic age in hypogonadotropic hypogonadism
but are low for age and corresponds with the bone
age in CDGP, where the tempo of maturation is
delayed.
• Serum thyroxine (T4), prolactin, IGF-1 and GH
stimulation tests if indicated.
Radiographic Investigations
• Bone age: In CDGP, the bone age is delayed and
corresponds with the height age and stage of puberty.
Bone age is usually slightly delayed in isolated
gonadotropin deficiency. It helps distinguish the two,
as in CDGP evidence of sexual maturation should be
evident by a bone age of 13 years whereas this may
not be so in isolated gonadotropin deficiency. In
patients with multiple pituitary hormone deficiency
the bone age is markedly delayed.
• Pelvic ultrasonography provides information about the
development of the uterus and ovaries.
• CT/MRI if indicated.
Treatment
Treatment of the cause whenever possible will result in
subsequent pubertal development. Patients with
constitutional delay require reassurance that there is
nothing wrong and that puberty though delayed, will
progress normally. Short-term low-dose hormonal
treatment with testosterone or estrogens for 3 to 6 months
may occasionally be required if the patient is
psychologically stressed. Permanent hypogonadism

requires long-term replacement therapy with monthly
testosterone injections in boys and cyclic estrogen-
progesterone treatment in girls.
BIBLIOGRAPHY
1. Bajpai A, Sharma J, Kabra M, Gupta A, Menon PSN. Long
acting GnRH analogue triptorelin therapy in central
isosexual precocious puberty. Indian Pediatr 2002;39:633-
39.
2. Bourguignon JP, Bertrand J, Rappaport R et al. Delayed
puberty and hypogonadism. In: Pediatric Endocrinology
- Physiology, Pathophysiology and Clinical Aspects,
Second edition. Maryland, 1993;404-19.
3. De Luca F, Argente J, Cavallo L, Crowne E, Delemarre-
Van de Waal HA, De Sanctis C, et al. Management of
puberty in constitutional delay of growth and puberty.
J Pediatr Endocrinol Metab 2001;14 Suppl 2:953-57.
17.7 Disorders of Sexual Differentiation
Normal Sexual Differentiation
All mammalian embryos are traditionally believed to
have an inherent tendency to develop as female. The SRY
gene on the Y chromosome actively induces the
formation of the testis and the male phenotype. The
gonads, internal genitalia (genital ducts) and the external
genitalia, which are bipotential are all influenced by
several genes and other factors necessary for male sexual
differentiation. In the absence of such influences, female
phenotype results. In recent years, many genes
contributing to the process of sex determination and
normal sexual differentiation during fetal life have been
discovered. There are also several claims made that
female sexual differentiation may no longer be
considered as a passive process or as occurring by
“default”.
The Gonads
The gonads in the embryo remain undifferentiated until
the sixth week of gestation. Subsequent evolution into
either a testis or ovary is directed by the genetic sex (XX
or XY) depending on whether the sperm fertilizing the
ovum carries a Y or X. The testis develops more rapidly
Endocrinology 947
4. Grumbach MM, Styne DM. Puberty: Ontogeny,
Neuroendocrinology, Physiology, and Disorders. In:
Wilson JD, Foster DW, Kronenberg HM, Larsen PR,
(Eds). Williams Textbook of Endocrinology, 9th edition.
WB Saunders Company; Philadelphia 1998;1509-625.
5. Rosenfield RL. Puberty in the female and its disorders.
In: Sperling MA (Ed). Pediatric Endocrinology, Second
edition. Saunders; Philadelphia, 2002;455-518.
6. Sizonenko PC, Bertrand J, Rappaport R, et al. Precocious
Puberty. In Pediatric Endocrinology —Physiology,
Pathophysiology and Clinical Aspects, 2nd edition.
Maryland, 1993;387-403.
7. Styne DM. The testes. In: Sperling MA (Ed) Pediatric
Endocrinology, Second edition. WB Saunders,
Philadelphia, 2002;565-628.
8. Tatò L, Savage MO, Antoniazzi F, Buzi F, Di Maio S,
Oostdijk W, et al. Optimal therapy of pubertal disorders
in precocious/early puberty. J Pediatr Endocrinol Metab
2001;14 Suppl 2:985-95.
P Raghupathy
than the ovary. Fetal testicular differentiation begins in
the seventh week of gestation, whereas ovarian develop-
ment begins not earlier than 17 weeks of gesta-
tion.
Testicular Differentiation
The SRY (sex-determining region on the Y-chromosome)
gene (with 204 amino acids) located on the short arm of
the Y chromosome (Yp 11.3) is the trigger for testicular
differentiation, by inducing development of Sertoli cells
and subsequently, seminiferous tubules and Leydig cell
formation in that order. SRY activates SOX9 (SRY-
hemeobOX-like gene), an autosomal gene (chromosome
17q24) and SF1 (steroidogenic factor 1) to induce
differentiation of the bipotential gonad into a testis. SRY
suppresses DAX1 which normally inhibits SOX9.
Ovarian Differentiation
DAX1, SOX3 and Wnt4 are the three candidate genes
currently known to suppress testicular differentiation.
DAX1 and SOX3 inhibit SF1 and SOX9, preventing Sertoli
cell differentiation, favoring granulosa cell development.
Wnt4 arrests the Leydig cell precursors and induces
948 IAP Textbook of Pediatrics
development of Mullerian ducts into fallopian tubes,
uterus, cervix and upper third of vagina. FOXL2 helps
in follicular development in the ovary and in suppression
of somatic testis formation in genetic females. Though
the effects of these genes have been argued to result in
ovarian differentiation, it should be remembered that
active testicular differentiation occurs much earlier when
compared to the ovarian.
Internal Genitalia
Testosterone initially under the control of human
chorionic gonadotropin is produced locally (paracrine)
by Leydig cells of the fetal testis on either side. It helps
in ipsilateral differentiation of the Wolffian ducts into
epididymis, vas deferens, seminal vesicles and
ejaculatory ducts. Anti-Mullerian hormone (AMH)
secreted by the Sertoli cells causes ipsilateral involution
of the Mullerian structures.
In female fetuses, Wolffian structures regress in the
absence of testosterone and Mullerian ducts persist in
the absence of AMH. However, Wnt4 gene appears to
play an important role in Mullerian duct differentiation
and fetal ovarian function.
External Genitalia
From the initial undifferentiated stage of the external
genitalia, masculinizing features develop under the
influence of dihydrotestosterone (DHT) formed
peripherally from testosterone by the action of
5α-reductase. This process is dependent on an adequate
number of functioning androgen receptors in the pubic
skin. Formation of female external genitalia does not
require any active process and will persist with normal
ovaries, in androgen insensitivity or even in the absence
of gonads, sex chromosome abnormalities, streak gonads
or non-functioning testes.
Abnormalities of Sexual Differentiation
When SRY protein undergoes mutation in its HMG box
(high mobility group) protein, testicular failure or genital
ambiguity will result. SOX9 mutation in 46,XY males
leads to a female phenotype and streak ovarian-like
gonads. Chromosomal abnormalities may lead to
disorders of male gonadal differentiation or give rise to
true hermaphroditism.
Wolffian development and Mullerian regression on
each side are dependent on the ipsilateral production or
testosterone and AMH respectively. Hence, abnor-
malities of the internal genitalia will be encountered,
based on the presence of gonadal elements on that side.
A streak gonad which produces neither testosterone nor
AMH, will give rise to poorly formed Mullerian
structures such as a hypoplastic or hemiuterus on the
side of the defective gonad.
Variable degrees of virilization of the female external
genitalia leading to sexual ambiguity will result when
exposed to androgens, either from the mother (intake or
excessive production of androgens in her body), or from
the fetus (congenital adrenal hyperplasia, aromatase
deficiency, true hermaphroditism or mixed gonadal
dysgenesis). Partial virilization producing ambiguity of
the external genitalia or complete virilization with a
normal-looking male external genitalia (penis and a fully
formed by empty scrotum) may occur in a genetic female
with congenital adrenal hyperplasia (CAH) due to 21-
hydroxylase deficiency. A normal-looking female
external genitalia (with testes in the labioscrotal folds)
may be a case of androgen insensitivity syndrome. A
genetic male may have undervirilization and present
with underdeveloped and ambiguous genitalia as in 17
α-hydroxylase deficiency or 3 β-hydroxysteroid dehydro-
genase deficiency. The appearance of the external
genitalia does not always give any diagnostic clinical
clues, for example, an infant with true hermaphroditism
and a virilized female with genital ambiguity may look
similar.
Ambiguous Genitalia (hermaphroditism)
Ambiguous genitalia may be defined as a developmental
discrepancy between the external genitalia and the
gonads. The genital abnormalities which need to be
investigated are listed in Table 17.7.1. In the past, these
disorders were usually classified into female pseudo-
hermaphroditism (FPH), male pseudohermaphroditism
(MPH) or true hermaphroditism (TH). The new
terminology recommended for disorders of sex
development (DSD) are mentioned in Table 17.7.2. The
new classification of DSD is presented in Table 17.7.3.
46,XX DSD
In this condition, the genotype is XX and the gonads (not
palpable) are ovaries, but the external genitalia are
virilized partially or fully. This results from exposure of
female fetus to androgens during the period of sexual
differentiation in early gestation.
 Endocrinology 949

TABLE 17.7.1. Genital abnormalities which TABLE 17.7.3: Suggested classification of DSD
need to be investigated
1. 46,XX DSD
Ambiguous genitalia A. Disorders of gonadal (ovarian) development
Severe hypospadias i. Ovotesticular DSD
± Undescended testes ii. Testicular DSD (e.g., SRY +, dup SOX9)
Micropenis iii. Gonadal dysgenesis
Bifid scrotum B. Androgen excess
Male with nonpalpable testes i. Fetal (e.g., 21-hydroxylase deficiency, 11-hydroxylase
Female with bilateral inguinal hernias deficiency)
Isolated clitoromegaly ii. Fetoplacental (aromatase deficiency, P450
Isolated labial fusion oxidoreductase)
Genital anomalies in syndromes iii. Maternal (luteoma, exogenous etc.)
C. Other
TABLE 17.7.2: New terminology recommended for DSD (e.g., cloacal extrophy, vaginal atresia, other syndromes)
2. 46,XY DSD
Old nomenclature Proposed terminology
A. Disorders of gonadal (testicular) development
Intersex DSD i. Complete gonadal dysgenesis (Swyer syndrome)
Male pseudohermaphrodite 46,XY DSD ii. Partial gonadal dysgenesis
Undervirilisation of an XY male iii. Gonadal regression
Undermasculinisation of an XY male iv. Ovotesticular DSD
B. Disorders in androgen synthesis or action
Female pseudohermaphrodite 46,XX DSD
i. Androgen biosynthesis defect (e.g., 17β-hydroxysteroid
Overvirilisation of an XX female
dehydrogenase deficiency, 5α-reductase deficiency,
Masculinisation of an XX female
StAR mutations
True hermaphrodite Ovotesticular DSD ii. Defect in androgen action (e.g., complete or partial
XX male or XX sex reversal 46,XX testicular DSD androgen insensitivity)
XY sex reversal 46,XY complete gonadal 3. Sex chromosome DSD
dysgenesis A. 45,X (Turner syndrome and variants)
B. 47,XXY (Klinefelter syndrome and variants)
C. 45,X/46,XY mixed gonadal dysgenesis
D. 46,XX/46,XY (chimeric)
46,XY DSD
In these cases, the genotype is XY, gonads (palpable) are
testes but the external genitalia are incompletely virilized, 2. 46,XY DSD—a genetic male with undervirilization
ambiguous or completely female. due to indequate production of androgens.
3. Sex chromosome DSD – (i) an infant with both
Sex Chromosome DSD ovarian and testicular tissues, (ii) Mixed gonadal
dysgenesis—an infant with 45, X/46, XY karyotype,
With the karyotype of 46,XX/46,XY (chimeric), both or
ovarian and testicular tissues are present either in the
4. The genital deformity may be a developmental error
same gonad (ovotestis) or opposite gonads (one gonad
as in severe hypospadiasis, persistent Mullerian duct
may be palpable or both gonads not palpable). The
syndrome, etc.
clinical features may resemble either 46,XX or 46,XY DSD.
Maternal history of drug intake during pregnancy
Majority of these cases have 46,XX karyotype.
and details of mother’s medical condition need to be
obtained. History of familial genital ambiguity and
CLINICAL APPROACH TO THE DIAGNOSIS OF
consanguinity is often helpful. CAH has an autosomal
INFANTS WITH AMBIGUOUS GENITALIA
recessive inheritance. History of multiple fetal wastages
Examination of the external genitalia is often unhelpful. and early neonatal deaths due to severe salt-losing variety
In the case of ambiguity, the possibilities will be: is common in CAH. If physical examination reveals the
1. 46,XX DSD—a genetic female with evidence of virili- presence of a gonad, it is most often a testis and the infant
zation following exposure to fetal (very common) or is a male. If there is no external gonad palpable, the
maternal androgens. genetic sex cannot be identified without the help of a
950 IAP Textbook of Pediatrics
karyotype. The phallus is measured for its length and
width of erectile tissue and examined for chordee.
Presence of separate openings of vagina and urethra
should be looked for as also pigmentation and rugosity
of labioscrotal folds.
It is often the responsibility of the pediatric
endocrinologist or primary care physician to inform the
parents of an infant born with uncertain sex and to
discuss with them openly about the nature of the defect
observed, details of all the investigations that will be
needed to establish the diagnosis, the sex of rearing best
suited for the infant, the available modalities and plan
of treatment, as well as to allay the anxiety and guilt of
the parents and other family members in repeated
sessions. To deal with this condition optimally, a full team
is ideal, viz. pediatric endocrinologist, family
pediatrician, pediatric surgeon or urologist, radiologist,
ultrasonologist, biochemist, cytogeneticist, pediatric
psychologist and most importantly, the child’s parents.
It is always important to collect together all possible
evidence for arriving at a diagnosis and then have
discussions with the parents. Although urgency is still
necessary, most parents will be willing to wait for a few
days longer and prefer to have all the diagnostic results
before making their decision about their child’s future.
Until the decision is made, it is better to refer to the infant
as ‘baby’ and not as ‘he’ or ‘she’.
Investigations
1. Serum sodium, potassium
2. Serum 17-hydroxyprogesterone (17OHP)
3. Serum DHEAS
4. Plasma renin activity
5. Serum 11-deoxycortisol
6. Ultrasound pelvis for the presence of uterus, gonads
7. Ultrasound abdomen for renal malformations
8. Retrograde genitogram
9. Karyotype.
Management
The commonest cause of ambiguous genitalia is 21-
hydroxylase deficiency in genetic females. Nearly 75
percent present with salt loss typically during the second
week of life. Hyperpigmentation of the skin, especially
the nipples, umbilicus and external genitalia should alert
one to the diagnosis even before salt losing manifes-
tations appear. This clinical sign is particularly useful in
males with CAH as they do not present with any
abnormality of the external genitalia but have a high risk
of shock due to salt loss. In the presence of a previous
family history, biochemical investigations may be
performed earlier to hasten the diagnosis. Virilized
females with CAH having uterus and ovaries are
assigned the female sex. Clitoral reduction and
genitoplasty are usually undertaken around 1 year of age
and care is taken to preserve the glans and the
neurovascular bundle. Recommendations for assignment
of sex in an individual with fully virilized male external
genitalia and presence of female internal sex structures
are still controversial. Reconstructive surgery for
hypospadias is needed in those with 5α reductase
deficiency at the time of puberty. Assignment of a female
sex to an individual with microphallus and fused
scrotum is being reconsidered and not always accepted
today by many in the medical profession. Testosterone
therapy is recommended for microphallus and fused
scrotum. In summary, there are no easy answers always
for the assignment of sex in disorders of sexual differen-
tiation.
BIBLIOGRAPHY
1. Federmann DD. Three facets of Sexual differentiation.
New Eng J Med 2004;350:323-4.
2. Grumbach MM, Hughes IA, Conte FA. Disorders of sex
differentiation. In: Larsen PR, Kronenberg HM, Melmed
S, Polonsky KS (Eds). Williams Textbook of Endo-
crinology, Saunders: Philadelphia 2003;10:842-1002.
3. Hughes IA. Disorders of sexual differentiation. Hormone
Research 2007;67(Suppl 1):91-95.
4. Lee PA, Houk CP, Ahmed SF, Hughes IA. Consensus
statement on management of intersex disorders.
Pediatrics 2006;118:488-500.
5. MacGillivray MH, Mazur T. Management of infant born
with Ambiguous Genitalia. In: MacGillivray MH,
Radovick S (Eds). Pediatric Endocrinology. Humana
Press, Totowa 2003;429-49.
6. MacLaughin DT, Donahoe PK. Sex determination and
differentiation. New Eng J Med 2004;350:367-78.
7. Quigley CA. Genetic basis of sex determination and sex
differentiation. DeGroot LJ, Jamesson JL, (Eds). Endocri-
nology, 4th edn. WB Saunders: Philadephia 2001;
1926-46.

17.8 Disorders of Adrenocortical Biosynthesis
The adrenal cortex produces several steroid hormones
such as cortisol, aldosterone and androgens. The ability
to convert cholesterol into steroidal hormones (steroid
biosynthesis) is present only in the adrenal cortex, gonads
of both sexes and the placenta. An enzymatic defect of
steroidogenesis may not affect the adrenal cortex and
gonads equally. Hence, disorders of sexual differentiation
may result from the biosynthetic pathway defects in the
adrenal cortex or the gonads or both.
Steroidogenesis
The adrenal cortex functions as two separate units
because of the enzymatic differences between the zona
glomerulosa and the inner two zones—zona fasciculata
and zona reticularis. The zona glomerulosa lacks
17 α-hydoxylase activity and therefore, cannot synthesize
17 α-hydroxypregnenolone and 17 α-hydroxyproge-
sterone (17-OHP), the precursors of cortisol and
androgens. The synthesis of aldosterone by this zone is
totally regulated by the renin-angiotensin system and by
potassium.
The two inner zones produce cortisol, androgens and
small quantities of estrogens. These two zones are
directly controlled by adrenocorticotropic hormone
(ACTH). They lack 18-dehydrogenase and so cannot
synthesize aldosterone.
The various enzymes involved in the biosynthetic
pathway of cortisol are given in Figure 17.8.1.
Corticotropin-releasing factor (CRF) produced by the
hypothalamus regulates ACTH. ACTH in turn induces
synthesis and secretion of steroids within minutes. The
conversion of cholesterol to pregnenolone is the major
site of ACTH action on the adrenal cortex and is the rate-
limiting step.
CONGENITAL ADRENAL HYPERPLASIA
In congenital adrenal hyperplasia (CAH), cortisol
synthesis from cholesterol is affected due to deficiency
of one of the several enzymes in the adrenal cortex (Fig.
17.8.1). ACTH elevation is secondary to plasma cortisol
deficiency via the negative feedback mechanism.
Overproduction of the hormonal precursors proximal to
Endocrinology 951
P Raghupathy
the block and deficiency of the hormones distal to the
blocked enzymatic step are responsible for the clinical
features encountered. Each of the five enzymatic defects
is inherited by an autosomal recessive mode and
produces a characteristic clinical and biochemical picture.
The genes and enzymes involved in adrenal steroido-
genesis are listed in the Table 17.8.1.
21-Hydroxylase Deficiency (21-OHD)
This is the most common enzyme deficiency seen in
nearly 90 percent of individuals with CAH. The exact
incidence of 21-OHD in India is unknown. In the West,
the incidence is reported to be 1 in 5,000 to 1 in 15,000.
17-OHP accumulates in the serum because it is not
converted to 11-deoxycortisol in the absence of 21-
hydroxylase. Similarly, progesterone accumulates
following lack of conversion to 11-deoxycorticosterone
(Fig. 17.8.1). The ultimate effect is cortisol deficiency and
ACTH elevation giving rise to adrenocortical
hyperplasia. As the formation of mineralocorticoids and
glucocorticoids from cholesterol is blocked, the
conversion of cholesterol flows largely into the androgen
pathway. The clinical varieties of this deficiency are:
a. Salt-wasting type in nearly 75 percent of 21-OHD. This
is the classic disorder presenting usually between 1
week and 1 month of age occurring with cortisol
deficiency along with salt wasting and hypovolemia
arising from aldosterone deficiency and the
natriuretic effect of accumulated precursors like
17-OHP. The effects of this enzyme deficiency begin
in the intrauterine period. Hence the accumulation
of excessive adrenal androgens causes virilization of
the external genitalia of a female infant seen at birth,
in both the salt-wasting and simple virilizing types.
b. Simple virilizing type without salt loss. Non-salt losers
with virilization account for about 25 percent of cases.
The absence of salt loss can be explained by a partial
defect in 21-OHD. Virilization is seen at birth in girls.
c. Non-classic (late onset) type. The presentation may also
be varied, such as adrenarche, early growth spurt, or
accelerated skeletal maturation. The manifestations
can also occur for the first time during adulthood as
hirsutism in women or reduced fertility in both sexes.
952 IAP Textbook of Pediatrics

Figure 17.8.1: Scheme of adrenal steroidogenesis. Chemical names of enzymes are shown next to the arrows, enclosed numbers
indicate traditional names of the enzymes: 1. 20, 22-desmolase, 2. 3β-hydroxysteroid dehydrogenase / isomerase, 3. 17α-
hydroxylase, 4. 17, 20-lyase, 5. 21-hydroxylase, 6. 11β-hydroxylase, 7. 18-hydroxylase, 8. 18-oxidase, 9. 17β-hydroxysteroid
dehydrogenase, 10. aromatase.
StAR = steroidogenic acute regulatory protein; DOC = 11-deoxycorticosterone

There is no hypertension. Use of appropriate sized
cuffs for measurement of blood pressure is essential. If
siblings are affected, they tend to have the same clinical
type.
Salt Loss
Salt loss may present as hypovolemic shock, especially
as unexplained dehydration and may also occur beyond
neonatal period in cases of infection induced stress
situations.
Virilization
The diagnosis of 21-OHD is easily identified in girls
because of genital ambiguity. In boys, however, the
condition can go unnoticed until toddler years, when
increased height velocity, increase in the size of the
external genitalia, early appearance of pubic hair and
other signs of male secondary sexual characteristics are
observed. Hyperpigmentation involving external
genitalia, nipples and umbilicus with a ‘tanned
appearance’ of skin may be a very important clue for
early diagnosis.
The degree of genital ambiguity does not correlate
with the form of 21-OHD. Virilization in the female may
present as mild clitoral hypertrophy, varying degrees of
ambiguity or complete masculinization with normal
looking male genitalia but with an empty scrotum. Thus,
absence of testes would be helpful in diagnosis.
Apart from the external virilizing and biochemical
features, there are no abnormalities in genetic sex,

TABLE 17.8.1. Genes and enzymes involved in adrenal steroidogenesis
Gene Chromosomal Enzyme
location
CYP11A1 15q23-q24 P450scc (CYP11A1)
HSD3B2 1p13.1 3bHSD (3bHSDII)
CYP17 10q24.3 P450c17 (CYP17)
CYP21A2 6p21.3 P450c21 (CYP21A2)
CYP11B1 8q21–22 P450c11 (CYP11B1)
CYP11B2 8q21–22 P450c18 (CYP11B2)
gonadal differentiation, or development of the internal
genitalia. The female infant will have normal ovaries,
fallopian tubes, uterus and proximal vagina. Postnatally
in untreated cases there will be continued virilization
effects with clitoromegaly or penile enlargement,
accelerated growth, advanced skeletal maturation far in
excess of the height age and premature appearance of
secondary sexual characteristics.
Laboratory Features
Hyponatremia, hyperkalemia, increased urinary sodium
losses due to renal salt wasting, high plasma renin
activity (PRA), accompanied by low serum and urinary
aldosterone levels, acidosis and uremia are the
biochemical features in salt-wasting type. Hypoglycemia
may also be present. Elevated serum 17-OHP, markedly
lowered serum cortisol, elevated levels of serum DHEAS,
and testosterone are diagnostic. On short synacthen
(ACTH) stimulation test, serum 17-OHP and DHEAS rise
more than 2–3 folds but there is no significant elevation
of serum cortisol. Urinary estimation of steroid
metabolites is not preferred nowadays. The difficulty
experienced in the 24-hour urine collection from an infant
with ambiguous genitalia is considerable. The results are
quite often difficult to interpret.
Nonclassic 21-OHD may be totally asymptomatic and
presents only with biochemical abnormalities as in the
classic cases and may be picked up only during family
studies. Non-classic cases may have only milder elevation
of 17-OHP, especially when performed in the afternoon
Endocrinology 953
Enzymatic activity Cellular location
Cholesterol desmolase Mitochondrion
(side chain cleavage)
3b-hydroxysteroid dehydrogenase Endoplasmic
reticulum
17a-hydroxylase/17,20 lyase Endoplasmic
reticulum
21-hydroxylase Endoplasmic
reticulum
11b-hydroxylase Mitochondrion
Aldosterone synthase Mitochondrion
(corticosterone 18-methylcorti-
coster one oxidase/ lyase)
or late forenoon. Hence it is preferable to get the
hormonal profile always in the mornings.
Treatment
The essential principles of treatment are to replace the
deficient hormones and to suppress the overproduction
of precursor hormones. Hydrocortisone is required in a
dose of 10 to 20 mg/m2/day in two or three divided
doses. Salt wasters require, in addition, 9 α-fluorohydro-
cortisone 0.1 to 0.3 mg (100–300 μg) per day. Sodium
chloride supplementation up to 1-3 g daily may be
needed in the infants and young child. The hormonal
profile reverts to the normal range with appropriate
treatment, which is monitored 3 to 6 monthly by
estimating 17-OHP and PRA values and appropriate
dosage adjustment is effected. The daily dose of
hydrocortisone may be doubled during acute stress
periods like infection.
In the newborn period at presentation, a large dose
of hydrocortisone and fluorohydrocortisone may be
required. Dosages are modified by monitoring serum
sodium and potassium daily and frequent serum 17-OHP
and PRA. Dose of hydrocortisone is gradually reduced
and changed over to 5 mg twice a day orally. In older
children, when higher dosage is given, a larger dose is
given at night, e.g. if the child needs 12.5 mg of
hydrocortisone per day, 5 mg is given in the morning
and 7.5 mg in the evening. This is done with a view to
suppress ACTH pulses during the night.
954 IAP Textbook of Pediatrics
Appropriate Sex Assignment
Assigning the appropriate sex is of paramount
importance. The affected female with CAH has the
potential for a normal fertile female role. Surgical
correction of the genital abnormality is carried out in girls
around 1 year of age by doing reduction clitoroplasty.
Definitive vaginoplasty will also be required.
It is very important that the parents understand the
nature of the disease, chronicity of the treatment required
lifelong, the complication arising from poor compliance,
and how steroids play an essential role in stress situations
which can be life-threatening if in appropriately
managed. Early epiphyseal fusion in both sexes will
eventually cause short stature, if treatment is irregular
and incomplete with the disease being poorly controlled.
The parents are given adequate health education
regarding this condition. They are advised that daily dose
of hydrocortisone must be doubled or tripled for a few
days during stress situations.
Prenatal Treatment
In families with an affected infant, prenatal treatment is
useful in subsequent pregnancies. The aim of prenatal
treatment is to prevent external genital deformity in the
female fetus due to virilization. As soon as pregnancy is
confirmed, the mother is commenced on oral
dexamethasone 20 μg/kg/day in 3 divided doses, even
prior to the fetal diagnosis being established. Karyotype
and DNA analysis are obtained by chorionic villus
sampling around 9-11 gestational weeks. If the fetus is a
male or an unaffected female, treatment is stopped.
Treatment is continued in the case of an affected female
infant. When conclusive evidence is obtained that the
fetus is affected, the parents may also be given the choice
of termination of pregnancy, irrespective of the sex of
the fetus.
Neonatal Screening
Screening of all newborns with filter paper 17-OHP is
carried out in many developed nations. It is not yet
determined whether this is mandatory.
α-HYDROXYLASE DEFICIENCY
11α
In this disorder which accounts for nearly 5 percent of
cases of CAH, cortisol and corticosterone are deficient
with overproduction of 11-deoxycortisol and 11-deoxy-
corticosterone. The precursor hormones are shunted into
the androgen pathway causing prenatal and postnatal
virilization. The accumulation of deoxycorticosterone
results in sodium and water retention, increased plasma
volume and hence causes hypertension. Serum level of
11-deoxycortisol elevation is diagnostic, PRA is
suppressed, serum aldosterone is lowered and
hypokalemia may be present. Glucocorticoid therapy is
effective in reversing all the abnormalities and inducing
remission.
17-HYDROXYLASE/ 17,20 LYASE DEFICIENCY
This is a rare disorder occurring with cortisol deficiency,
ACTH excess, overproduction of DOC causing
hypertension and hypokalemia. Affected males are
incompletely virilized (male pseudohermaphroditism)
owing to diminished androgen production and may be
phenotypically female or ambiguous. In addition, ACTH
excess driven by cortisol deficiency causes
mineralocorticoid excess and hypertension. PRA and
aldosterone are low. Glucocorticoid therapy suppresses
overproduction of the hormones.
β-HYDROXYSTEROID/ 4,5 ISOMERASE
3β
DEFICIENCY
Classic and nonclassic forms are seen in this disorder.
Salt wasting, deficiency of cortisol and aldosterone are
the usual manifestations of this condition. In the
nonclassic form, there is no aldosterone deficiency. Males
with this condition may show undervirilization with
ambiguity of external genitalia owing to under-
production of testosterone in utero. Pseudovaginal
hypospadias may be present in the males due to absence
of potent androgens. But the excessive collection of the
weak androgen, DHEAS, may cause clitoral enlargement
in the female. Most of them have aldosterone deficiency
with elevation of PRA. Hyperpigmentation is seen and
serum ACTH level is high. Treatment is with
glucocorticoids.
LIPOID ADRENAL HYPERPLASIA
In this rare StAR protein deficiency disorder, there is a
global deficiency of all adrenal hormones; gluco-
corticoids, mineralocorticoids and sex hormones, which
affects adrenal cortex and gonads. Gonadal steroids are
also absent. Clinical presentation is very early in life with
salt wasting crisis. Females have no abnormality of

internal or external genitalia. Males are phenotypically
female but may have inguinal gonads. Sex hormone
replacement will be necessary in those with under-
virilization or in those with delayed puberty with the
objective of achieving normal pubertal development,
normal sexual function, and fertility.
Conclusion
Knowledge regarding CAH is widening constantly. The
chromosomal locations and nature of the genes encoding
the various enzymes needed for adrenocortical
biosynthesis, the cellular locations, functions and
abnormalities of these enzymes, the pathophysiology of
adrenocortical disorders, the clinical features and
laboratory parameters have been documented further.
Prenatal diagnosis and treatment as well as newborn
17.9 Disorders of Adrenal Glands
The adrenal cortex comprises of three distinct anatomical
areas—outer zona glomerulosa (responsible for
mineralocorticoid production), middle zona fasciculata
(responsible for glucocorticoid production) and inner
zona reticularis (responsible for androgen production).
The adrenocortical hormones are crucial for maintenance
of fluid and electrolyte balance (mineralocorticoids),
intermediary metabolism (glucocorticoids) and sexual
development (androgens).
Steroidogenesis involves conversion of cholesterol to
steroid hormones in a process mediated by a group of
P450 enzymes. The disorders resulting from various
enzyme deficiency states are discussed in Chapter 17.8.
The hypothalamic–pituitary–adrenal (HPA) axis is
responsible for the maintenance of normal cortisol levels.
This involves close interaction of three hormones—
corticotropin secreting hormone (CRH) produced by the
hypothalamus, ACTH produced by the anterior pituitary
and cortisol secreted by the adrenals. Aldosterone and
androgen secretions are independent of the HPA axis.
This explains the lack of salt wasting crisis in children
with hypothalamic–pituitary disorders.
ADRENAL INSUFFICIENCY
Adrenal insufficiency is relatively rare in children. Signs
and symptoms are often nonspecific—as a result the
diagnosis may not be suspected early. If unrecognized,
Endocrinology 955
screening are practised widely. However, we are yet to
find an ideal way of keeping the disease under good
control in an effort to mimic normal physiology.
BIBLIOGRAPHY
1. Grumbach MM, Hughes IA, Conte FA. Disorders of sex
differentiation. In: Larsen PR, Kronenberg HM, Melmed
S, Polonsky KS (Eds). Williams Textbook of Endocrino-
logy, 10th edn. Saunders, Philadelphia 2003:;913-33.
2. Hughes IA. Congenital adrenal hyperplasia: a lifelong
disorder. Hormone Research 2007;68(suppl 5):84-89.
3. New MI, Ghizzoni L. Congenital Adrenal Hyperplasia.
In: Lifshitz F (Ed). Pediatric Endocrinology. 4th ed.
Marcel Dekker, New York 2003;175-92.
4. Wajnrah MP, New MI. Defects of Adrenal Steroidogenesis.
In: DeGroot LJ, Jamesson JL, (Eds). Endocrinology, 4th
ed. WB Saunders, Philadelphia 2001;1721-39.
5. White PC, Speiser PW. Congenital adrenal hyperplasia due to
21-hydroxylase deficiency. Endocrine Reviews 2000;21:245-91.
PSN Menon
adrenal insufficiency may present with life–threatening
cardiovascular collapse.
Classification
Adrenal insufficiency can be classified as primary or
secondary; congenital or acquired. In primary adrenal
insufficiency (commonly referred to as Addison disease)
production of glucocorticoid (cortisol) and, frequently,
mineralocorticoid hormones by adrenal cortex is
decreased. In secondary adrenocortical insufficiency,
there is lack of CRH secretion from the hypothalamus
and/or ACTH secretion from the pituitary resulting in
hypofunction of the adrenal cortex. In secondary adrenal
insufficiency, mineralocorticoid function is preserved.
Etiology
The common causes of adrenal cortical insufficiency are
given in Table 17.9.1. Primary adrenal deficiency is
relatively uncommon. Adrenal infiltration by tuber-
culosis is uncommon in children compared to adults. In
a large pediatrics series, CAH accounted for over 70% of
cases of primary; the most common was CAH due to
21–hydroxylase deficiency. Compared to primary,
secondary form is much more common. The most
common cause of acute adrenal insufficiency in the West
is withdrawal or omission of glucocorticoids in patients
being treated with long term pharmacologic doses.
956 IAP Textbook of Pediatrics

TABLE 17.9.1: Etiology of adrenal insufficiency Clinical Features

A. Primary Clinical features depend on the severity and the etiology

Congenital of the disease. Children with acute adrenal insufficiency
1. Congenital adrenal hyperplasia (CAH)— generally present with acute dehydration, hypotension,
• 21–hydroxylase deficiency (CYP21) hypoglycemia, or altered mental status. Acute adrenal
• 3β–hydroxysteroid dehydrogenase deficiency insufficiency may be triggered by infection or trauma,
(HSD3B2)
• 11β–hydroxylase deficiency (CYP11B2)
but may also occur without an obvious concomitant
• Cholesterol desmolase deficiency (CYP11A) illness or stress. Hypoglycemia is most common in young
• Lipoid hyperplasia (STAR) children.
2. Congenital adrenal hypoplasia (SF1, DAX1) Patients with chronic adrenal insufficiency usually
3. Triple A or Allgrove syndrome (AAAS) complain of fatigue, muscle weakness, nausea, vomiting,
4. ACTH resistance (MC2R, MRAP)
appetite loss, weight loss and recurrent abdominal pain.
5. Glucocorticoid resistance (GCCR)
6. Metabolic diseases—Adrenoleukodystrophy (ABCD1), Blood pressure is often low. Often hyperpigmentation is
Zellweger syndrome (PEX), Smith–Lemli–Opitz seen over genitalia, axillae, nipple, joints, umbilicus,
syndrome(DCHR7), Wolman disease (LIPA) palmar creases, buccal mucosa, recent scars and other
7. Mitochondrial diseases — Kearne–Sayre syndrome exposed parts of skin due to elevation of pro–
Acquired
opiomelanocortin and melanocyte–stimulating hormone.
1. Autoimmune adrenalitis—
• Isolated
Salt craving is common in chronic primary adrenal
• Polyglandular syndromes—Types I (AIRE) and II insufficiency. Hyperpigmentation and salt craving are
2. Hemorrhage and infarction—Trauma, Waterhouse– not observed in patients with secondary adrenal
Friderichsen syndrome insufficiency.
3. Drugs—Aminoglutethimide, mitotane, ketoconazole, Unless there is a history of recent pharmacologic
metyrapone
glucocorticoid therapy, secondary adrenal insufficiency
4. Infections—
• Viral: HIV, cytomegalovirus is usually associated with signs of other pituitary
• Fungal: Coccidiomycosis, histoplasmosis hormone deficiencies such as growth failure, delayed
• Mycobacterial: Tuberculosis puberty, secondary hypothyroidism, and/or diabetes
• Parasitic: Amebic insipidus (polyuria and polydipsia).
5. Infiltration—Hemochromatosis, histiocytosis, neoplasm
B. Secondary
Congenital Adrenal Hypoplasia
Hypothalamus
1. Congenital—Septo–optic dysplasia (HESX1), CRH Two forms of this condition are known. In the autosomal
deficiency recessive form the adrenal glands are extremely small.
2. Acquired—
a. Steroid withdrawal after prolonged administration
The second, cytomegalic type is inherited as an X–linked
b. Inflammatory disorders recessive disorder and is caused by mutations of the
c. Trauma DAX1 gene. It usually manifests in the neonatal period
d. Radiation therapy with severe salt wasting, but the onset may be delayed
e. Surgery for several years. It may also be associated with
f. Tumors
hypogonadotropic hypogonadism, Duchenne muscular
g. Infiltrative disease: Sarcoidosis, histiocytosis X
Pituitary dystrophy and cerebral malformations.
1. Congenital —
a. Aplasia/hypoplasia Diagnosis
b. Multiple anterior pituitary hormone deficiencies Hyponatremia and hyperkalemia are common in
(PROP1) primary adrenal insufficiency due to poor aldosterone
c. Isolated ACTH deficiency
2. Acquired —
secretion. Hypoglycemia is common in both primary and
a. Steroid withdrawal after prolonged administration secondary adrenal insufficiency. It is advised to collect a
b. Trauma venous sample at the time of hypoglycemia in all
c. Tumors: Craniopharyngioma neonates for glucose, cortisol, GH, and insulin levels.
d. Radiation therapy Primary adrenal insufficiency is confirmed by
e. Lymphocytic hypophysitis
documentation of an elevated plasma ACTH level (>100

pg/mL) and a low serum cortisol level (generally < 10
μg/dL). If doubtful, ACTH–stimulation test (250 μg or
15 μg/kg for infants < 2 years, IV) is performed — in
primary adrenal insufficiency, the peak cortisol level is
subnormal (< 18 μg/dL 60 minutes after ACTH
administration). Mineralocorticoid deficiency is
confirmed by relatively low aldosterone levels with high
renin or PRA, with or without hyponatremia and/or
hyperkalemia.
Secondary adrenal insufficiency is associated with
low blood cortisol and low ACTH levels. Confirmation
of HPA axis insufficiency may be more difficult. The
insulin–induced hypoglycemia (serum cortisol measured
60 minutes after 0.05–0.15 U/kg of IV regular insulin) is
not preferred because of the risk of hypoglycemic seizure.
There may not be any increment after short (1 μg IV)
and long (250 μg) ACTH stimulation (expected cortisol
response >18 μg/dL after 30–60 minutes). Other
alternatives include CRH test (1 μg/kg IV over 2 minutes;
expected response: 2 fold increase in ACTH level at 15
minutes and 3–4 fold increase in cortisol levels at 15–30
minutes) and glucagon test (0.1 mg/kg SC).
Further evaluation for multiple pituitary hormone
deficiencies, isolated ACTH deficiency, or primary
adrenal insufficiency will depend on the preliminary
tests. X–ray abdomen may show adrenal calcification.
Ultrasound or CT scans are useful in diagnosis of adrenal
lesions. MRI of brain may show abnormalities of HP axis.
Antibody screen may be useful.
Management
Management of acute adrenal crisis should be immediate.
In the hypotensive patient, rapid restoration of
intravascular volume with IV infusion of 20–25 ml/kg
of 0.9 percent saline in 5–10 percent dextrose is needed.
Additional dextrose should be administered as required
to treat hypoglycemia.
Glucocorticoid should be given simultaneously in
stress doses. Hydrocortisone is the treatment of choice
because of its mineralocorticoid activity. The recommen-
ded stress dose of hydrocortisone is 50 to 75 mg/m2 IV
initially, followed by 50 to 75 mg/m2/day IV divided in
4 doses. Once acute manifestations are controlled, cortisol
may be given orally 5 mg twice a day for infants or
10–15 mg daily for older children. The dose should be
increased in stress situations.
A salt retaining agent such as fluorohydrocortisone
should be given in a dose of 0.05–0.1 mg daily to maintain
electrolyte balance. Liberal salt intake is advised.
Endocrinology 957
HYPERFUNCTION OF THE ADRENAL CORTEX
Hyperfunction of the adrenal cortex may be associated
with excess production of glucocorticoids, mineralo-
corticoids, androgens or estrogens. Most children with
adrenocortical hyperfunction have increased secretion
of more than one hormone. These disorders are rare in
childhood. A high index of suspicion is essential for
diagnosis as most of them present with nonspecific
features.
GLUCOCORTICOID EXCESS STATES—CUSHING
SYNDROME
Cushing syndrome is the most common disorder of
adrenocortical hyperfunction. It is a generic term used
to describe clinical findings caused by prolonged
glucocorticoid excess. Cushing syndrome has been
described at all age groups including neonatal period
and infancy and account for 5–10% of all reported cases.
Etiology
Hypercortisolism in Cushing syndrome may be due to
increased endogenous production or exogenous adminis-
tration. Pharmacological glucocorticoid treatment is the
most common cause of childhood Cushing syndrome.
Increased adrenal glucocorticoid production might occur
in response to increased ACTH levels or represent
autonomous adrenal hyperfunction (Table 17.9.2).
Adrenal pathology is more likely in young children,
while pituitary causes are more common after puberty.
Excessive adrenal production of cortisol may be due to
an adrenal adenoma, carcinoma or nodular hyperplasia.
Adrenal tumours are more common in girls. Adrenal
TABLE 17.9.2: Etiology of Cushing syndrome in children
ACTH–dependent
Hypothalamic — Increased CRH production by tumor
Pituitary — Increased ACTH production —Microadenoma,
macroadenoma
Ectopic — Neuroblastoma, carcinoids, Wilms tumour, islet
cell tumor
ACTH–independent
Adrenal tumors — Carcinoma, adenoma
Pigmented nodular hyperplasia
McCune–Albright syndrome
Multiple endocrine neoplasia
Exogenous
Glucocorticoid — High dose or prolonged oral, parenteral,
topical, inhaled
ACTH
958 IAP Textbook of Pediatrics

adenomas almost always secrete cortisol with minimal

secretion of mineralocorticoids or sex steroids, while
adrenal carcinomas tend to secrete excess cortisol,
mineralocorticoids and androgens.
Cushing syndrome may be secondary to an ACTH–
secreting tumor of the pituitary, termed Cushing disease,
often a basophilic pituitary adenoma. It leads to bilateral
adrenal hyperplasia. The incidence of pituitary Cushing
disease in children is rare as compared with adults.
Cushing syndrome may be due to ectopic production
of ACTH from malignant tumors of bronchus, thymus
or pancreas. It is extremely rare in children.
McCune–Albright syndrome due to a somatic mutation
of Gsα protein, may present with ACTH–independent
Cushing syndrome due to constitutional activation of
ACTH receptor. It is associated with fibrous dysplasia,
café-au-lait spots and other endocrinopathies including
precocious puberty and hyperthyroidism. Figure 17.9.1: Eight-year-old girl with Cushing syndrome due
to pituitary microadenoma. Note central obesity and moon
facies
Clinical Features
Unlike adults, the clinical manifestations of Cushing
syndrome especially in the young child are frequently
due to an adrenal tumor. Children differ from adults in
their clinical features. The classical features such as
central obesity, striae, moon facies and buffalo hump are
rare in young children. Growth failure coupled with weight
gain is the most common feature in children. However,
it is an extremely rare cause of childhood obesity. The
fat distribution is often centripetal with accumulation on
the face, neck and abdomen. The extremities appear
wasted with muscle weakness (Figs 17.9.1 and 17.9.2).
Other common clinical features include hypertension,
Figure 17.9.2: Eight-year-old girl with Cushing syndrome.
delayed puberty, lethargy, bone pain, and obsessive– Note buffalo hump and hypertrichosis
compulsive behavioural disorders. There may be
thinning of skin with purple striae (frequently seen on
the abdomen, buttocks, thighs and axillae) and easy Diagnosis
bruising. ACTH–dependent Cushing syndrome is The first step in the evaluation of a child with suspected
characterised by hyperpigmentation due to increased Cushing syndrome is to exclude exogenous causes of
secretion of melanocyte stimulating hormone (MSH). hypercortisolism. Associated signs of androgen excess
Impaired immune function is also known. Androgen leading to virilisation with premature pubarche, acne,
excess leads to hirsutism, acne, deepening of voice and clitoromegaly and penile enlargement, thus, suggest the
rarely clitoral hypertrophy. possibility of virilising adrenal carcinoma. The evaluation
Children with ectopic ACTH production usually lack of children with Cushing syndrome after exclusion of
classical features of Cushing syndrome. This is due to an adrenal tumor is more complex because many of the
rapid progression and shorter duration of the disease. diagnostic tests are based on studies in adults, and then
These children usually present with hypertension and extrapolated for children. An algorithmic approach to
hypokalemic alkalosis. diagnosis of Cushing syndrome is given in Fig. 17.9.3.
 Endocrinology 959

Figure 17.9.3: Approach to a child with Cushing syndrome (Source: Bajpai A, Sharma J, Menon PSN. Practical Pediatric
Endocrinology, 1st edition. Jaypee Brothers Medical Publishers (P) Ltd., New Delhi, 2003)
960 IAP Textbook of Pediatrics
Loss of diurnal rhythm is the earliest biochemical
marker of hypercortisolism. Usually cortisol is highest
at 9 AM and lowest at midnight. The normal plasma
cortisol levels range between 5-25 μg/dL (140–690 nmol/
L) in the early morning, which is reduced to less than
half by 11 pm. Morning cortisol levels are not elevated
in many patients with Cushing syndrome, whereas late–
night cortisol is usually increased.
Estimation of urinary excretion of free cortisol (UFC) is
a good screening test for Cushing syndrome. Normal
levels vary between 25-75 μg/m2/day and UFC levels
>75 μg/m2/day are suggestive of Cushing syndrome.
Although UFC may be useful to confirm Cushing’s
syndrome, its sensitivity and specificity are not optimal
as an initial screening test.
Salivary cortisol is better alternative and being used
in advanced laboratories. Salivary cortisol level > 8.6
nmol/L is suggestive of Cushing syndrome.
Overnight dexamethasone suppression is a commonly
used screening test for adrenal pathology. Following
administration of 1 mg of dexamethasone at 12 midnight,
plasma cortisol is estimated in the morning sample.
Cortisol levels below 5 μg/dl indicate non-adrenal cause
for obesity.
Low dose dexamethasone suppression test (LDDST) is
used for confirmation of Cushing syndrome. It is based
on the principle that dexamethasone will suppress
ACTH, and hence cortisol release in normal subjects,
whereas patients with corticotroph adenomas will not
suppress below a specified cut–off. This test involves the
measurement of serum cortisol or UFC before and after
oral dexamethasone (5 μg/kg per dose, every 6 hours
for 2 days or 1.25 mg/m2/day divided into 4 doses given
over 2 days). Serum cortisol levels > 5μg/dL is diagnostic
of Cushing syndrome. It should be remembered that
there is significant variability in the biological behavior
of corticotroph adenomas, as a result neither the
overnight nor LDDST test reliably rules out Cushing
syndrome using standard cutoffs for serum cortisol.
Urinary 17–ketosteroids are increased if virilization
is present. Adrenal androgens such as DHEA and
DHEAS are normal.
ACTH levels are low in adrenal tumors and nodular
hyperplasia; normal or mildly elevated in Cushing
disease and markedly elevated in ectopic ACTH
syndrome. Currently available ACTH assays reliably
differentiate ACTH–independent (ACTH levels <5 pg/
mL) from ACTH–dependent conditions (ACTH levels
>15 pg/mL). Children with ACTH levels between 5–15
pg/mL are best evaluated by the CRH stimulation test.
Increase in ACTH levels after intravenous CRH (1 μg/
kg, maximum 100 μg, sampling basal and after 30 and
60 minutes) is suggestive of ACTH–dependent etiology
while no increase is expected in children with autonomous
adrenal production or ectopic ACTH production.
High dose dexamethasone test (HDDST – 2 mg every
6 hours or 40 μg/kg every 6 hours for 2 days) will reduce
plasma cortisol in normal children and bilateral adrenal
hyperplasia, but not in children with adrenal tumors or
ectopic ACTH syndrome.
Other lab features include polycythemia, eosinopenia
and lymphopenia. Intermittent hyperglycemia without
glucosuria is common. There may be hypokalemia and
metabolic alkalosis. Serum calcium is normal.
Phosphorus concentrations may be low.
Radiological evaluation shows retarded bone age
usually, but may be advanced in children with
virilization. Osteoporosis and pathological fractures may
be present. If adrenal tumor is present, there may be
calcification and displacement of kidney. The tumors can
be localized by adrenal imaging using ultrasound, CT or
MRI. Pituitary MRI imaging often picks up corticotroph
microadenomas in < 25% cases. The use of dynamic MRI
(with IV gadolinium) with spoiled gradient sequences
may increase the sensitivity. Radiological evaluation
should not be performed before definitive endocrine
characterization. This is extremely important as non–
functional pituitary and adrenal lesions are common.
Thus, identification of an adrenal or pituitary lesion alone
in the absence of endocrine features is not sufficient to
establish the cause.
Inferior petrosal sinus sampling (IPSS) is the test
available for identifying the source of ACTH production
and may be performed in children with ACTH–
dependent CS with normal neuroimaging. The
experience with children is limited.
Management
Resection of adrenal lesion is recommended in children
with adrenal adenoma and carcinoma. Prolonged cortisol
excess causes suppression of the normal contralateral
adrenal. This mandates close monitoring for adrenal
insufficiency in the perioperative period. Unilateral
adrenalectomy is advised for benign cortical adenoma
and subtotal adrenalectomy for bilateral. Total
adrenalectomy can result in Nelson’s syndrome

characterized by enlargement of sella and hyper-
melanosis. Trans–sphenoidal resection of pituitary
adenoma is recommended for children with Cushing
disease. The success rate varies from 66–80%. Pituitary
irradiation has been tried in surgical failure.
Adrenal carcinoma is highly malignant and has a high
rate of recurrence. Chemotherapy with mitotane or
cisplatin is ineffective in children with recurrence of the
disease. Medical management of childhood CS with
inhibitors of steroidogenesis (ketoconazole, cyprohep-
tadine and mitotane) has been tried but is largely
disappointing.
HYPERALDOSTERONISM
Primary hyperaldosteronism due to increased adrenal
aldosterone production is extremely rare in children.
These include aldosterone producing adrenal adenoma,
familial primary hyperaldosteronism and much rarely
adrenal carcinoma. Secondary hyperaldosteronism
results from factors that activate renin–angiotensin
system. The most common clinical features of primary
hyperaldosteronism are due to hypertension and
hypokalemic alkalosis manifesting as fatigue, muscle
cramps and weakness, polyuria, nocturia and poor
growth. This condition needs to be differentiated from
Bartter syndrome, in which plasma renin activity is
elevated with normal blood pressure.
Hyperaldosteronism should be managed with salt
restriction and anti–aldosterone agent, spironolactone.
PHEOCHROMOCYTOMA
Pheochromocytoma is a catecholamine–secreting tumor
which arises from the chromaffin cells of adrenal
medulla. It may arise from abdominal sympathetic chain,
periadrenal area, urinary bladder, thoracic cavity or
cervical region. It is rare in children and accounts for only
2 percent of cases of secondary hypertension. It usually
coexists with other syndrome or tumors such as
neurofibromatosis (von Recklinghausen disease and von
Hippel–Lindau disease). Pheochromocytoma also forms
a part of the multiple endocrine neoplasia type II.
Clinical Features
Clinical features are due to hypersecretion of
catecholamines. These include hypertension, sustained
more often than paroxysmal. There may be associated
Endocrinology 961
headache, palpitation, pallor, sweating, nausea,
vomiting, visual disturbances, polyuria and polydipsia.
Convulsions due to hypertensive encephalopathy may
occur.
Diagnosis
Demonstration of increased urinary excretion of
catecholamines and their derivatives confirms the
diagnosis. The predominant plasma catecholamine is
noradrenaline and the total urinary catecholamines are
more than 300 μg/24 hours. Urinary excretion of
vanillylmandelic acid (VMA), which is a major
metabolite of catecholamine, is increased. Plasma renin
levels are elevated. Ultrasound, CT scan or MRI scans,
arteriography, 123I–MIBG (metaiodiobenzylguanidine)
scintigraphy and vena caval samplings are used for
localization of the tumor. Often the tumors are multiple.
Management
Surgical removal of the tumor is the choice of treatment.
Preoperative alpha–blockade is done by administration
of phenoxybenzamine or prazocin. Recently calcium
channel blocking agent, nifedipine, has been tried with
some success.
BIBLIOGRAPHY
1. Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and
classification of Cushing syndrome: A consensus
statement. J Clin Endocrinol Metab 2003;88:5593–602.
2. Bajpai A, Sharma J, Menon PSN. Practical Pediatric
Endocrinology, 1st edition. Jaypee Brothers Medical
Publishers (P) Ltd: New Delhi, 2003.
3. Desai MP, Menon PSN, Bhatia V (Eds). Pediatric
Endocrine Disorders, 2nd edition. Orient Longman,
Hyderabad. 2008;326–398.
4. Findling JW, Raff H. Screening and diagnosis of Cushing
syndrome. Endocrinol Clin Metab North Am 2005;
34:385–402.
5. Lindsay JR, Nieman LK. Differential diagnosis and
imaging in Cushing syndrome. Endocrinol Clin Metab
North Am 2005;34:403–23.
6. Miller WL. The adrenal cortex. In Clinical Pediatric
Endocrinology, (eds) C Brook, P Clayton, R Brown. 5th
edition. Oxford: Blackwell Scientific. 2005;293–351.
7. Moshang T Jr. Cushing’s disease, 70 years later. And the
beat goes on. J Clin Endocrinol Metab 2003;88:31–3.
8. Perry R, Kecha O, Paquette J et al. Primary adrenal
insufficiency in children: twenty years experience at the
Sainte-Justine Hospital, Montreal. J Clin Endocrinol
Metab 2005;90:3243–50.
962 IAP Textbook of Pediatrics

9. Root AW, Shulman DI. Clinical adrenal disorders. In:
Pescovitz OH, Eugster EA, eds. Pediatric Endocrinology,
Mechanisms, Manifestations, and Management.
11.
Philadelphia, PA: Lippincott, Williams and Wilkins;
2004;568–600.
10. Shulman DI, Palmert MR, Kemp SF, for the Lawson
Wilkins Drug and Therapeutics Committee. Adrenal
Insufficiency: Still a Cause of Morbidity and Death in
Childhood. Pediatrics 2007;119:e484–e494
Storr HL, Chan LF, Grossman AB, Savage MO. Paediatric
Cushing’s syndrome: epidemiology, investigation and
therapeutic advances. Trends Endocrinol Metab
2007;18:167–74. Epub 2007 Apr 6.

17.10 Diabetes Mellitus

Vijayalakshmi Bhatia

INTRODUCTION
Diabetes mellitus is a common disorder of fuel
metabolism. In children, it is found most frequently due
to an absolute deficiency of insulin secretion, due to
destruction of the beta cells of the pancreatic islets. The
disease is associated with a number of short and long-
term complications, many of which are linked with the
degree of blood glucose control. In addition, diabetes in
childhood and adolescence affects growth and puberty,
and often psychological wellbeing. Diabetes is best
managed by a team of personnel including a diabetes
nurse/educator, dietician and psychologist in addition
to the doctor.
CLASSIFICATION AND DIAGNOSTIC CRITERIA
Diabetes mellitus is not a single entity. It is a group of
disorders of varying etiology and pathogenesis, resulting
in the same metabolic syndrome. The old classification
by the World Health Organization categorized patients
as insulin-dependent and non-insulin-dependent. This
was replaced in 1997 by a classification based on etiology
(Table 17.10.1). By this classification, the typical insulin-
dependent, ketosis-prone patient is classified as type 1
diabetes. The non-insulin-requiring, non-ketosis-prone,
usually obese patient seen during adolescence is
classified as type 2 diabetes. Pediatricians in India may
occasionally encounter an additional type of diabetes that
is due to a calcific chronic pancreatitis, which may
clinically be insulin-dependent or non-insulin-
dependent, which is now be classified under diseases of
the pancreas. Another type of diabetes presentation seen
in developing countries is that of a non-obese patient
requiring insulin for glucose control but not exhibiting
ketosis when off insulin. This was earlier termed protein
deficient pancreatic diabetes (PDPD) by the WHO. This
terminology has largely been discarded now, as no direct
role of protein deficiency in the etiology of permanent
diabetes has been found. This entity has not found a place
in the new classification because its etiology is not clear.
TABLE 17.10.1: Etiological classification of diabetes mellitus
1. Type 1 diabetes
A. Immune mediated
B. Idiopathic
2. Type 2 diabetes
3. Other specific types
A. Genetic defects of beta cell function
HNF-1 alpha, 4 alpha and glucokinase (formerly MODY
3, 1 and 2)
Mitochondrial DNA.
B. Genetic defects in insulin action
Type A insulin resistance, leprechaunism, Rabson-
Mendenhall syndrome, lipoatrophic diabetes.
C. Diseases of exocrine pancreas
Fibrocalcific pancreatopathy, cystic fibrosis, hemo-
chromatosis .
D. Endocrinopathies
Cushing syndrome, pheochromocytoma, hyperthyroidism,
gigantism/acromegaly.
E. Drug or chemical induced
Pentamidine, glucocorticoids, phenytoin, thiazides,
diazoxide.
F. Infections
Congenital rubella, cytomegalovirus
G. Uncommon forms of immune-mediated diabetes
Stiffman syndrome, anti-insulin receptor antibodies.
H. Other genetic syndromes associated with diabetes
Down, Klinefelter, Turner, Wolfram, Friedreich’s ataxia,
Laurence-Moon-Biedl, Prader-Willi, myo-tonic dystrophy.
4. Gestational diabetes mellitus

TABLE 17.10.2: Diagnostic criteria for diabetes mellitus
1. Symptoms of diabetes plus random plasma glucose > 200
mg/dL (on two separate occasions if symptoms not typical
or hyperglycemia not unequivocal), or
2. Fasting plasma glucose > 126 mg/dL on two occasions, or
3. Two-hour plasma glucose > 200 mg/dL during oral
glucose tolerance test on two occasions (glucose load 1.75
gm/kg).
The cut-off limits for the diagnosis of diabetes mellitus
have also been lowered in the last decade (Table 17.10.2).
Most children with diabetes present with classical
symptoms, and hence need only two random blood sugar
values to confirm the diagnosis.
Only type 1 diabetes will be further discussed.
TYPE 1 DIABETES MELLITUS
Epidemiology
The prevalence of diabetes among school children (up
to 18 years of age) in USA is approximately 1 in 500.
Prevalence in migrant Indian children in the UK (0.54
per 1000) was found to be less than that of the local
childhood population (0.99 per 1000). Reliable prevalence
and incidence data from India are not available. The
incidence of new cases varies with geographical location,
being highest in Finland and Sweden (40 per 100,000
children per year) and lowest in Japan (less than 1 per
100,000 children per year). Boys and girls are equally at
risk. The incidence in European countries is increasing
at the rate of 3% per year.
Etiology and Pathogenesis
Type 1 diabetes is a chronic autoimmune disease
involving only the beta cells, with gradual loss of insulin
secretion. Patients have a genetic predisposition to the
disease, though only a few subjects so predisposed
develop the disease. It is thought that an environmental
factor is necessary to trigger the onset of autoimmunity.
Autoimmune destruction is a slow process, and the
decline in insulin production occurs over a period of
months to years, overt diabetes becoming manifest when
beta cell reserve is below 20 percent of normal.
Genetics of Type 1 Diabetes
The inheritance of diabetes is polygenic. In comparison
to a 0.6 percent lifetime risk (for a white Caucasian) to
Endocrinology 963
develop diabetes, a sibling of a proband may be said to
have a 3 to 6 percent risk of developing diabetes, and an
offspring a 2 to 6 percent risk (with a diabetic father
conferring greater risk than a diabetic mother). The major
susceptibility loci are the human leukocyte antigen (HLA)
Class II genes, and the insulin gene. Two other recently
discovered loci are the CTLA 4 (Cytotoxic T-Lymphocyte
Antigen 4) and PTPN22 gene (protein tyrosine
phosphatase N22). In almost all races, including Indians,
HLA-DR3 and DR4 antigens are associated with
increased risk of type 1 diabetes, whereas HLA-DR15/
DQ6 confers protection. Further analysis has shown that
HLA-DQ region alleles confer even greater risk for type
1 diabetes. If position 57 of the beta chain of the DQ region
is occupied by the amino acid, aspartic acid, protection
against type 1 diabetes is conferred. Conversely, a non-
aspartic acid residue at this position is associated with a
100-fold increased relative risk in white Caucasians. More
importantly, it is being recognised that genetic
susceptibility is associated not with particular DR or DQ
molecules but with an entire haplotype. However,
studies in identical twins with type 1 diabetes have
shown that the identical twin of a proband has only a 50
percent risk of developing type 1 diabetes, suggesting a
role for postnatal (environmental) factors.
Environmental Factors
Viruses especially coxsackie and other enteroviruses, are
the most commonly implicated environmental factor.
Evidences include seasonal differences in the incidence
of diabetes and episodes of viral infection frequently
preceding the onset of diabetes. However, the only viral
infection directly predisposing to diabetes is congenital
rubella infection, in which 20 percent of affected children
develop diabetes. Other proposed environmental agents
include the role of early weaning to cow’s milk (through
albumin/casein), toxins (e.g. nitrosamines) and stress.
Environmental factors may induce autoimmunity by
molecular mimicry or by directly stimulating cytokine
production.
Pathogenesis of Autoimmune Destruction
Numerous evidences exist for an autoimmune etiology
of type 1 diabetes. Diabetes is frequently associated with
conditions of known autoimmune etiology like
Hashimoto thyroiditis, pernicious anemia and Addison
disease. It is also associated with the presence of many
964 IAP Textbook of Pediatrics
autoantibodies. About 80 to 90 percent of newly
diagnosed type 1 diabetes patients (30 to 40% in India)
have islet cell antibodies (ICA). A similar number is also
positive for antibodies against glutamic acid
decarboxylase (GAD), an enzyme present in the islet and
other neuroendocrine tissue. Anti-insulin autoantibodies
are present in 30 to 40 percent of newly diagnosed
patients. Studies in siblings of type 1 diabetes probands
have shown that 60 to 80 percent of first degree relatives
positive for more than 2 autoantibodies go on to develop
diabetes within 5 years.
Lastly, abnormalities in “T” lymphocyte function
exist in type 1 diabetes patients and animal models.
Experiments with animal models of type 1 diabetes have
shown that manipulation of the immune response can
enhance or decrease the development of diabetes, and
type 1 diabetes can be transferred by T cells.
With these evidences, a clearer picture of the
pathogenesis is emerging. Some crucial antigen(s) of the
beta cell, presented by the antigen presenting cells of the
immune system, are presented to specific “T”
lymphocytes in conjunction with specific HLA-D locus
molecules. The activation of “T” lymphocytes sets off a
series of responses including cytokine production, which
amplify the immune response, ultimately resulting in
beta cell destruction.
These evidences of the autoimmune nature of type 1
diabetes, together with the possibility, albeit imperfect,
of predicting which siblings of a proband will go on to
develop diabetes, have led to the commencement of
many trials (using insulin, nicotinamide, etc.) for the
prevention of type 1 diabetes. A discussion of these is
beyond the scope of this book. It may be said that all
trials for the prevention of type 1 diabetes are at best
experimental at present.
Pathophysiology
Insulin acts mainly on three tissues: liver, muscle and
adipose tissue. It induces glucose-uptake, glycogen
synthesis and lipogenesis in the liver, and stops
gluconeogenesis. In muscle, insulin brings about glucose
uptake and oxidation, and glycogen synthesis. In adipose
tissue, glucose-uptake and lipid synthesis occur. Thus,
in diabetes mellitus, hyperglycemia results due to
glycogenolysis, gluconeogenesis, lipolysis and absence
of glucose uptake. Concomitant rise in the counter-
regulatory hormones (glucagon, epinephrine, cortisol
and growth hormone) aggravates hyperglycemia and
ketogenesis.
While lipolysis is caused by insulin deficiency,
enhanced oxidation of the fatty acids so produced is
induced by glucagon. Glucagon induces the carnitine
palmitoyl transferase system of enzymes, which
translocates fatty acids into mitochondria for beta
oxidation, and thus causes ketogenesis.
When blood sugar exceeds the renal threshold of 180
mg/dL, glycosuria, diuresis, electrolyte loss, dehydration
and hyperosmolality result. Untreated dehydration and
acidosis cause cerebral obtundation as well as circulatory
failure.
Clinical Features
Diabetes in childhood typically presents with polyuria,
polydipsia, polyphagia, weight loss and weakness.
Ketoacidosis is heralded by vomiting, dehydration,
abdominal pain, deep and rapid (Kussmaul) respiration
and the fruity odor of acetone in the breath. Ketoacidosis
may mimic an abdominal surgical emergency. Severe
acidosis is accompanied by decreasing consciousness and
hypotension. The presence of fever is an important clue
to infection.
Laboratory findings include glycosuria, hyper-
glycemia, ketonemia and ketonuria. Leukocytosis may
be present without infection. Hypertriglyceridemia is
typical. Diabetic ketoacidosis (DKA) is usually
characterized by normal serum sodium, normal or
initially raised serum potassium, significant ketonemia
(serum ketone positive on a qualitative test even on 1:1
dilution), blood pH below 7.3 and bicarbonate below 15
mEq/L. The metabolic acidosis of DKA exhibits an
increased anion gap (>10 mmol), due to unmeasurable
anions of ketoacids.
Diagnosis
In a patient who presents with the classical symptoms of
polyuria, thirst and weight loss, the diagnosis of diabetes
is straightforward, and requires only the demonstration
of hyperglycemia. In a child with an accidental finding
of glycosuria, one must differentiate diabetes mellitus
from renal glycosuria or Fanconi syndrome. Ketonuria
can occur in starvation, and, in adolescents, after an
alcohol binge on an empty stomach. Both these
conditions will not be accompanied by hyperglycemia
and ketonemia will be mild (not positive in dilute serum).

The child presenting with acidosis must be
differentiated from other causes of metabolic acidosis
with increased anion gap, like uremia, lactic acidosis and
salicylate poisoning. Every child presenting in a coma
must have a blood sugar and urine ketone test to detect
diabetic ketoacidosis.
MANAGEMENT
Management of diabetes mellitus includes treatment of
DKA, post-acidosis therapy in hospital and management
of diabetes at home.
Treatment of Ketoacidosis
Initial laboratory evaluation should include blood sugar,
blood and/or urine ketone, serum sodium, potassium,
chloride, bicarbonate, calcium, phosphorus, arterial
blood gas analysis, electrocardiogram, blood culture and
urine microscopic examination. The bladder should be
catheterized in comatose patients.
In mild DKA (with blood glucose below 500 mg/dL,
small urine ketones, mild dehydration and no acidosis),
the child can be given oral rehydration with appropriate
(sugar-free) fluid and insulin therapy started as below
(see Post-acidosis Insulin Therapy).
Treatment of Severe DKA
Fluid and Electrolytes
The child in DKA is usually moderately to severely
dehydrated. Therefore, the quantity of deficit fluid to be
replaced is 75 to 85 ml per kg of current weight. A rate of
10-20 ml per kg within the first hour helps establish
circulatory stability if needed. The remainder of the
deficit fluid is given over the next 48 hours, along with
the maintenance for the period.
Sudden introduction of hypo-osmolal fluids has been
implicated in the etiology of cerebral edema, a dreaded
complication of DKA. The most commonly used
approach in children is to start therapy with normal
saline, but to switch to half normal saline after the first
hour or after circulatory stability is achieved. Potassium
(40 mEq/L) should be added to the infusion as soon as
urine formation is ascertained, after the first hour of
fluids, as body potassium is severely depleted in DKA.
It may be temporarily delayed it there is evidence of
hyperkalemia on the electrocardiogram.
Endocrinology 965
Though total body phosphorus is also depleted in
DKA, its administration has not been shown to alter the
course of the patient, on critical evaluation of available
studies. Recent recommendations do not advise
phosphorus administration.
Alkali Therapy
Unnecessary alkali therapy in DKA is dangerous. It can
precipitate cerebral edema by increasing central nervous
system acidosis, precipitating hypokalemia, shifting the
oxygen dissociation curve to the left and causing
alkalosis. Sodium bicarbonate may be indicated for
symptomatic hyperkalemia or if the blood pH persists
at < 6.9 after the first hour of rehydration, with
cardiovascular instability. The dose to be infused is
calculated by the formula: (ml of sodium bicarbonate =
0.15 × base deficit × kg body weight). The amount
(usually 40 ml) is never given as a bolus, but added to a
0.5 N saline infusion over 2 hours. Alkali therapy should
be stopped when pH is > 7.0.
Insulin Therapy
The continuous low-dose insulin infusion is the method
of choice for treating children with DKA. Regular insulin,
0.1 units per kg, is given as a continuous normal saline
infusion at the rate of 0.1 units per kg per hour (recent
recommendations do not advise an insulin bolus for
children). The goal is to slowly decrease blood sugar by
50 to 100 mg/dL every hour. The infusion of insulin is
stopped only when acidosis has normalized, which
occurs only after normalization of hyperglycemia.
Therefore, when blood glucose decreases to 250 to 300
mg/dL, 5 percent dextrose is added to the intravenous
fluid infusion.
After correction of acidosis (which may take 24 hours
or longer in severe DKA), the child is ready to be started
on subcutaneous insulin therapy. An initial dose (0.2 to
0.4 units per kg) of regular insulin is given, half an hour
after which the insulin infusion is stopped and the child
allowed to eat. Such a regimen of insulin plus meal is
carried out every 6-8 hours until the child can be reliably
predicted to eat, after which twice daily doses of regular
(plain) plus intermediate-acting (NPH) insulin before
breakfast and dinner are started, with a lunch time dose
of plain insulin if needed.
966 IAP Textbook of Pediatrics
Monitoring During DKA
Clinical parameters like vital signs, hydration, sensorium,
pupils, urine output, fluid infused, insulin infusion rate,
etc. must be monitored every hour and a flow sheet
should be carefully maintained. Capillary blood glucose
by fingerprick should be done at the bedside every hour
initially and later every 2 hours. Serum sodium,
potassium and bicarbonate should be measured every 4
hours initially and later 6 hourly. Urine ketones, serum
phosphorus and calcium may be done every 8-12 hours.
Urine ketones may seem to worsen or persist for long,
despite clinical improvement. This is because with insulin
therapy, betahydroxy-butyrate, an unmeasured ketone
present in larger quantities in DKA, is converted to
acetone and acetoacetate, the measured ketones. This
should not be interpreted as indicative of worsening.
Complications of DKA
Cerebral edema: Clinically symptomatic cerebral edema
occurs in 1 to 2 percent of children with DKA and has a
high mortality of 50 percent. It usually occurs during
insulin therapy, when the child actually appears to be
responding to treatment. The etiology is not clear, but
has been linked to too rapid correction of hyper-
osmolality, excessive use of alkali, high initial blood urea
and greater hypocapnia, and lack of rise of serum sodium
during treatment. Early signs include change in
sensorium (drowsiness or agitation), headache, vomiting,
comparative decrease in heart rate or increase in blood
pressure. Pupillary changes, papilledema and upgoing
plantars are late signs. Prompt therapy with mannitol
(without necessarily waiting for a CT scan to confirm
the diagnosis) is indicated.
Others: Acute gastric dilatation or erosive gastritis,
vascular thromboses and respiratory distress syndrome.
POST-ACIDOSIS THERAPY
After stabilization of the acidotic state, the following
issues must be addressed: (i) management of
precipitating factor for DKA, like infection or emotional
stress, (ii) subcutaneous insulin therapy, (iii) nutrition,
(iv) education of the family for home management of
diabetes, and (v) psychological and social support for
the patient and the family.
Subcutaneous Insulin Therapy
Subcutaneous insulin therapy should be started when
acidosis subsides. A mixture of regular and intermediate-
acting (NPH) insulin is given twice a day, half an hour
before breakfast and dinner. This is the so-called split-
mix regimen. The total daily dose (0.5 to 1.0 units per kg)
is roughly divided into two-thirds to be given before
breakfast and one-third before dinner. Two-thirds of each
dose should consist of NPH insulin, and one-third,
approximately, of regular insulin. These are just initial
guidelines. From the next day, doses should be titrated
according to blood sugar responses obtained the previous
day. The addition of a plain insulin dose at lunchtime is
useful for better control of blood sugars.
Bovine insulin, previously the least expensive insulin
available in India, is now no longer available. Insulins
available in India contain 40 units per ml or 100 units
per ml. Care must be taken to administer U40 insulin
only with a U40 syringe and likewise U 100 insulin must
be matched with a U 100 syringe. The two insulins,
regular and NPH, can be drawn into the same syringe,
first regular, followed by NPH, to be given as a single
subcutaneous injection. Disposable insulin syringes have
clearer markings and less dead space than glass ones.
Suitable sites for insulin injection are the back of upper
arm, front of thigh, abdomen and buttocks. The injection
site must be different each time, to avoid lipodystrophy.
Insulin is ideally stored in a refrigerator (never frozen).
Families who do not have the facility can store it in a
damp cloth in the coolest portion of the house. In addition
to insulin, analogs of insulin are now available, which
have unique features providing greater flexibility and
lower chances of hypoglycemia. Insulin lispro and aspart,
which have minor amino acid differences from insulin,
have a quicker onset and shorter duration of action than
regular insulin. This makes them suitable for use in
toddlers, who cannot be depended upon to eat at a
particular time, as the injection can be given after the
child has actually started eating. The analogs glargine
and detemir are poorly soluble at the pH of subcutaneous
tissue and hence are peakless. They provide a basal 24
hour insulin in blood, without the extent of hypoglycemia
found with NPH. Unfortunately, these analogs cost
significantly more than regular and NPH insulins.

Nutrition
The ideal diet for a child with diabetes is nothing but a
healthy meal plan for any member of the family, with
the additional requirement of avoidance of simple sugars.
The total daily calories should be calculated from age,
weight, pubertal status and recommended dietary
allowance calculations, tempered with the knowledge
of the child’s dietary pattern before the illness. A rough
guideline is 1000 calories at 1 year age, and additional
100 calories per year of age after that, up to puberty.
Approximately 55 to 65 percent of calories should derive
from carbohydrates, 15 percent from protein and 20 to
30 percent from fat. Foods rich in fiber (whole pulses,
whole grain cereal, vegetable, and fruit) should be
encouraged as they have a low glycemic index. Foods
rich in fat, especially saturated fat, are to be avoided. The
day’s meal plan should be divided into 3 meals
(breakfast, lunch and dinner) and 2 to 3 snacks
(midmorning, evening and bedtime). However, these
schedules can be tailored according to the individual
needs of the child and family, with insulin doses adjusted
accordingly. It must be borne in mind that the patient is
a child, for whose emotional wellbeing we must accept
some flexibility in the “dos” and “don’ts” of dietary
management. Hence, items with simple sugar or excess
fat must be allowed on special occasions like birthdays
or festivals.
Monitoring
The importance of excellent blood glucose control in
minimizing, preventing or delaying long-term
complications of diabetes is now well-established. To this
end, it is essential for blood sugars to be monitored
frequently so as to take steps to prevent or treat high
blood sugars.
Home Monitoring
With the advent of glucose oxidase strips, blood glucose
can be measured at home using strips with a reflectance
meter. Urine glucose (positive only when blood glucose
rises above 180 to 200 mg/dL) is less informative than
blood glucose testing. Unfortunately, blood glucose
testing is expensive. A combination of blood and urine
glucose testing schedules can be used.
Ideally, capillary blood glucose should be tested daily
fasting, pre-lunch, pre-dinner and at bedtime. Post-meal
sugars may be tested on one or two days a week, and a 1
Endocrinology 967
or 2 a.m. test to rule out nocturnal hypoglycemia, once
in 2 weeks. Blood glucose should also be tested to confirm
symptoms of hypoglycemia, whenever possible. A high
blood sugar before a meal may be dealt with by taking a
small additional dose of regular insulin. When blood
sugar is persistently high (> 300 mg/dL) and on days of
fever/other sickness, urine must be tested for ketones.
This rigorous schedule of testing requires a motivated
patient and supportive family interested in excellent
blood glucose control. The pediatrician must be careful
to individualize these instructions. Table 17.10.3
describes the blood glucose goals for intensive therapy
as well as conventional therapy.
Those who test urine sugar must do so on a second
void specimen. Urine sugar testing by test strips does
not work out costlier than using Benedict’s reagent, and
due to far greater convenience, is likely to encourage
compliance.
Laboratory Monitoring
Home glucose monitoring does not give an integrated
picture of blood glucose control over the long-term. This
deficiency is made up by performing glycosylated
hemoglobin (HbA1c) measurement once in 3 months. It
represents the fraction of hemoglobin to which glucose
has got attached, over the lifespan of a red blood cell.
The normal value in people without diabetes is 4 to 6
percent. A value of up to 7 percent in a patient indicates
excellent blood glucose control; a value between 7 and 8
percent is regarded as good, and greater than 8 percent
indicates scope for much improvement.
Education of the Patient and Family
Blood sugar patterns in diabetes are not necessarily stable
from day to day. Variations are brought about by changes
in exercise and meal pattern, emotional status, etc. Thus,
successful therapy of diabetes is not possible without the
patient and/or family assuming responsibility for day to
TABLE 17.10.3: Goals of conventional and intensive therapy
Conventional therapy
HbA1c 7.5–8.5 percent
Pre-meal blood glucose 120–160 mg/dL
Absence of polyuria and ketonuria
Intensive therapy
HbA1c 6.0–7.0 percent
Pre-meal blood glucose 80–120 mg/dL
Post-meal blood glucose < 180 mg/dL
968 IAP Textbook of Pediatrics
day care. This requires that the family be educated in
diabetes management techniques. Diabetes management,
as well as teaching, is best carried by a team consisting of
the doctor, diabetes nurse/educator, dietician,
psychologist and social worker. In addition to insulin
therapy, nutrition, monitoring, and hypoglycemia,
patients must be taught the importance of exercise as well
as management during days of unrelated sickness.
Perhaps the single most important message for patients,
in relation to sick days, is that insulin must not be stopped.
On the other hand, insulin requirement may actually rise
during illness.
Complications of Diabetes
Hypoglycemic Reaction
Mismatch between insulin dose on the one hand, and
meal and exercise on the other, results in hypoglycemia
quite frequently in the life of a child with diabetes.
Defined as a blood sugar of < 60 mg/dL, it is heralded
by adrenergic symptoms like sweating, pallor, trembling
and tachycardia. Patients are taught to recognize these
symptoms and institute treatment (see below). If
unrecognized, blood glucose levels may drop further,
leading to neuroglycopenic symptoms like drowsiness,
confusion, coma or seizures. Most often, though, the
release of counter-regulatory hormones at a level of 55
to 60 mg/dL leads not only to the warning (adrenergic)
signs, but also to a rebound rise in blood glucose.
Treatment of Hypoglycemia
It is always advisable to first confirm the symptoms of
hypoglycemia with a blood sugar test. For immediate
rise in blood sugar, simple sugar (5 to 10 gm) in the form
of sugar, glucose, fruit juice or a carbonated drink must
be taken. In addition, a small snack of protein plus
carbohydrate must be eaten. The unconscious child with
hypoglycemia can be treated at home with 0.5 mg (1.0
mg in the adolescent) of glucagon given subcutaneously.
If glucagon is not available, the child should receive
intravenous glucose in the nearest emergency center.
After an episode of severe hypoglycemia is treated,
the family must assess the reasons for its happening.
Preventable factors like missed meals or exercise
uncompensated with food, must be recognized.
Necessary reductions in insulin dosage must be
instituted, if hypoglycemia shows a recurring pattern.
Long-term Complications
Microvascular (affecting the eye, kidneys and nerves) and
macrovascular (causing cerebrovascular and coronary
heart disease) complications are responsible for long-
term morbidity and mortality in diabetes mellitus.
Growth retardation and pubertal delay are additional
issues in childhood and adolescent diabetes. Pathogenetic
mechanisms implicated include glycosylation of proteins,
abnormalities in the polyol pathway, growth factors,
platelet function defects, hyperinsulinemia, and free
radical induced damage. While the pathogenesis of each
is not yet perfectly clear, large follow-up studies like the
diabetes control and complications trial (DCCT) have
clearly established a strong correlation between poor
blood glucose control and frequency of complications.
Thus, the onus is on all those who care for children with
diabetes, to encourage the best possible metabolic control.
Intensive insulin therapy aimed at maintaining near
normal blood sugars is however, associated with a 3 times
greater risk of severe hypoglycemia (coma/convulsions)
than conventional insulin therapy. Therefore, it is not
advisable in young children (particularly below 7 years
of age), or for those who do not have constant access to
emergency care.
Complications of diabetes usually do not set in before
a duration of diabetes of at least 3 to 5 years. Background
retinopathy occurs in almost 90 percent after 15 year’s
duration, but vision threatening (proliferative) retino-
pathy occurs in only 25 percent patients after 25 years.
Similarly, end-stage renal disease occurs in 15 to 20
percent of patients after a similar duration. These figures
have almost halved in the last 3 decades, the fall in
complication rate being attributable to improved blood
glucose control due to availability of home blood glucose
testing strips. It has been hitherto believed that
complications do not occur in the prepubertal diabetic
child, irrespective of duration of diabetes. However,
recent prospective studies indicate that this may not be
entirely true, and that prepubertal children must be
screened for complications after a duration of diabetes
of 3 to 5 years.

BIBLIOGRAPHY
1. Alemzadeh R, Wyatt DT: Diabetes mellitus. In Behram
RE, Kliegman RM, Jenson HB, et al (Eds): Nelson
Textbook of Pediatrics (17th ed). Philadelphia 2004;
1947-72.
2. American Diabetes Association: Clinical practice
recommendations Updated yearly and available free of
cost at www.diabetes.org
3. Atkinson MA, Maclaren NK. The pathogenesis of insulin-
dependent diabetes mellitus. N Engl J Med 1994;
331:1428-36.
4. Daneman D. Type 1 diabetes. Lancet 2006;367:847-58.
5. Diabetes Control and Complications Trial. The effect of
long-term intensified insulin treatment on the
development of microvascular complications of diabetes
mellitus. N Engl J Med 1993;329:304-9.
Endocrinology 969
6. Dunger DB, Sperling MA, Acerini CL, et al: ESPE/LWPES
consensus statement on diabetic ketoacidosis in children
and adolescents. Arch Dis Child 2004;89:188-94.
7. Glaser NS, Barnett P, McCaslin I, Nelson D et al: Risk
factors for cerebral edema in children with diabetic
ketoacidosis. The Pediatric Emergency Medicine
Collaborative Research Committee of the AAP. N Eng J
Med 2001;344:264-69.
8. Rachneil M, Perlman K, Daneman D. Insulin analogues
in children and teens with type 1 diabetes: advantages
and caveats. Pediatr Clin North Am 2005;52:1651-75
9. Report of the American Diabetes Association expert
committee on the diagnosis and classification of diabetes
mellitus. Diabetes Care 1997;20:1183-97.
10. Rosenbloom AL, Schatz DA, Krischer JP et al: Prevention
and treatment of diabetes in children. J Clin Endocrinol
Metab 2000;85:494-522.
18.1 Basic Genetics for Genetic Counseling: ML Kulkarni ..................................................................................................................... 972
18.2 Common Genetic Disorders: ML Kulkarni ......................................................................................................................................... 989
18.3 New Genetics and Advances in Genetics: ML Kulkarni ................................................................................................................ 1013
18.4 Inborn Errors of Metabolism: ML Kulkarni ....................................................................................................................................... 1029
972 IAP Textbook of Pediatrics
18.1 Basic Genetics for Genetic Counseling
INTRODUCTION
Genetic diseases are ubiquitous, affecting all human
beings wherever they live. They place considerable health
and economic burden not only on affected people and
their families but also on the community. As more
environmental diseases are successfully controlled, those
that are wholly or partly genetically determined are
becoming more important.
Despite a general fall in perinatal mortality rate, the
incidence of lethal malformations in newborn infants
remains constant. Between 2 to 5 percent of all liveborn
infants have genetic disorders or congenital malfor-
mations. Many common diseases in adult life also have a
considerable genetic predisposition, including coronary
heart disease, diabetes, and cancer.
The prevalence of various genetic diseases is given in
Table 18.1.1.
TABLE 18.1.1: Types and prevalence of genetic disorders
Types of genetic diseases Estimated
prevalence per
1000 pop.
Single gene
Autosomal dominant 2-10
Autosomal recessive 2 Conventional
X-linked recessive 1-2
Chromosomal abnormalities 6-7
Common disorders with appreciable 7-10
genetic component
Congenital malformation 20
Total 38-51
In general, human diseases may be seen as being on a
spectrum from those diseases which are exclusively genetic
to those which are exclusively environmental. Conditions
like Duchenne muscular dystrophy and Down syndrome
are purely genetic in origin, whereas scurvy and
tuberculosis are purely environmental. Between the
extremes, are many common diseases like diabetes
mellitus, ischemic heart disease and congenital malfor-
mations in which both genetic and environmental factors
are involved and these conditions are referred to as
multifactorial.
ML Kulkarni
With emphasis on small family size, people are more
concerned about total wellbeing of children and in a
situation like this, even rarer genetic disorders should
cause concern to medical people. Further in south India
where inbreeding has been practiced for more than 3500
years, the load of genetic disorders due to autosomal
recessive genes is high and needs greater emphasis on
prevention and early treatment of these disorders. The
younger medical graduates should walk into the 21st
century armed with basic and practical knowledge of
common genetic disorders.
GENETIC COUNSELING
Definition
Genetic counseling has been defined as “an educational
process that seeks to assist affected and/or at risk
individuals to understand the nature of the genetic
disorder, its transmission and the options available to
them in management and family planning”. The counselor
offers investigations, options and support whereas the
“consultant” (the person who seeks the advice) makes his
own decision which is known as non-directive counseling.
Indications for Genetic Counseling
(i) A diagnosed genetic disease, (ii) Detection of carrier
state in family members for Mendelian disorders, (iii)
Investigation and diagnosis of possible genetic disease,
(iv) Diagnosis of mental handicap or dysmorphic child,
(v) Diagnosis of malformation in neonates or stillbirths,
(vi) Genetic investigation of recurrent pregnancy loss, (vii)
Genetic management of high risk pregnancies, (viii) Inter-
pretation of abnormal prenatal tests, (ix) Environmental
exposure to drugs, infections, radiation, (x)
Consanguineous marriages, (xi) Advanced maternal age.
In Modern Era
(i) Involvement of the members of the family for genetic
linkage or gene tracking studies, (ii) Counseling those
patients on genetic register for long-term contact and
support with modern information available for those
diseases, e.g. Duchenne muscular dystrophy.
 Genetics 973

TABLE 18.1.2 Classification of genetic disorders Mendelian (Single Gene) Disorders

Classification of genetic disorders Disorders caused by a defect in a single gene follow the
A. Genetic disorders due to traditional modes of inheritance.
patterns of inheritance described by Mendel. Individual
i. Mendelian disorders: (Single gene) disorders of this type are often rare but are important
• Autosomal dominant (AD) because they are numerous (3000-4000 single gene traits
• Autosomal recessive (AR) have been listed). Risks within an affected family are
• X-linked recessive (XLR)
• X-linked dominant (XLD) usually high and are calculated by knowing the mode of
ii. Chromosomal disorders: inheritance and details of the family pedigree. Table 18.1.3
• Numerical abnormalities summarizes the concept of single gene disorders.
• Structural abnormalities
iii. Multifactorial disorders
iv. Somatic cell mutations Autosomal Dominant Disorders
B. Genetic disorders due to nontraditional modes of inheritance.
i. Mosaicism The disorders have the following features:
ii. Genomic imprinting a. Normally, there is a pair of genes (alleles) for each
iii. Uniparental disomy (UPD) function that are located at same loci on homologous
iv. Inheritance of unstable mutations
v. Cytoplasmic/mitochondrial inheritance
chromosomes. A single mutant gene is dominant if it
causes an evident abnormality, i.e. in the heterozy-
A brief review of basic principles of genetics is reviewed gous state, the disease manifests itself.
in the following paragraphs that are relevant for genetic b. The abnormal gene is passed from one generation to
counseling. Table 18.1.2 gives the types of genetic disorders another in a “vertical fashion”, i.e. parents and patients
and their classification. are similarly affected (Fig. 18.1.1A).

TABLE 18.1.3: Normal and major mutant gene inheritance (Mendelian inheritance)
(adapted from Smith’s Recognizable Pattern of Human Malformation)
Normal Except for the XY, there is a pair of genes for each function, located at the same loci on sister chromosomes.
One pair of normal genes is represented as dots on a homologous pair of chromosomes

Dominant A single mutant changed gene is dominant if it causes an evident abnormality. The chance of inheritance of the
mutant gene () is the same as the chance of inheriting a particular chromosome of the pair: 50 percent

Heterozygous A single mutant gene is recessive () if it causes no evident abnormality, the function being well covered by
recessive the normal partner gene (allele). Such an individual may be referred to as a heterozygous carrier

Homozygous When both genes are recessive mutant (), the abnormal effect is expressed. The parents are generally
recessive carriers, and their risk of having another affected offspring is the chance of receiving the mutant from one
parent (50%) times the chance from the other parent (50%), or 25 percent for each offspring

An X-linked recessive will be expressed in the male because he has no normal partner gene. His daughters,
receiving the X, will all be carriers, and his sons, receiving the Y, will all be normal
X-linked recessive

An X-linked recessive will not show overt expression in the female because at least part of her “active” X’s will
contain the normal gene. The risk for affected sons and carrier daughters will each be 50 percent
974 IAP Textbook of Pediatrics
Figure 18.1.1A to D: AD disorders: (A) Vertical transmission,
(B) 50% risk at each pregnancy, (C) Lack of penetrance in “*”,
(D) Homozygosity
c. If one of the parents is affected the risk of recurrence is
50 percent in each subsequent pregnancy (Fig. 18.1.IB).
d. Both sexes may be affected.
e. The degree of expressivity may vary in the same family,
e.g. in a full blown picture, the individual with Marfan
syndrome may have defects of the skeletal system,
cardiovascular system and of the eye, but in a family
of Marfan syndrome, the manifestations may vary in
different individuals.
f. The unaffected members of the family will not transmit
the disease. Except in a rare situation there can be lack
of penetrance, wherein the person carries the gene but
disease is not manifested in him, but has transmitted
to his offspring (Fig. 18.1.1C).
g. Spontaneous new mutations should be suspected if a
dominantly inherited condition is seen in a patient
whose parents are normal. Proportion of patients
affected by new mutations varies in autosomal
dominant disorders, e.g. in achondroplasia, 80 percent
of cases are due to fresh mutations; in Marfan
syndrome 30 percent; in Apert syndrome 96 percent;
in Neurofibromatosis 40 percent.
h. Examples of autosomal dominant disorders: achon-
droplasia, Huntington’s chorea, Marfan syndrome,
acute intermittent porphyria, myotonic dystrophy,
adult polycystic kidney disease, Noonan syndrome,
neurofibromatosis, tuberous sclerosis, epidermolysis
bullosa (some forms), osteogenesis imperfecta (some
forms), fascioscapulohumeral dystrophy, polyposis
coli, familial hypercholesterolemia.
i. Homozygosity i.e. the offspring getting double dose of
the defective gene from both parents is rare but when it
occurs, the disease is very severe, e.g. in homozygous
achondroplasia the infant dies in the neonatal period
(Fig. 18.1.ID).
Autosomal Recessive Disorders
The disorders have the following features:
a. Autosomal recessive disorders occur in a person
whose both healthy parents carry the same recessive
gene.
b. The pattern of transmission is called horizontal
because the siblings are affected and the parents are
phenotypically normal. However, they are geno-
typically abnormal, i.e. heterozygous carriers
(Fig. 18.1.2A).
c. If both parents are carriers, the risk of having an
affected child is 25 percent for each pregnancy and
risk for producing a carrier child is 50 percent for each
pregnancy (Fig. 18.1.2B).
d. Males and females are equally affected.
e. Parental consanguinity is often found in autosomal
recessive traits (Fig. 18.1.2C).
f. All children of an affected individual will be carriers if
the partner is normal.
g. Heterozygous carriers though phenotypically normal
may have some biochemical abnormalities, e.g.
hemoglobinopathies, Tay-Sachs disease, etc.
h. Examples of autosomal recessive disorders: Congenital
adrenal hyperplasia, cystic fibrosis, galactosemia,
Friedreich’s ataxia, epidermolysis bullosa (some
forms), diastropic dwarfism, hemochro-matosis,
homocystinuria, Hurler syndrome, Laurence Moon
Biedl syndrome, oculocutaneous albinism, phenyl-
ketonuria, sickle cell disease, Tay-Sachs disease,
thalassemia.
 Genetics 975

Figures 18.1.3 A and B: XLR disorders: (A) Oblique transmis-

sion, and (B) Boys-50% risk affected, girls-50% risk carrier

g. Carriers may have biochemical abnormalities, e.g.

increased CPK levels in Duchenne muscular dystrophy.
Figures 18.1.2 A to C: AR disorders: (A) Horizontal transmis- h. Examples of XLR conditions: Hemophilia A, B;
sion, (B) 25% risk, and (C) Consanguinity in AR (affected Duchenne muscular dystrophy, Becker muscular
marrying a carrier
dystrophy, anhidrotic ectodermal dysplasia, color
blindness, Fabry’s disease, glucose-6-phosphate
X-Linked Recessive Disorders
dehydrogenase deficiency, Hunter syndrome, Lesch-
These disorders have the following features: Nyhan syndrome, Menke’s syndrome, ocular albinism.
a. In X-linked recessive conditions only males are affected
as there is no corresponding allele (Fig. 18.1.3A). All X-linked dominant Disorders
his daughters will be carriers as they receive abnormal
These disorders have the following features:
X from father.
a. These disorders manifest even in XX females as it is a
b. An X-linked recessive trait will not manifest in females
dominant gene (Fig. 18.1.4).
as the other X contains normal partner gene. Fifty
b. The gene is transmitted in families in the same way as
percent sons will be affected and 50 percent daughters
X-linked recessive genes, giving rise to an excess of
will be carriers when the mother is a carrier (Fig.
affected females.
18.1.3B).
c. In some disorders the condition is lethal in hemizygous
c. Normal sons cannot transmit the disease.
males. In this case there will be fewer males than
d. The pattern of inheritance here is called “oblique” as
expected in the family, all of whom will be healthy,
only males on the maternal side are affected, i.e.
and an excess of females, half of whom will be affected.
maternal uncles, patient’s mother’s maternal uncles
d. There is no male to male transmission in this pattern
and mother’s sister’s sons (Fig. 18.1.3A).
of inheritance.
e. Females may be affected if an affected male marries a
carrier female or in Turner syndrome where there is Examples of XLD disorders: Incontinentia pigmenti,
only one X (45, X). orofaciodigital syndrome, hypophosphatemic familial
f. Fresh mutations are known. vitamin D resistant rickets.
976 IAP Textbook of Pediatrics
Figure 18.1.4: XLD disorders
Figure 18.1.5: Y-linked disorders
Y-linked disorders are rare and cause minor phenotypic
features. Only males are affected who get their abnormal
genes from their father (Fig. 18.1.5). Examples: Porcupine
skin, hairy pinna, webbed toes and frontal baldness. Like
surname, the trait is transmitted only to sons. Here the
disorder is transmitted father to son like surname.
Chromosomal Disorders
The correct chromosome complement in humans was
established in 1956, and the first chromosomal disorders
(Down, Turner, and Klinefelter syndromes) were defined
in 1959. Since then refinements in techniques of performing
and examining samples have lead to the description of a
number of disorders that are due to chromosomal
abnormalities.
Chromosomes (chromos = coloured; soma = body), are
thread like structures within the nucleus of the cell that
have special affinity for certain stains.
The chromosomes are package materials for DNA that
carry hereditary information. There are 46 chromosomes
in the nucleus of each somatic cell (diploid number),
whereas mature germ cell, i.e. ovum and sperm contain 23
chromosomes (haploid number).
The 46 chromosomes in somatic cell, are organized
into 23 pairs. The paired chromosomes responsible for
Figure 18.1.6: X and Y chromosomes with banding
patterns and idiogram
sex-determination are known as sex chromosomal pair;
these are XX in females and XY in males (Fig. 18.1.6). The
22 pairs of chromosomes other than sex chromosomes are
known as autosomes. One chromosome in each pair
comes from mother and the other from the father.
Each chromosome has a short arm designated as “p”
and a long arm “q”, both arms are joined by a constriction
known as a centromere “C” (Fig. 18.1.7). The types of
chromosomes are metacentric (centromere is in the
middle), submetacentric (centromere towards the short
arm) and acrocentric (with secondary constriction and
satellites).
Each chromosome can be identified by light micro-
scopy with staining technique that give banding features
specific for each chromosome (Fig. 18.1.6). High resolution
banding techniques help detection of minor structural
abnormalities.
Mitosis, occurs in dividing somatic cells from
fertilization onward, and it is the process whereby the
genetically identical daughter cells are generated from a
cell (Fig. 18.1.8). During meiosis (Fig. 18.1.9), which is the
nuclear division giving rise to gametes, recombination
occurs between homologous parental chromosomes. The
exchange of chromosomal material leads to the separation
of genes originally located on the same chromosome, and
gives rise to genetic variation within families.
The great majority of chromosomal disorders have an
extremely low risk of recurrence in a family. Chromosomal
 Genetics 977

Figure 18.1.7: Structure and types of chromosomes

Figure 18.1.8: Human mitosis

Figure 18.1.9: Human meiosis

aneuploidies have a relation with maternal age.
Recurrence risks for various chromosomal disorders are
calculated based on empiric risk figures available. These
risk figures are calculated from the actual study of the
population.
Multifactorial Disorders
The disorders have the following features:
i. Nearly 60 percent of birth defects are due to this kind
of inheritance. Here, the abnormality is as a
consequence of minor differences at many gene loci,
no one of which may be held totally responsible for
the abnormality. These disorders are influenced
strongly by environmental factors, e.g. congenital
dislocation of the hip is more common in breech
deliveries.
ii. Recurrence risks are much less compared to single
gene disorders. The risk of same type of defect in
offspring of unaffected parent is around 2 to 5 percent
and this is 20 to 40 times the risk for general
population.
978 IAP Textbook of Pediatrics
iii. Rarer the disorders, lower the recurrence risk,
iv. More severe the degree of structural defect, greater is
the recurrence risk from the same.
v. The risk increases with the number of affected
members.
vi. When there is a marked sex difference in incidence,
the risks are greater when the affected individual is
of the rarely affected sex. Ex: In congenital hyper-
trophic pyloric stenosis, when a female child is
affected, recurrences are very high in the family.
vii. Risk is less for distant relatives.
viii. Examples of multifactorial disorders are schizo-
phrenia, asthma, cleft lip and palate, coronary heart
disease, hypertension, neural tube defects and
dislocation of hip.
Somatic Cell Mutations
Some cancers can be inherited as simple Mendelian traits,
with clear patterns of transmission, this is the exception
rather than the rule. Even though most cancers involve
quite substantial changes in the genetic material, such
mutations are somatic and there is no risk to further
generations.
GENETIC DISORDERS DUE TO NONTRADITIONAL
MODES OF INHERITANCE
Some genetic traits are not determined by an equal genetic
contribution from both parents, and disorders that were
previously thought to be inherited on a Mendelian fashion
are now being assigned alternate genetic mechanisms.
These nontraditional modes of inheritance include: (a)
mosaicism, (b) genomic imprinting, (c) uniparental disomy,
(d) inheritance of unstable mutations, (e) cytoplasmic
inheritance (mitochondrial inheritance).
Mosaicism
Somatic mosaicism is the term used to describe the finding
of two different cell lines in one individual that are derived
from a single zygote (i.e. coming from a single egg and
sperm). It occurs as a postzygotic event (after fertilization).
The mosaicism may be for (i) chromosomal abnormalities
or (ii) single gene mutations.
Chromosomal Mosaicism
It has been recognized in cultured lymphocytes of patients
with chromosomal aneuploidy syndromes.
Example: (i) Down syndrome: 1 to 2 percent of cases are
mosaic for trisomy 21. (ii) Turner syndrome: 30 to 40 percent
of cases are mosaics with two cell lines 45X/46 XX and/
or 45 X/46 XY, (iii) triploid phenotype: lethal, (iv) diploid/
triploid phenotype: IUGR, dysmorphism and mental
retardation, (v) Pallister-Killian syndrome: due to
mosaicism for isochromosome 12p, characterized by
mental retardation, coarse facies, pigmentary skin
anomalies and cardiovascular anomalies, (vi) hypo-
melanosis of Ito characterized by pigmentary abnor-
malities of the skin (hypopigmented whorls), ocular,
dental, musculoskeletal and central nervous system
abnormalities.
Single Gene Mosaicism
Somatic mosaicism for single gene mutations.
Example: McCune-Albright syndrome (MAS) is a sporadic
disorder characterized by polyostotic fibrous dysplasia,
cafe-au-lait pigmentation, sexual precocity, and
hyperfunction of multiple endocrine glands. Recent
research has shown that MAS is due to mutations in the
stimulatory G protein of adenyl cyclase.
Germline Mosaicism
Germline mosaicism refers to the presence of mosaicism
in the germ cells found in the gonads. The mosaicism may
be for chromosomal abnormality or a singlegene mutation.
Germ line mosaicism has been found in Duchenne
muscular dystrophy, chronic granulomatous disease and
osteogenesis imperfecta.
Genomic Imprinting (Fig. 18.1.10)
During the last decade, several new mechanisms of genetic
inheritances have been recognized and one such is genomic
imprinting. For many years it was thought that the
expression of the gene is the same whether it came from
father or mother. Genomic imprinting means that the
expression of the gene depends on the parent of origin.
The genes are modified during gametogenesis and as a
result either inactivated or activated. The modification
mechanism is not yet understood but methylation of genes
may be an important mechanism.
Two best known examples for genomic imprinting are
Prader-Willi syndrome and Angelman syndrome. Prader-
Willi syndrome is characterized by neonatal hypotonia
with subsequent hyperphagia and obesity. Angelman’s

Figure 18.1.10: Paternal and maternal imprinting
syndrome (Happy Puppet Syndrome) is characterized by
mental retardation, characteristic movements (ataxia or
puppet like gait) and sociable character often with bursts
of laughter. Both disorders are due to deletion in the
chromosome 15q 11-13 region. If the deletion is inherited
from the father, Prader-Willi syndrome will result and if
the deletion is inherited from the mother it results in
Angelman’s syndrome.
There are several other examples for imprinted gene
like Beckwith-Wiedemann syndrome and transient
neonatal diabetes mellitus.
Uniparental Disomy
An individual inherits a pair of homologous chromo-
somes, one from the father and the other from the mother.
Recent DNA technology has revealed that an individual
may inherit both homologous chromosomes from only one
of his parents and this situation is called as uniparental
disomy. This is possible because of an error in either stages
of meiosis.
This type of inheritance has been shown to be the cause
of a father with hemophilia having an affected son and of
a child with cystic fibrosis being born to a couple in which
only the mother was a carrier. It is to be noted that sons of
a hemophilic father are normally not affected and a child
Genetics 979
will be born with cystic fibrosis only when both the parents
are carriers for the abnormal gene. Uniparental disomy is
also responsible for a rare overgrowth syndrome known
as Beckwith-Wiedemann syndrome.
Unstable Mutation (Triplet Nucleotide Repeats)
One of the examples of unstable mutation or triplet
nucleotide repeats is Fragile X syndrome. Fragile X
mutation consists of an increase in the size of region in
fragile X mental retardation gene (FMR-1). This region
contains a long CGG trinucleotide repeat sequence. In the
DNA of normal person there are between 10 to 15 copies
of this triplet repeat and these are inherited in a stable
fashion. A small increase between 50 to 200 makes this
repeat sequence unstable a condition called as premutation.
A man carrying pre-mutation is known as ‘normal
transmitting male’. All his daughters will inherit the
premutation and will be of normal intelligence. But when
the daughters have their sons there is a significant risk
that the premutation will undergo a further increase in
size during meiosis. If this reaches a critical size of greater
than 200 CGG triplets it becomes a full mutation. Full
mutation is unstable during female meiosis and in somatic
mitotic division, the expansion suppresses transcription
of FMR-1 gene and possibly adjacent genes also. In males
980 IAP Textbook of Pediatrics
with large expansion and to a lesser extent in females this
results in clinical features of fragile X syndrome.
Similar mutations have been reported in myotonic
dystrophy, Huntington’s chorea, and Kennedy’s disease
(spinal and bulbar muscular atrophy). Variability in age
of onset and clinical severity is common to all.
Mitochondrial Inheritance (Figs 18.1.11 and 18.1.12)
Mitochondria are intracellular organelles which are
ubiquitous in eukaryotes and are essential for survival.
Their primary function is to support aerobic respiration
and to provide ATP for intracellular metabolic pathways.
Mitochondria contain their own DNA (mtDNA), which is
thought to be a remnant from the time that they were free
living organisms before forming a symbiotic relationship
with eukaryotes. Human mtDNA is a circular double
stranded molecule (Fig. 18.1.11) and codes for 22 tRNAs 2
rRNAs and 13 proteins. The human mtDNA is still entirely
dependent on the nuclear DNA for the provision of
enzymes for replication, transcription and translation.
Disease characteristics Mitochondrial diseases are a
clinically heterogeneous group of disorders that arise as a
result of dysfunction of the mitochondrial respiratory
chain. They can be caused by mutations of nuclear or
mitochondrial DNA (mtDNA). Some mitochondrial
disorders only affect a single organ (such as the eye in
Leber hereditary optic neuropathy [LHON]), but many
involve multiple organ systems and often present with
Figure 18.1.11: A mitochondrion with its
circular DNA is illustrated
prominent neurologic and myopathic features. Mito-
chondrial disorders may present at any age. In general
terms, nuclear DNA mutations present in childhood and
mtDNA mutations (primary or secondary to a nuclear DNA
abnormality) present in late childhood or adult life. Many
affected individuals display a cluster of clinical features
that fall into a discrete clinical syndrome. Table 18.1.4
enumerates the clinical features which should make the
clinician keep mitochondrial disorders in his differential
diagnosis.
Diagnosis/testing In some individuals, the clinical picture
is characteristic of a specific mitochondrial disorder (e.g.,
LHON, NARP, or maternally inherited LS), and the
diagnosis can be confirmed by molecular genetic testing
of DNA extracted from a blood sample. In many
individuals, such is not the case, and a more structured
approach is needed, including family history, blood and/
or CSF lactate concentration, neuroimaging, cardiac
evaluation, and muscle biopsy for histologic or histo-
chemical evidence of mitochondrial disease, and
molecular genetic testing for a mtDNA mutation. Table
18.1.5 shows some of the common mitochondrial disorders
with their salient clinical features.
Management
The management of mitochondrial disease is largely
supportive. Management issues may include early
diagnosis and treatment of diabetes mellitus, cardiac
pacing, ptosis correction, and intraocular lens replacement
for cataracts. A “shot gun” therapy with multiple vitamins
and cofactors has also been recommended. These
supplements serve two possible roles: enzyme function
enhancement and serving as antioxidants which may
slow the progression of the disease. Table 18.1.6 shows
some of the supplements that may be useful in supporting
a mitochondrial disorder. The use of supplements remains
controversial, as no benefit has been proven under
controlled conditions.
Genetics of mitochondrial disorders: Mitochondrial
disorders may be caused by defects of nuclear DNA or
mtDNA. Nuclear gene defects may be inherited in an
autosomal recessive manner or an autosomal dominant
manner. Mitochondrial DNA defects are transmitted by
maternal inheritance (Fig. 18.1.12). Mitochondrial DNA
deletions generally occur de novo and thus cause disease
in one family member only, with no significant risk to
other family members. Mitochondrial DNA point
 Genetics 981

TABLE 18.1.4: When to suspect mitochondrial disorders?

Organ system Possible problems
Brain Developmental delays, mental retardation, dementia, seizures, neuropsychiatric disturbances, atypical
cerebral palsy, migraines, strokes
Nerves Weakness (which may be intermittend), neuropathic pain, absent reflexes, gastrointestinal problem
(GE reflux, constipation, pseudo-obstruction), fainting, absent or excessive sweating resulting in
temperature regulation problems
Muscles Weakness, hypotonia, cramping, muscle pain
Kidneys Proximal renal tubular wasting resulting in loss of protein, magnesium, phosphorous, calcium and
other electrolytes
Heart Cardiac conduction defects (heart blocks), cardiomyopathy
Liver Hypoglycemia (low blood sugar), liver failure
Eyes Visual loss and blindness
Ears Hearing loss and deafness
Pancreas and Other Glands Diabetes and exocrine pancreatic failure (inability to make digestive enzymes), parathyroid failure
(low calcium)
Systemic Failure to gain weight, short stature, fatigue, respiratory problems including intermittent air hunger,
vomiting

TABLE 18.1.5: Mitochondrial disorders and their salient features

Disorder Primary features Additional features

Chronic progressive external • External ophthalmoplegia • Mild proximal myopathy

ophthalmoplegia (CPEO)
Kearns-Sayre syndrome (KSS)
Pearson syndrome
Infantile myopathy and lactic acidosis
(fatal and non-fatal forms)
Leigh syndrome (LS)
Neurogenic weakness with ataxia
and retinitis pigmentosa (NARP)
Mitochondrial
encephalomyopathy with lactic
acidosis and stroke-like episodes
(MELAS)
• Bilateral ptosis
• PEO onset before age 20 years • Bilateral deafness
• Pigmentary retinopathy • Myopathy
• One of the following: CSF protein greater than • Dysphagia
1 g/L, cerebellar ataxia, heart block • Diabetes mellitus
• Hypoparathyroidism
• Dementia
• Sideroblastic anemia of childhood • Renal tubular defect
• Pancytopenia
• Exocrine pancreatic failure
• Hypotonia in the first year of life • Fetal form may be associated
• Feeding and respiratory difficulties with a cardiomyopathy and/or
the Toni-Fanconi-Debre syndrome
• Subacute relapsing encephalopathy • Basal gangila lucencies
• Cerebellar and brain-stem signs • Maternal history of neurologic disease
• Infantile onset or Leigh syndrome
• Late-childhood or adult-onset • Basal ganglia lucencies
peripheral neuropathy • Abnormal electroretinogram
• Ataxia • Sensorimotor neuropathy
• Pigmentary retinopathy
• Stroke-like episodes before age 40 years • Diabetes mellitus
• Seizures and/or demetia • Cardiomyopathy (initially
• Ragged-red fibers and/or lactic acidosis hypertrophic; later dilated)
• Bilateral deafness
• Pigmentary retinopathy
• Cerebellar ataxia
Contd.
982 IAP Textbook of Pediatrics

Contd...

Disorder Primary features Additional features

Myoclonic epilepsy with ragged- • Myoclonus • Dementia

red fibers (MERRF) • Seizures • Optic atrophy
• Cerebellar ataxia • Bilateral deafness
• Myopathy • Peripheral neuropathy
• Spasticity
• Multiple lipomata
Leber hereditary optic • Subacute painless bilateral visual failure • Dystonia
neuropathy (LHON) • Males:females ~ 4:1 • Cardiac pre-excitation syndromes
• Median age of onset 24 years

mutations and duplications may be transmitted down the
maternal line. The father of a proband is not at risk of
having the disease causing mtDNA mutation, but the
mother of a proband (usually) has the mitochondrial
mutation and may or may not have symptoms. A male
does not transmit the mtDNA mutation to his offspring. A
female harboring a heteroplasmic mtDNA point mutation
may transmit a variable amount of mutant mtDNA to her
offspring, resulting in considerable clinical variability
among sibs within the same family. Since each cell contains
several mitochondria, the diseased cell may contain a
mixture of normal and mutated mitochondria; a state
called heteroplasmy.

Genetic Counseling
In essence genetic counseling consists of an effective
communication process that addresses an individual’s
concerns relating to the development and/or transmission
of a hereditary disease.
There are five steps in genetic counseling (Table 18.1.7).

Figure 18.1.12: Mitochondrial disorders Diagnosis

An accurate diagnosis is the first essential requirement
TABLE 18.1.6: Shotgun therapy for mitochondrial disorders for genetic counseling. This may not always be
Supplement Dose Range straightforward as genetic disease is often variable in its
expression and different members of a family with the
CoQ10 4.3 mg/kg/day or 60-120 mg per day or
a dose to reach a
same disorder may present to different specialties with
target blood level disease manifestations of the condition. Conversely,
levo-carnitine (Carnitor®) variable, 25-100 mg/kg/day, some argue disorders which are clinically similar, may follow different
against carnitine inheritance patterns in different families.
unless carnitine deficient The first and most important step in diagnosis of genetic
Thiamine (Bl) 50-100 mg a day
disorders is construction of a family tree. The pattern of
Riboflavin (B2) 50-100+ mg a day
Nicotinamide (B3) 50-100 mg a day inheritance can be shown from the pedigree, for example,
Vitamin E 200-400 IU; 3 times a day vertical transmission in autosomal dominant disorders,
Vitamin C 100-500 mg SR; 3 times a day horizontal transmission in autosomal recessive disorders
Lipoic Acid (a-lipoate) 12.5 mg/kg/day in 3 divided doses and oblique transmission in X-linked recessive disorders.
Selinium 25-50 micrograms a day
Standard pedigree symbols in pedigree charting are given
b-carotene 10,000 IU; every other day to daily
in (Fig. 18.1.13).
 Genetics 983

TABLE 18.1.7: The steps in genetic counseling relatives and older members of the family should be
interviewed and special investigations like radiology,
1. Diagnosis-based on history, physical examination and
cytology, DNA studies and histology may have to be done.
investigations
2. Risk assessment A team approach, with the help from other specialists like
3. Communication orthopedicians, radiologists and ophthalmologists for
4. Discussion of option arriving at a proper diagnosis can be conducted. Newer
5. Long term contact and support tests should be applied when available for reconfirmation
of previous diagnosis.

Risk Estimation
The mathematical risk calculated from data on a pedigree
may often be modified by additional information from
specific tests to detect carriers. Risk can be expressed as
either a percentage or a fraction. Approximate risks in
some multifactorial disorders are represented in
(Table 18.1.8).
Detection of carriers: “A carrier is an individual who
possesses in heterozygous state the gene determining an
inherited disorder, and who is essentially healthy at the
time of the study”. Identifying carriers of genetic disorders
in families or populations at risk plays an important part
in preventing genetic disease.
Obligate carriers: Families in which there is a genetic
disorder, some members must be carriers because of the
way in which the condition is inherited, these are called
as obligate carriers. A pedigree will indicate a person to
be an obligate carrier, the following are some of the
examples in different modes of inheritance: (i) Autosomal
dominant: Person with affected parent and child, (ii)
Autosomal recessive: Parents and child (children) of
affected person, (iii) X-linked recessive: Woman with two
affected sons or one affected son and another affected male
maternal relative and all daughters of an affected man.
Table 18.1.9 gives examples of various Mendelian
disorders amenable to carrier detection.
The carrier state can be determined by clinical signs,
analysis of genes, analysis of gene products and secon-
dary biochemical abnormalities such as raised serum
creatine kinase activity in Duchenne and Becker’s
muscular dystrophies. The various techniques used for
carrier detection are depicted in Table 18.1.10.

Figure 18.1.13: Pedigree symbols Communication

Counseling should be done as early as possible. A good
All affected individuals must be examined, asymp- rapport should be established between the patient and
tomatic individuals should also be examined to exclude the counselor. Both parents should be present for the
mild or early disease. Home visits should be made, distant discussion. The genetic basis for the problem should be
984 IAP Textbook of Pediatrics

TABLE 18.1.8: Empirical recurrence risk in common multifactorial disorders

Disorder Incidence Sex ratio Normal parents Affected parents Affected parents
per 100 M:F having 2nd having an affected having 2nd affected
affected child child (Risk in %) ‘child (Risk in %)
(Risk in %)

Dislocation of hip 0.07 1:6 4 4 10

Club foot 0.10 2:1 3 3 10
Scoliosis 0.22 1:6 7 5 -
Spinabifida 0.30 2:3 5 3 -
Cleft palate 0.04 2:3 2 7 15
Cleft lip and palate 0.10 3:2 4 4 10
Asthma 3-4 1:1 10 26 -
Diabetes mellitus 0.20 1:1 8 8 10
Schizophrenia 1-2 1:1 10 16 -

TABLE 18.1.9: Mendelian disorders amenable to carrier detection

Autosomal dominant Autosomal recessive X-linked recessive

1. Familial hypercholesterolemia Population based screening 1. Ocular albinism

2. Adult polycystic kidney disease 1. Thalassemia 2. Hemophilia A
2. Tay-Sachs disease
3. Neurofibromatosis 3. Sickle cell disease 3. Hemophilia B
4. Tuberous sclerosis Family based screening 4. Duchenne muscular dystrophy
1. α-1-Antitrypsin deficiency 5. Mucopolysaccharidosis
2. Congenital adrenal hyperplasia II (Hunter’s syndrome)
5. Myotonic dystrophy 3. Cystic fibrosis
4. Galactosemia
6. Malignant hyperpyrexia 5. Mucopolysaccharidosis
7. Huntington’s chorea 6. Phenylketonuria

described using simple language and visual aids. Patients
or relatives should be encouraged to clear their doubts
about the condition.
Discussion of options: Options like prenatal
diagnosis, abortion, not having children or adoption
should be discussed.
Long-term Contact and Support
A combined approach is necessary for continuing support
to the patient and his family. Involvement of the genetic
counselor, family practitioner, specialist genetic nurse,
social worker and enlistment of other medical specialties
for diagnosis, treatment, etc. should be ensured. Support
groups provide psychological support for families by
bringing them into contact with others with a similar
problem. All families with an affected member, and carriers
of specific genetic disorder, should be put in touch with
relevant support groups where those exist. Such groups
identify the concerns of families and allow the community
to participate in developing service. Long-term follow-up
should also be ensured via genetic registers.
Genetic Counseling in an Era of Prenatal Diagnosis
Prenatal diagnosis of genetic disorder has been possible
because of great advances in techniques of obtaining fetal
tissues, as well as development in cytogenetics,
biochemical techniques and recombinant DNA
technology. The technical advances especially in
molecular genetics and availabilities of various prenatal
diagnostic techniques have added a new dimension in
the process of genetic counseling.
Prenatal diagnosis: Determination of the status (genetic
or otherwise) of the fetus by a variety of techniques
(chromosomal, biochemical, DNA, etc.), using a variety of
procedures.
Chorionic villus sampling (CVS): A technique for
obtaining fetal cells for prenatal diagnosis by biopsy of
the placenta, now usually done transabdominally after
10 weeks of pregnancy. Transcervically it can be done at
8-11 weeks of gestation.
 Genetics 985

TABLE 18.1.10: Approaches of carrier detection Fetoscopy: A fine caliber endoscope is inserted into the
uterus. The direct visualization of the fetus is possible
Approaches Examples
and fetal blood sampling can be done.
1. DNA analysis
Specific gene probe: Thalassemias, Duchenne and Embryoscopy: This is an experimental technique used in
deletion detectable in Becker muscular dystrophy, the first trimester of pregnancy. A rigid endoscope inserted
some cases. hemophilia A and B, a1- through the cervix into the space between the amnion and
Unique change in a antitrypsin deficiency,
chorion is used to visualize the embryo and for diagnosis
restriction fragment Sickle cell disease
length polymorphism of structural malformations.
2. Biochemical, primary FISH Molecular cytogenetics has given rise to the powerful
defect known
Enzyme deficiency Hexosaminidase A(Tay-Sachs)
new technology or fluorescent in situ hybridization (FISH).
disease A fluorescently labeled DNA probe is hybridized to a
Nonenzymatic protein Factor VIII assays standard chromosome preparation on a microscopic slide.
defect (hemophilia A) This method is useful in detecting chromosomal
3. Biochemcial, primary abnormalities, both numerical and microdeletion
defect
syndromes.
Unknown Serum creatine kinase
(Duchenne muscular dystrophy) The various techniques used in prenatal diagnosis,
Inaccessible Phenylalanine Ioad their timing, method and complications are summarized
(phenylketonuria) in Table 18.1.11.
4. Physiological
Electroretinography X-linked retinitis pigmentosa
MANAGEMENT OF GENETIC DISORDERS
electromyography Muscular dystrophies
(myotonic and Duchenne) A brief discussion of principles of management of genetic
5. Cytogenetic studies Chromosome translocation disorders is given in the following paragraphs, which is
Minor deletion syndromes
Fragile X syndrome
of relevance to genetic counseling. The successful
6. Microscopy treatment of genetic disorders requires accurate diagnosis,
Blood Sickle cell disease, knowledge of biochemical basis of the disorder and early
Thalassemias intervention.
Biopsy Duchenne dystrophy
Ocular slit-lamp X-linked ichthyosis, myotonic
Major Principles
dystrophy
7. Radiology Tuberous sclerosis (cerebral (i) Restriction of potentially toxic environmental agents,
calcification)
(ii) Replacement of missing gene product, deranged organ
8. Clinical Skin (Fabry’s disease)
Eye (choroideremia) or even gene itself, (iii) Removal of either toxic substances
Muscle (Duchenne dystrophy) of organs, (iv) Metabolic manipulation, (v) Surgical
management.

Amniocentesis: It is the withdrawal of amniotic fluid from
the amniotic sac surrounding the fetus. If amniocentesis
is done at 15 to 16 weeks of gestation, the process is called
conventional amniocentesis, and if done between 11 to
15 weeks then called early amniocentesis; the latter
procedure is still experimental. Early amniocentesis is
considered to be useful for cytogenetic studies.
Cordocentesis: Withdrawing blood from the umbilical
vein under ultrasound guidance, cordocentesis helps in
prenatal diagnosis of genetic disorders and under-
standing of fetal physiology, development and meta-
bolism.
Restriction
Examples for restriction are: (a) Phenylketonuria –
phenylalanine should be restricted in the diet, (b)
Galactosemia – galactose should be eliminated from the
diet early in life. If prenatal diagnosis is made, the mother
should not drink milk in pregnancy, (c) G-6-PD deficiency
– primaquine, sulpha drugs and fava beans should be
restricted, (d) Acute intermittent porphyria – pheno-
barbitone, sulpha drugs, estrogen, etc. should be restricted,
(e) Alpha-1 antitrypsin deficiency – restriction of cigarette
smoking prolongs or prevents the development of
pulmonary emphysema, (f) Familial hypercholestero-
lemia – cholesterol and saturated fats should be restricted.
986 IAP Textbook of Pediatrics

TABLE 18.1.11: Prenatal diagnosis

Fetal tissues Techniques Timing Studies done Risk

(weeks) on tissues
Amniotic a. Conventional 15-16 AFP/AChe Abortion, needle
fluid amniocentesis hCG puncture injuries,
b. Early 11-14 placental abruption
amniocnetesis chorioamnionitis,
preterm labor.
Amniocytes a. Conventional 15-16 Cell culture for
amniocentesis karyotypes,
b. Early 11-14 enzyme assay
amniocentesis DNA studies, FISH
Chorionic a. Transvaginal 9-11 Biochemical, 2% fetal loss, limb
villi b. Transabdominal 12-24 Chromosomal defects, mosaicism and
DNA maternal bleeding.
Fetal blood a. Fetoscopic 18-20 Coagulation factor 1 % fetal loss,
aspiration Immunoglobulin Rhesus
b. Cordocentesis 16-20 antibodies sensitization, fetal
estimation; DNA infection, PROM
and enzyme study,
karyotype, FISH
Fetal liver a. Fetoscopic 18-20 Enzyme assay as in ?
biopsy OTC deficiency
b. Percutaneous
biopsy
Fetal skin a. Fetoscopic 18-20 Histopathology ?
biopsy
b. Percutaneous
biopsy
Fetal muscle a. Fetoscopic 18-20 Histopathology ?
biopsy
b. Percutaneous
biopsy
Maternal serum Maternal blood 12-14 AFP/UE3/hCG Nil
Fetal cells Flow cytometry, 1st FISH, fetal sexing Nil
in maternal PCR/monoclonal trimester DNA tests
circulation antibodies
Preimplantation IVF biopsy of 4-8 cells DNA, PCR, ?
embryo biopsy blastocysts stage enzyme assay

AFP –Alpha fetoprotein IVF– In vitro fertilization

PCR– Polymerase chain reaction UE3– Unconjugated estriol
AChe– Acetylcholinesterase
PROM– Premature rupture of membranes
hCG– human chorionic gonadotrophin
OTC– Ornithine trans carbamylase

Replacement e. Cystinosis Kidney transplantation.

Examples for the replacement mode of treatment are:
a. Hemophilia A and B: The treatment aims at replacement
of factor VIII and factor IX by transfusion respectively.
b. Diabetes mellitus: Insulin is the agent replaced.
c. Alpha-1 antitrypsin deficiency: Can be successfully
treated by replacement with recombinant alpha-1 anti-
trypsin.
d. Congenital adrenal hyperplasia: The agents replaced
are cortisone and aldosterone.
f. Adenosine deaminase deficiency: Bone marrow trans-
plantation or somatic cell gene therapy.
g. Familial hypercholesterolemia: Liver transplantation.
Removal
The examples are: (a) Wilson’s disease: It is an autosomal
recessive disorder characterized by accumulation of
copper in various organs like the liver, brain and kidneys.
The copper can be effectively chelated by oral

administration of penicillamine; (b) Hemochromatosis:
The excess iron stores are removed by repeated
phlebotomy; (c) Familial Polyposis coli: Colectomy is
advised to prevent carcinoma of colon, which develops
during the fourth decade of life.
Metabolic Manipulation
Metabolic manipulation can correct certain types of
disorders which are: (a) Neural tube defects: Periconcep-
tional folic acid therapy has shown to prevent neural tube
defects (b) Homocystinuria: Classic homocystinuria is due
to deficiency of cystathionine synthetase. Among these,
40 percent of patients respond to high doses of vitamin B6.
(c) Crigler-Najjar syndrome type II: These patients benefit
by oral phenobarbitone administration which induces
hepatic glucuronyl transferase activity; (d) Methylmalonic
acidemia: Administration of vitamin B12; (e) Multiple
carboxylase deficiency: Administration of biotin (co-
factor); (f) Familial hypercholesterolemia: Lovastatin to
block endogenous synthesis of cholesterol; (g) Ornithine
transcarbamylase deficiency: Sodium benzoate and
phenylacetate to conjugate glycine and glutamate.
Surgical Management
Surgical management can be considered in certain cases
like: (a) Congenital adrenal hyperplasia: Clitoroplasty and
vaginal reconstruction surgery; (b) Marfan syndrome:
Surgery for aortic dilatation; (c) Hydrocephalus: Shunt
surgery; (d) Obstructive uropathy: Intrauterine shunt or
correction; (e) Diaphragmatic hernia: Repair.
GENE THERAPY
Gene therapy was conceptualized in early 1970s and has
been subjected to many clinical trials since then. In spite
of the technical difficulties, recent advances in gene
transfer is likely to increase its clinical usefulness.
Definition
Gene therapy is a novel approach to treat, cure, or
ultimately prevent a disease by changing the expression
of a person’s genes. This involves the efficient introduction
of functional genes into the appropriate cells of the patient
in order to produce sufficient amounts of protein encoded
by the transferred gene (transgene) so as to precisely and
permanently correct the disorder.
Genetics 987
Approaches to Gene Therapy
Two general strategies are used to deliver genes to specific
tissues and correct genetic defects.
1. Ex vivo approach: The target cells are removed from the
body and a new gene is introduced in vitro by one of
the gene delivery methods.
2. In vivo approach (Direct gene transfer): The
therapeutic gene is introduced directly into the affected
tissue without removing cells from the body. This
requires specially designed vehicles for cells specific
gene targeting.
Types of Gene Therapy
Somatic Cell Therapy
This involves insertion of a therapeutic gene into somatic
cells such as fibroblasts, myoblasts, epithelial cells,
endothelial cells, nervous, glial cells, etc. which can correct
the genetic defect in the individual, but transgene cannot
be passed on to the siblings of the individual.
Germline Therapy
This involves the introduction of a foreign gene into germ
cells like sperm, ovum or fertilized egg, resulting in their
expression in both somatic as well as germ cells of the
offspring. This is not advocated in humans.
Methods of Gene Delivery
A therapeutic gene can be delivered into target cells by a
variety of methods, which include physical, chemical and
biological methods, which can be used either individually
or in combination, these methods are given in Table
18.1.12.
Hurdles in Gene Therapy
Gene therapy is very young and experimental. Many
factors have prevented researchers from developing
successful gene therapy techniques.
• Identification of an ideal gene delivery tool or vector.
An ideal vector should have the following merits.
- Efficiently transfer genes to appropriate cells.
- Accommodate foreign genes of sufficient size.
- Achieve sufficient expression in the recipient cell.
- Non-immunogenic, non-toxic, non-infective and
safe.
988 IAP Textbook of Pediatrics

TABLE 18.1.12: Methods of gene delivery defect resulting in deficiency of antigen specific immunity,
introduction of genetically reconstituted stem cells and
Physical
bone marrow cells have demonstrated clinical efficacy. In
Parenteral injection
Microinjection SCID due to adenosine deaminase deficiency similar
Aerosol treatment was found to be beneficial. Following are the
Gene gun other candidate monogenic disorders under trial for gene
Chemical therapy.
Calcium phosphate • Cystic fibrosis
DEAE-dextran
Liposomes
• α-1 antitrypsin deficiency
• Hemophilia A and B
Biological
Viral vectors
• Gaucher’s disease
- Retro virus • β-hemoglobinopathies
- Adeno virus • Familial hypercholesterolemia
- Herpes simplex virus • Phenylketonuria
Neo-organ implants
Tissue transplantation Prenatal Treatment
Human artificial chromosome
Others Certain genetic disorders when diagnosed prenatally can
Receptor-mediated delivery be treated effectively; for example, in the case of
Virally directed enzyme prodrug therapy methylmalonic acidemia, if B12 is given to the mother, the
• Understanding the precise function of a gene in terms deficiency can be reverted.
of its action and interaction with other genes and Other modalities of prenatal treatment, still in an
environmental factors. experimental stage are:
• Some diseases involve more than one gene. 1. Stem cell transplantation
• High cost and ethical issues. 2. Somatic cell therapy
3. Germ cell therapy
Clinical Trials 4. Organ transplantation
Even though gene therapy was initially conceptualized 5. Preimplantation embryo treatment.
for treatment of single gene disorders, presently most of
the clinical trials are directed towards cancer therapy. BIBLIOGRAPHY
Induction of immune response against tumor cells,
replacement of tumor suppressor genes, introduction of 1. Emery AEH (Ed): Principles and Practice in Medical
Genetics. (3rd edn): London: Churchill Livingstone 1999.
toxic genes, which can induce selective killing of tumor
2. Gelehrter TD (Ed): Principles of Medical Genetics. (2nd
cells, introduction of tumor cell specific lytic viruses, etc. edn): Baltimore: Williams and Wilkins 1998.
are the approaches that are being tried in cancer 3. Harper PS (Ed): Practical genetic counseling. (3rd edn):
treatment. London: Butterworth Heineman 1998.
In X-linked severe combined immunodeficiency (SCID) 4. Zeviani.M, Donato SD: Mitochondrial disorders. Brain
due to deficiency of interleukin-2 receptor gamma chain 2004;127, 2153-72.
 Genetics 989

18.2 Common Genetic Disorders

ML Kulkarni

CHROMOSOMAL DISORDERS common type of aneuploidy is ‘trisomy’. Lack of

About 15 to 20 percent of all first trimester conceptions are
estimated to be lost spontaneously, and half of these have
chromosomal abnormality. The incidence of chromosomal
abnormalities increases in offspring born to mothers after
the age of 35 years, after the birth of one baby with
chromosomal anomalies or when either of the parents is
carrying a balanced translocation of the chromosome. The
different types of chromosomal abnormalities have been
described in Table 18.2.1
Numerical Abnormalities
A cell with the exact multiple of the haploid number, e.g.
46, 69, 92 is referred to as ‘euploid’. Euploid cells with
more than the normal diploid number of 46 chromosomes
is called ‘polyploid’. Cells deviating from one of the
euploid numbers are called ‘aneuploid’. The most
chromosome is called ‘monosomy’.
Trisomy: The presence of one chromosome additional to
the normal homologous pair, e.g. Trisomy 21 (Down
syndrome).
Monosomy: A chromosomal number one less than the
diploid number, i.e. (45 X ), example Turner syndrome,
where there is only one X in a female instead of two.
Monosomy for autosomes is not compatible with life.
Mosaicism: An individual with two or more cell lines
derived from a single zygote. The clinical examples
include 1 percent of all Down syndrome cases and some
cases of Turner syndrome.
Polyploidy: Pure polyploidy is lethal in humans, but
individuals with mosaicism have been known to survive.

TABLE 18.2.1: Types of chromosomal disorders

S. No Types of disorder Examples Outcome

Numerical
1. Polyploidy Triploidy Lethal
(69 chromosomes)
2. Aneuploidy Trisomy of chrom 21 Down syndrome
Trisomy of chrom 18 Edward syndrome
Trisomy of chrom 13 Patau syndrome
45X chrom monosomy Turner syndrome
47XXY Klinefelter Syndrome
Structural
1. Deletion Terminal deletion 5p Cri-du-chat Syndrome
Interstitial deletion 11 P Found in Wilms’ tumor
2. Inversion Inversion 9q Normal variant
3. Duplication Isochromosome X Infertility in Females
(fusion of long arms
with loss of short arms)
4. Ring chromosome Ring chromosome 18 Mental retardation syndrome
5. Fragile site Fragile X Mental retardation syndrome
6. Translocation Reciprocal Balanced translocations, cause no
abnormality.
Robertsonian Unbalanced, cause spontaneous abortions
or syndromes of multiple physical and mental
handicaps
990 IAP Textbook of Pediatrics
Structural Abnormalities
Translocation (Fig. 18.2.1)
The transfer of all or a segment of a chromosome from one
chromosome to another nonhomologous chromosome,
usually through a reciprocal event during meiosis.
It can be :
i. Balanced in which a full complement of genetic
material is present. In the next generation there is a
risk of offspring inheriting an unbalanced form.
ii. Unbalanced Full complement of genetic material is
not present due to deletion or duplication. Balanced
translocation cases have no abnormalities.
Unbalanced translocations result in spontaneous
abortions or syndromes of multiple physical and
mental defects, e.g. 4 percent of Down syndrome cases
are due to translocation between chromosome 21 and
chromosomes 13,14, or 15. During the translocation
of 2 acrocentric chromosomes in this type, the small
fragment formed by fusion of 2 short arms is usually
lost, which is known as Robertsonian translocation.
(Fig. 18.2.2)
Figure 18.2.1: Different types of chromosomal aberrations. For simplicity
hypothetical loci A-D are marked on the chromosome
Deletion (Fig. 18.2.1)
Loss of portion of a chromosome, either terminal or
interstitial: A deletion at the terminal portion of short
arm of the 5th chromosome produces cri-du-chat
syndrome. A deletion in the middle portion of short arm
of the 11th chromosome (interstitial deletion), is seen in
Wilms’ tumor.
Fragile Site (Fig. 18.2.3)
Constriction at sites other than centromere is known as
“fragile site” and show a tendency to break. A “fragile
site” on the long arm of the chromosome is associated
with one of the most common types of X-linked mental
retardation, known as “Fragile X syndrome”.
Duplication
It is the presence of two copies of a segment of chromosome.
It arises by unequal crossing over during meiosis.
Contiguous Gene Syndrome (CGS) (Fig. 18.2.4)
CGS arises by involvement of genes that are adjacent to
each other on a chromosome. Contiguous gene syndromes

Figure 18.2.2: Robertsonian translocation of the two acrocen-
tric chromosomes 14 and 21, the small fragement formed by
fusion of the two short arms is usually lost
Figure 18.2.3: Fragile site
involve micro deletion or micro duplication. Most of these
occur as sporadic events but sometimes may simulate
Mendelian inheritance. The clinical presentation can be
extremely variable as deletion and duplication vary in
size. Some deletions are so small that they cannot be
detected by cytogenetic techniques but molecular
Genetics 991
Figure 18.2.4: Contiguous gene syndrome “Wilms’ tumor,
Aniridia, Genitourinary malformations and Retardation
techniques have to be used. Examples for CGS are Wilms’
tumor (Deletion 11p 15), Prader Willi/Angelman
syndrome, Rubinstein-Taybi syndrome, Miller Dieker
syndrome, DiGeorge syndrome, etc.
Mutation in Triplet Repeat Exapansion
These result in neurological disorders. Examples include:
Fragile X syndrome, Huntington chorea, spinocerebellar
ataxia, spinal and bulbar muscular atrophy, and myotonic
dystrophy. Features of some less common chromosomal
disorders have been described in Table 18.2.2.
DOWN SYNDROME
Down syndrome is one of the best recognized and the
most common serious chromosomal disorder which is
usually caused by an extra copy of chromosome 21
(Trisomy 21), (Fig. 18.2.5) characterized clinically, by
growth retardation, varying degree of mental retardation
and a spectrum of somatic abnormalities including head
and facial features.
992 IAP Textbook of Pediatrics

TABLE 18.2.2: Features of some less common chromosomal disorders

Condition Incidence Clinical features

Trisomy 18 (Edward syndrome) 1 in 8000 births Mental retardation, hypertonia, failure to thrive, low birth ‘weight, prominent
occiput, micrognathia, low set malformed ears, congenital heart disease
mainly VSD and PDA, short sternum, diaphragmatic hernia, renal anomalies,
overlapping of fingers, rocker bottom feet, death in infancy.
Trisomy 13 (patau syndrome) 1 in 20,000 Births Mental retardation, microcephaly, cleft lip ± paiate, midline scalp defects,
microphathalmia, colobomata, low set malformed ears, congenital heart
disease, polycystic kidneys, cryptorchidism, polydactyly, simian crease,
early death.
Multiple X female 1 in 1200 female births Triple X female are apparently normal except for tall stature, higher the
47 XXX, number of X chromosome, more severe is the mental retardation. Menstrual
48 XXXX abnormalities may be present.
49 XXXXX
XYY 1.5 per 1000 newborn Although more prevalent among inmates of high security institutions,the
Syndrome male infant syndrome is less strongly associated with aggressive behavior than
previously thought. Mild mental retardation, behavioral problems and tall
stature are usual features.

during the formation of egg or sperm (meiotic

nondysjunction). In more than 75 percent of cases, the
extra 21 is of maternal origin and in the remaining paternal.
The incidence of trisomic Down syndrome in live births
increases with advancing maternal age and the recurrence
risk is approximately 1 percent. The recurrence in
translocation type of Down syndrome does not depend
on maternal age, but is related to sex of the parent carrying
the translocation and the involved chromosome in
translocation and the risk is usually higher. Patients with
mosaic Down syndrome tend to have less marked physical
stigmata and higher intelligence.

Figure 18.2.5: Down syndrome—Karyotype showing
Trisomy 21 in a female
Etiology
Down syndrome has an incidence of approximately 1:700
live births. Ninety five percent of individuals with Down
syndrome have three copies of chromosome 21 (Trisomy
21); in 4 percent the extra chromosome is not free but is
translocated to another chromosome, usually to number
14 and occasionally to 22 or 21 and in 1 percent there is
mosaicism, wherein, both normal and trisomy 21 cell lines
are present in the body (Mosaic). In trisomic Down
syndrome, the extra 21 results from faulty cell division
Clinical Features
A large number of clinical characteristics have been
described in Down syndrome (Table 18.2.3), many of them
have diagnostic value. Except for the mongoloid facies,
no single feature is always present or pathognomonic.
Mental retardation is constant but nonspecific finding that
becomes apparent in later part of infancy.
Brachycephaly with flat occiput, small head, flat
rounded face, upward slant of the eyes (mongoloid slant),
small nose with depressed nasal bridge, inner epicanthic
folds, protruding tongue and small misshapen ears form
the characteristic “mongoloid facies” (Fig. 18.2.6). oblique
palpebral fissure, epicanthic folds, spotting of iris
(Brushfields spots) and cataract, form the most
characteristic and diagnostically valuable ocular signs in
Down syndrome. The neck is short and broad and skin
and subcutaneous tissue may be loose and abundant
especially during infancy. Asymptomatic atlantoaxial
 Genetics 993

TABLE 18.2.3: Clinical Features of Down Syndrome Contd.

• Joint laxity
Mongoloid facies • Short stature
• Brachycephaly with flat occiput • Dislocation of patella and hip
• Small head, Flat round face • Small pelvis
• Depressed nasal bridge • Atlantoaxial dislocation
• Inner epicanthal folds • 12th rib anomaly- either absent or rudimentary.
• Protruding tongue Hematological system
• Small ears • Higher incidence of Acute leukemia
Ocular system • Congenital thrombocytopenia
• Brushfield spots • Neonatal jaundice
• Congenital cataract Dental problems
• Nystagmus, Strabismus • Delayed dentition
• Hypotelorism (decreased interpupillary distance) • Small and malformed teeth
• Blepharitis • Aplasia of enamel
• Keratoconus • Congenital absence of various permanent teeth
• Refractory errors • Malocclusions and Periodontal diseases
• Cataract after 25 years of age Ten critical signs of Down syndrome in Newborn
Ears (Halls criteria)
• Small low set ears • Oblique palpebral fissures
• Deafness (sensorineural/conductive) • Dysplastic ears
Hands and feet • Excessive skin on back of neck
• Simian crease • Flattened features
• Short broad hands, Clinodactly • Single palmar crease on either hand
• Hypoplasia of middle phalanx of 5th finger • Dysplastic middle phalynx on the 5th digit of either hand
• Gap between 1st and 2nd toes (sandle gap) • Hyper flexibility
• Distal position of palmar axial triradius • Muscular hypotonia
• Ulnar loops in all digits • Dysplastic pelvis
Central nervous system • Absence of Moro’s reflex
• Mental retardation
• Hypotonia dislocation occurs in 12 to 20 percent of individuals with
• Autistic behavior Down syndrome.
• Reactive depression in adolescents Short stature is a characteristic finding in Down
• Alzheimer’s disease after 25 years of age syndrome, varying in degree at different ages. The
Cardiovascular system
shortness of extremities is typical of Down syndrome. The
• Congenital heart disease in 40% cases
• AV canal defects – Ostium primum, atrioventricularis communis
are most common.
• VSD, PDA, TOF, Secundum ASD, Simple pulmonary stenosis,
Isolated aberrant subclavian artery.
Gastrointestinal system
• Atresia of gut- duodenal, oesophageal and anal.
• Hirschsprung’s disease
Genitalia
• Small penis
• Cryptorchidism
• Bulbous vulva
Immune system
• Frequent infection, Trace element deficiency
• Autoimmune disease, Celiac disease
Endocrine system
• Congenital hypothyroidism
• Girls- fertile
• Boys- always sterile.
Musculoskeletal system
• Hypotonia
Contd. Figure 18.2.6: Down syndrome—typical facial feature
994 IAP Textbook of Pediatrics
hands are short, the fingers are short and the fifth finger is
short and incurved (clinodactly). The feet are short, broad
and thick. The space between first and second toes is
frequently widened(sandle gap) and a plantar crease
extends proximally from this space.
Approximately 40 percent of children with Down
syndrome have congenital heart disease which are
responsible for early mortality in these children. The most
often observed cardiac lesion is an atrioventricular canal
(as a part of endocardial cushion defect), followed by
ventricular septal defect, tetralogy of Fallot, patent ductus
arteriosus, and atrial septal defect. Patients with Down
syndrome have an increased incidence of duodenal
atresia, annular pancreas and imperforate anus.
Hematological malignancies are more often associated
with Down syndrome than in general population. A
transient myeloproliferative disorder in the newborn or
infant, a well recognized increased incidence of acute
leukemia during the first decade of life and recently
described rare variant of acute megakaryoblastic leukemia
are frequent hematological abnormalities seen in Down
syndrome.
Respiratory diseases mainly pneumonia, represent one
of the major causes of mortality in Down syndrome. In
addition to muscular hypotonia, associated congenital
heart disease and pulmonary hypertension, the defects in
immunological system play an important contributory role
for respiratory diseases. A derangement of B-cell function,
a profound impairment of T-cell mediated immunity and
an alteration of the phagocytic function of polymorphs,
account for the well-known high incidence of infections
in Down syndrome. Hypothyrodism, increased frequency
of thyroid auto antibodies both in children with Down
syndrome and their mothers are frequent associations,
whereas, hyperthyroidism is an occasional association.
Both males and females with Down syndrome, display
fairly normal sexual development. Skin infection and
psychiatric disorder are the problems in adolescents. The
girls may menstruate and can be fertile but males are
always infertile and have low serum testosterone levels.
The adult patients with Down syndrome have additional
problems of cataract, hypothyroidism, mitral valve
prolapse, hearing loss and Alzheimer’s disease.
Scalp hair in Down syndrome is fine, soft and often
sparse. The prevalence of alopecia areata is high (6%) and
it tends to be extensive and persistant possibly due to
autoimmune mechanism.
Loose folds of skin are found on the nape of the neck in
early infancy. Cutis marmorata, acrocyanosis of extremities
are common in early infancy. With advancing years, the
skin tends to become more dry and hyperkeratotic specially
in areas of abrasion like wrists, elbows, ankles and knees.
Angular stomatitis, chronic blepharitis and a purulent
nasal discharge presumably related in part to abnor-
malities of the skin of the margins of the mouth, eyelids
and nose are frequently seen in Down syndrome patients.
Chelosis, fissuring of tongue (scrotal tongue) become
more obvious with advancing age. The syringomas,
represent benign tumors of eccrine structures and children
with Down syndrome have an incidence of 10 to 37
percent.
Young children with Down syndrome, usually develop
skin infection in the perigenital area, buttocks and thighs.
These infectious lesions usually start out as follicular
pustules, which subsequently, may develop into abscesses
if not treated promptly. Approximately 50 to 60 percent of
adolescents with Down syndrome have skin infection.
The dentition is usually delayed and irregular. The
teeth are consistently small and malformed and aplasia
of enamel is common. Congenital absence of various
permanent teeth and malocclusions are common, whereas
caries is less common. A relatively high incidence of
periodontal disease has been reported in patients with
Down syndrome.
Many dermatoglyphic changes like simian crease,
distal position of palmar axial triradius and ulnar loops
in all digits are characteristic.
Diagnosis
Diagnosis depends mainly on the characteristic clinical
features. Cytogenetic studies have important etiological
implications and help in genetic counseling.
Prenatal diagnosis of Down syndrome is offered to
women with high risk, i.e. advanced maternal age,
previous history of a child with Down syndrome and
translocation carriers or partners of translocation
carriers.
Prenatal Diagnosis
Confirmation of Down syndrome in an unborn fetus
requires cytogenetic studies done on chorionic villi,
amniocytes or fetal blood cells. However, screening can
 Genetics 995

TABLE 18.2.4: Prenatal diagnosis Down syndrome (Figures used as a biochemical marker, when the test is called
in parenthesis indicate appropriate time for the test.) quadruple test, and the detection rate is around 80 percent.
MATERNAL SERUM MARKERS
Biochemical markers like pregnancy associated
• Alpha fetoprotein (AFP) - decreased (14-16 weeks) placental protein A (PAPP –A) and hCG are being used
• Unconjugated estriol (UE3) - decreased (14-16 weeks) recently for assessing risk of Down syndrome in the first
• Human chorionic gonadotropins - increased (14- 16 weeks) trimester, called combined test. Further it has been observed
(hCG) that in Down syndrome during 8 to 12 weeks of gestation,
• Pregnancy associated placental - increased (10- 13 weeks)
the nuchal fold thickness is increased (>4mm). the
protein A (PAPP-A)
increased nuchal fold thickness along with increased hCG
AMNIOCENTESIS
• Early (11-14 weeks) - Karyotype on cultured and presence of PAPP –A in first trimester when taken
amniocytes together is called as first trimester integrated test. The
• Conventional - FISH on uncultured cells combination of quadruple test and first trimester
(14-16 weeks)
CORDOCENTESIS (18-20 weeks)
• Fetal lymphocytes; culture for karyotype; FISH on non dividing SCREENING—FIRST TRIMESTER
fetal cells
CHORIONIC VILLUS SAMPLING (9-11 weeks) Markers Predictive value False positive
• Direct preparation or short term culture for karyotype
Maternal serum markers
ULTRASOUND (11-20 weeks) • PAPP-A
• Nuchal fold >4mm (8-12 weeks) • Free β-hCG 65% 5%
• Double bubble in abdomen (duodenal atresia)
• Choroid plexus papilloma Fetal markers
• Decreased interorbital distance • Nuchal thickness of 57-73% 5%
• Pyelectasia > 4mm on
• Short femur ultrasound.
• Clinodactly
• Macroglossia
• Absent nasal bone (8-12 weeks) SCREENING – SECOND TRIMESTER
• Echogenic bowel
• Echogenic spot in the heart Maternal serum Cut-off value (MoM) Predictive False
FETAL ECHOCARDIOGRAPHY markers value positive
• Atrioventricular canal defects
• AFP ↓ 0.5
FISH • hCG ↑ 2.5 Triple 69% 5%
• Fetal cells in maternal circulation • E3 ↓ 0.5
• Inhibin A ↑ 1.9 Quadruple 76% 5%

be done for Down syndrome during pregnancy taking

into account factors like maternal age and the levels of INTEGRATED FIRST AND SECOND
some biochemical markers in maternal blood. Methods of TRIMESTER SCREENING
prenatal diagnosis in Down syndrome are summarized
in Table 18.2.4. 1st Trimester
• PAPP-A
Screening Tests • Free βhCG 85%
• Nuchal translucency
It is observed that pregnancy associated with Down
syndrome has low AFP (α-feto protein), low UE3 2nd Trimester 94%
• MSAFP↓ 69%
(unconjugated estriol) and high hCG (human chorionic
• E3↓
gonadotrophin) during second trimester. If all the • hCG↑ 76%
3 markers are included, the so called triple test detects • Inhibin↑
60 percent of all Down syndrome pregnancies. Recently
(percentage indicates accuracy of predicition)
elevated levels of inhibin during second trimester is also
996 IAP Textbook of Pediatrics
integrated test is called integrated test of second trimester,
which has a detection rate of 94 percent. Serum integrated
test is a variant of the integrated test using serum
biochemical markers only (PAPP-A in first trimester and
quadruple test in second trimester). This test is being
evaluated.
For screening Down syndrome associated pregnancies,
there has been a recent interest in ultrasound markers
during second trimester of pregnancy that include choroid
plexus papilloma, atrioventricular canal defect, short
femur, duodenal atresia, pyelectasia, hyper echoic bowel,
etc. For ultrasonographic evaluation exact gestational age
assessment is required.
Confirmatory Test
Chorionic Villus Sampling
This procedure is done between 8 to 11 weeks of gestation
under ultrasound guidance either by transcervical or by
transabdominal aspiration of chorionic villi.
Chromosomal analysis can be directly done on the
specimen obtained, as these cells are dividing and the
results will be obtained within 24 hours. The sample can
be used for FISH technique to detect Down syndrome.
Sometimes chromosome analysis is done after a short term
culture for 2 to 3 days. The advantage of chorionic villi
biopsy is early results and early termination of pregnancy
if Down syndrome is confirmed. The procedure associated
risk of pregnancy loss is around 2 to 3 percent.
Fetal Umbilical Blood Sampling
This is done at 18 to 20 weeks of gestation and the fetal
blood cells obtained are subjected to chromosomal culture.
The results will be available within a week. By FISH
technique results can be obtained within few hours.
Fetal Cells in Maternal Circulation
It is recently observed that fetal cells are present in the
maternal circulation in the first trimester. These cells can
be separated by special techniques like flow cytometry
and used for chromosomal analysis using FISH and PCR.
Fetal DNA in Maternal Plasma
Recently it has been possible to get fetal DNA in maternal
plasma in the first trimester, that is used for molecular
diagnosis of Down syndrome.
Amniocentesis
The conventional amniocentesis done at 14 to 16 weeks of
gestation involves the aspiration of 10 to 20 ml of amniotic
fluid through the abdominal wall under ultrasound
guidance using no. 20 G needle. The sample is centrifuged
to yield a pellet of cells and supernatant fluid. In Down
syndrome, AFP levels will be low in amniotic fluid. The
cell pellet is cultured for about 2 to 3 weeks to obtain
sufficient cells for chromosomal study. Uncultured cells
can be used for FISH. The procedure of amniocentesis is
associated with 0.5 to 1 percent risk of miscarriage. Recent
trials of early amniocentesis at 12 to 14 weeks have yielded
comparable result.
Counseling
A parent of a child with Down syndrome should be
counseled with tact, compassion and truthfulness. The
parents should be told about the associated problems and
the importance of early stimulation should be highlighted.
The risk of recurrence should be clearly told to the parents.
The risk of Down syndrome increases with maternal age,
the risk at 20 years of age is 1:1528, at 30 years it is 1:909,
35 years it is 1:384 and 45 years it is 1:28.
The risk of Down syndrome in relation to maternal
age found at amniocentesis is 3.9 per 100 at 35 years of
age and 44.2 per 100 at 45 years of age. The risk of
translocation Down syndrome in subsequent live births
is given in Table 18.2.5.
TABLE 18.2.5: Translocation Down syndrome: Risk in
subsequent live births
Types of Parent carrying balanced Risk to
translocation Translocation offspring (%)
14/21 Mother 10
Father 2.5
Neither parent <1
21/21 100
Health Supervision
In the Table 18.2.6 enumerates the health supervision
guidelines put forth by the American Academy of
Pediatrics.
TURNER SYNDROME
Turner syndrome was first described in 1938 by Dr Henry
Turner and subsequently became the first disorder
recognized to have a chromosomal basis.
 TABLE 18.2.6: Health supervision for children with down syndrome–committee on genetics

Prenatal Infancy, 1 Month to 1 year Early childhood, 1 to 5 years Late Childhood, Adolescence,
5 to 13 years 13 to 21 years
Neonatal 2 months 4 months 6 months 9 months 12 months 15 months 18 months 24 months 3 years 4 years
Annual Annual
Diagnosis
Karyotype review† • •
Phenotype review • •
Recurrence risk • •
Anticipatory guidance
Early intervention services • • • • • • • • • • •
Reproductive options •‡ •‡ •‡ • •
Family support • • • • • • • • • • • • • •
Support groups • • • •
Long-term planning • • •§ •§
Sexuality • •
Medical evaluation
Growth 0 0 0 0 0 0 0 0 0 0 0 0 0
Thyroid screening 0¶ 0 0 0 0 0 0 0
Hearing screening 0 S/0 S/0 S/0 S/0 S/0‡ S/0‡ S/0‡ S/0‡ S/0§ S/0
Vision screening S/0 S/0‡ S/0 S/0 S/0‡ S/0 S/0‡ S/0 S/0 S/0 # S/0
Cervical spine roentgenogram 0**
Echocardiogram • 0
CBC 0 0
Psychosocial
Development and behavioral S/0S/0 S/0 S/0 S/0 S/0 S/0 S/0 S/0 S/0 S/0 S/0 S/0 S/0
School perfomance 0 0 0 0 0
Socialization S S S

* Assure compliance with the American Academy of Pediatrics “Recommendations for Preventive Pediatric Health Care”
• - to be performed; S - subjective, by history; and 0 - objective, by a standard testing method
† Or at time diagnosis
‡ Discuss referral to specialist
§ Give once in this age group
¶ According to state law
# As needed
Genetics
997
998 IAP Textbook of Pediatrics

Etiology TABLE 18.2.8: Clinical features of Turner syndrome

The incidence is approximately 1 in 2500 female live births Typical features
and parental age has no effect on the incidence. Although • Short stature
• Webbed neck
60 percent of patients with Turner syndrome have a 45X • Lymphedema in infancy
karyotype, a variety of chromosomal abnormalities are • Low posterior hair line
seen with the syndrome (Table 18.2.7). • Cubitus valgus
• Gonadal dysgenesis
Craniofacial anomalies
TABLE 18.2.7: Chromosome abnormalities in Tuner syndrome
• Triangular face
1. 45X 60 percent • Antimongoloid eye slant
2. Mosaic XX/X 15 percent • Ptosis
3. Isochromosome Xq or Xp 10 percent • High arched palate
• Multiple naevi
4. 46 X del(X) 5 percent
• Convex nails
5. 46 X ring (X) 5 percent
• Broad chest, widely placed nipples
6. With Y chromosome 5 percent • Scoliosis
• Deafness
• Horse-shoe kidneys
It usually arises from mitotic rather than meiotic error • Urinary tract infection
and is not associated with an increase of recurrence in • Glucose intolerance
further pregnancies. The X-chromosome is maternal in • Skeletal dysgenesis
origin in 76 percent and paternal in 24 percent. The Cardiovascular system 1/3 cases
• Bicuspid aortic valve (50%)
presence of XY cell line in mosaic Turner syndrome may • Coarctation of aorta (20-50%)
be associated with virilization at birth and again at puberty • Mitral valve prolapse
and 20 percent risk of gonadoblastoma. • Dissecting aortic aneurysm
• Idiopathic hypertension
Clinical Features (Table 18.2.8) Others
• Variable psychomotor development
The clinical features depend on chromosome constitution • Defects in spatial perception
of the individuals. The patients with 45X Turner syndrome • Perceptual motor organization and fine motor skills
At birth
(classical Turner syndrome) show many characteristic
• Lymphedema especially in the dorsum of hand
somatic abnormalities. However, short stature and streak • Redundant skin over the back of neck
ovaries are constant findings irrespective of chromosomal • Hydrops and cystic hygroma are seen in utero
constitutions. Puberty
• Primary amenorrhea
At birth : The newborn may present with lymphedema
• Failure of secondary sexual development
especially in the dorsum of the hands and feet and there • Streak gonads
may be redundant skin over the back of the neck. Hydrops • Almost invariably sterile females
and cystic hygroma are seen in utero and may occasionally
be present in the neonate.
Childhood (Fig. 18.2.7): In childhood, Turner syndrome
may present with short stature, short webbed neck with
low posterior hairline, shield shaped chest and widely
spaced nipples, cubitus valgus, pigmentary naevi, cardiac
anomalies like coarctation of the aorta, around 60 percent
will have renal tract abnormalities (horse shoe kidneys
and duplex ureters), mental development is normal.

Puberty

At puberty, Turner syndrome may present for the first time

with primary amenorrhea and failure of secondary sexual
development. Streak gonads are found with ultrasound Figure 18.2.7: Turner syndrome—Short stature and cubitus valgus
 Genetics 999

and at laparotomy. The patients are almost invariably
sterile, but menstruation and secondary sexual development
may be induced by estrogen replacement. Girls with Turner
syndrome have a normal life span. Hypertension and
osteoporosis may be complications in adult life.
Diagnosis
In the past Turner syndrome was diagnosed solely by
buccal smear analysis, this technique is not always reliable,
therefore chromosome analysis with full banding should
be done.
Treatment
Health supervision for Turner syndrome is given in Table
18.2.9. Cyclic estrogen and progesterone therapy in
phenotypic female at postpubertal age will improve
physical development, induce regular menstrual cycles
thus have great psychological benefit. Several attempts
are made to accelerate the growth rate and increase the
adult height of girls with Turner syndrome by use of
growth hormone, anabolic steroids and estrogens.
Oxandrolone (an anabolic steroid) in very low doses of
1.25 mg daily is helpful.
KLINEFELTER SYNDROME
This syndrome was first described by Klinefelter,
Reifenstein, and Albright in 1942 with characteristic
feature that become evident at adolescence (Table 18.2.10).
Etiology
Approximately 1 in 1000 newborn males has a 47 XXY
Karyotype and an additional1.2 per 10,000 show 46 XY/
47 XXY mosaicism. The extra X is maternal in origin in 67
percent and paternal in 33 percent. Advanced maternal
age results in increased meiotic nondisjunction resulting
in Klinefelter syndrome. The classical Klinefelter syndrome
has 47 XXY chromosomal constitution. In the so called
“Variant Klinefelter syndrome” there are multiple X-
chromosomes or mosaicism. The greater the number of
chromosomes from XXY to XXXXY, the more severe the
mental retardation and other clinical features.

TABLE 18.2.9: Health supervision for Turner syndrome

System Timing Clinical issue Intervention

Auditory At diagnosis and every 1-5 yrs Sensorineural deafness Hearing evaluation, audiology;
thereafter hearing aids

Childhood Recurrent otitis media Pressure equalizing tubes

Bones 10 yrs to adulthood Osteopenia; osteoporosis Vitamin D supplementation
Bisphosphonate therapy

Cardiovascular At diagnosis Congenital heart defects Cardiovascular evaluation

Dental 7yrs and older Malocclusion Orthodontic evaluation

Genetic At all ages Presence of Y chromosomal material Laproscopic gonadectomy to

prevent gonadoblastoma
Immune At diagnosis Thyroditis (hypo or hyperthyroid) Thyroid function test

Hepatic Every 1-2 yrs after 6 yrs of age Liver enzymes persistently elevated USG to evaluate for hepatic
steatosis; hepatology consult
Lymphatic Younger than 2 yrs Lymphedema Support stockings; decongestive
physiotherapy

Metabolic All ages Diabetes; obesity Annual fasting plasma glucose

screening, target body mass index

Skeletal 9 mths to adulthood Short stature hGH+/- oxandrolone

Ophthalmic At diagnosis Strabismus;hyperopia Ophthalmic evaluation

Renal At diagnosis Congenital malformation Renal USG

Reproductive Prepubertal Adulthood PubertyInfertility Estrogen therapy Assisted

reproduction or infertility consult
Adulthood Estrogen deficiency Female sex hormone replacement
1000 IAP Textbook of Pediatrics
TABLE 18.2.10 : Klinefelter syndrome (47 XXY-characteristics)
• Infertility (azoospermia or oligospermia)
• Small, firm testis
• Small phallus, cryptorchidism, hypospadiasis
• Hypergonadotropic hypogonadism
• Gynecomastia
• Tall (+10 cm on the average), slender body with long legs
• Osteoporosis
• Breast cancer
• High FSH, LH and low testosterone
• Motor delay or dysfunction
• Speech and language difficulties
• Attention deficits
• Learning disabilities
• Dyslexia
• Psychosocial or behavioural problems
Clinical Features (Fig. 18.2.8)
Patients with classical description with mental retar-
dation, hypogonadism and gynecomastia form only a
small minority of large spectrum. Most of the patients are
tall with eunuchoid proportions and long legs. They are
on an average 10 cm taller than XY males and have altered
body proportions with low upper-to-lower-segment ratio.
Figure 18.2.8: Klinefelter’s syndrome—Gynecomastia
and long limbs
The concentration of testosterone tends to be low. The
concentrations of serum estriol are normal or increased
and gonadotropin concentrations are elevated. Gyneco-
mastia occurs in 40 to 50 percent of the patients at puberty,
as a result of increased ratio of serum estriol to testosterone.
Breast cancer occurs in approximately 4 percent of the
patients, an incidence 20 times higher than in normal
males.
Small testes, phallus, cryptorchidism and hypostasis
occur in some patients. azoospermia and infertility are
common.
Most patients have psychiatric and behavioral
disorders. Affected children may be immature, excessively
shy, anxious and aggressive and may engage in antisocial
acts.
Increased incidence of pulmonary disease, varicose
veins, diabetes in Klinefelter syndrome is known.
Extragonadal germcell tumors especially of the media-
stinum and cerebral germinomas also occur with higher
frequency.
Diagnosis
The diagnosis should be suspected in prepubertal
children who have long legs, smaller than normal testes,
small phallus, learning disorders, delay in language
development. Mental retardation or psychosocial behavior
problems. Diagnosis of the syndrome in patients after
puberty is not difficult, by the findings of the typical
phenotype of tall stature; incomplete virillization, small
firm testes, and elevated serum gonadotropin concen-
trations. The diagnosis can be confirmed by the finding of
the 47, XXY karyotype. Testicular biopsy after puberty
reveals hyalinization of seminiferous tubules, adeno-
matous clumping of Leydig cells and azoospermia.
Treatment
It has been suggested that treatment with testosterone
should be stated by 11 to 12 years of age to initiate puberty
and prevent physical and psychological complications of
hypogonadism. At the same time this would prevent
excessive adult height. Psychologically disturbing or
persisting gynecomastia should be corrected by reduction
mammoplasty. Early intervention for learning and
behavioral disorders may be beneficial.
• Testosterone therapy: it has been suggested that
treatment with testosterone should be started by 11 –
12 years of age to initiate puberty and prevent physical
and psychosocial complications of hypogonadism.

Treatment could be started with 50mg of testosterone
enanthate IM monthly and when the bone age is 11 or
12, increasing to 100mg IM; when bone age is
14 increases the dose to 200-250mg every three to four
weeks, when full virilization is desired or when
growth is ending.
• Speech therapy: to develop skills in understanding
and production of complex language. Early inter-
vention for learning and behavioral disorders may be
beneficial.
• Physical therapy: in boys who are hypotonic or having
delayed motor skills.
• Occupational therapy: if boys with 47 XXY have fine
motor dyspraxia, occupational therapy is indicated.
• Educational services: males with 47 XXY should
receive a comprehensive psycho educational eva-
luation to assess their areas of strengths and
weaknesses.
FRAGILE X SYNDROME
Fragile X syndrome has the unique distinction of being
both the most common inherited cause of learning
difficulties and the first disorder in which a dynamic
mutation was identified. Martin and Bell described the
condition in 1940s before the chromosome era, and it has
been also called Martin-Bell syndrome, which has an
incidence rate of 1 in 5000 males and accounts for 4-8% of
all males with learning difficulties.
Etiology
The term fragile X syndrome derives from the presence of
a fragile site expressed as a isochromatid gap in the
metaphase chromosome at map position Xq 27.3 on the
distal portion of the long arm of X-chromosome in a
proportion of cells of affected individual.
The gene was designated FMR-1 for fragile X mental
retardation. The DNA segments show a peculiar stretch
of trinucleotide repeats in the FMR 1 gene that increase
the size of the specific DNA fragment of the X-chromosome
in Xq 27.3; a trinucleotide sequence (cytosine, guanine,
guanine = CGG) repeated a number of times. In normal
individual the repeat copies range from as low as 6 to as
high as 45 (Fig. 18.2.9).
In the members of families affected with the fragile X
syndrome, there are two types of mutations:
(i) Premutation; (ii) Full mutation.
Genetics 1001
Figure 18.2.9: Fragile site on X-chromosome has CGG repeats
more than 230 and normal X has 6 to 52 CGG repeats
Premutation
Members with trinucleotide repeat copies ranging between
50 to 230 have no phenotypic effect and no intellectual
impairment, and the mutations are termed premutations.
These are fragile X carriers and may produce children or
grandchildren affected with the syndrome. Premutations
may become full mutations after oogenesis, although
premutations may also remain as premutations in some
offsprings. The daughters of transmitting males (normal
males with a premutation) always inherit approximately
the same number of CGG repeats as found in the fathers.
There may be some variations in the number of repeats,
but the number remains in the premutation range, less
than 230.
In daughters of transmitting males, amplification of
the premutation to a full mutation occurs much more
frequently, resulting in a risk of 74 percent in grandsons
produced by the daughters of normal transmitting males.
Full Mutation
In members affected with the fragile X syndrome, the
trinucleotide repeat is expanded, so that many hundreds
of copies are present, more than 230 copies, and this
mutation is called full mutation. Only approximately
53 percent of females with the full mutation are mentally
impaired. In general the expression of phenotypic
manifestation is less severe in females, in keeping with
the X-linked dominant inheritance. This is probably
related to females having a functional allele on their
nonfragile X-chromosome.
The FMFR-1 gene is expressed in many tissues, the
brain showing the highest levels of expression, in addition
1002 IAP Textbook of Pediatrics

to the heart, lymphocytes, testis, uterus, and placenta, but Diagnosis

it is not expressed in liver, lung, kidney, muscle or pancreas.
Clinical Features (Fig. 18.2.10)
In the fragile X syndrome, 20 percent of the males (normal
transmitting males) and about 50 to 65 percent of
heterozygote females have no obvious features. Eighty
percent of the males and 35 percent of the female carriers
of the fragile X gene are developmentally delayed. The IQ
of the males is between 30 and 55 and sometimes extends
into the mildly retarded, borderline normal range.
The possibility of fragile X syndrome should be suspected
in males and females with mental retardation and the
phenotypic changes and the diagnosis confirmed by DNA
testing. DNA testing has replaced cytogenetic fragile X
testing as the diagnostic method. For cytogenetic
demonstration of fragile site on longarm of X –chromo-
some (Figs 18.2.11 and 18.2.12), the cells have to be cultured
in folic acid deficient media. Cytogenesis demonstration
of fragile site even with this technique is only 50 percent
and large number of cells have to be examined for
demonstration of fragile site which is time consuming.
DNA testing can distinguish, in a single test, between
the normal genotype, the premutation, and the full
mutation. Candidates for testing for fragile X syndrome
include familial mental retardation specially when two
males are affected, prepubertal children with overgrowth,
developmental delay, autism, hyperactivity, hand

Figure 18.2.10: Plain karyotype picture showing fragile site

on long arm of X chromosome.

The characteristic features of fragile X syndrome

are outlined in the Table 18.2.11.

TABLE 18.2.11: Fragile X-characteristics

1. Growth - Overgrowth postnatally
2. Craniofacial - Large ears, Prominent forehead, Long
face-Prominent jaw, Macrocephaly
palate, High-arched palate
3. Neurologic - Mental retardation
4. Behavioral - Temper tantrum, Hyperactivity, Autism,
Extreme shyness
5. Others - Joint looseness, Pes planus, Soft skin,
Mitral value prolapse.
6. Genitalia - Macroorchidism (males) after puberty
7. Inheritance - X linked with premutations and full
Figure 18.2.11 Electron microscopic view of
mutations.
the fragile site on Xq.

Figure 18.2.12: Cat cry syndrome
clapping, temperamental outbursts, extreme shyness, even
in the absence of other physical features or family history.
Treatment
No treatment is known, except for supportive measures
for the psychological and behavioral disorders. No
treatment is usually needed for the overgrowth.
5p- (CRI-DU-CHAT SYNDROME)
Cri-du-chat syndrome is one of the most common
chromosomal deletion syndromes, with an estimated
incidence of 1 in 50,000 births. About 70 percent of the
affected newborns are females, but the survival rate
appears to be better for males than females.
The syndrome derives its name from the striking cat
like cry that is heard in infancy. This cry is related to the
hyperplastic larynx and tends to lessen with increasing
age and growth of the larynx.
The clinical features in cri-du-chat syndrome are :
1. General – low birth weight, mental retardation, cat-
like cry.
2. Craniofacies (Fig. 18.2.12) microcephaly, round face,
hypertelorism, epicanthus, antimongoloid palpebral
fissure, microphthalmia, low set malformed ears,
preauricular tags.
3. Thorax - congenital heart disease (occasional).
Genetics 1003
4. Pelvis and abdomen-inguinal hernia, diastasis recti,
small iliac winds.
5. Hands and feet-short metacarpals or metatarsals,
partial syndactyly, pes planus, simian crease.
SINGLE GENE DISORDERS
MARFAN SYNDROME
Marfan syndrome is an autosomal dominant (sporadic in
15-30 percent) disorder with complete penetrance but
variable expressivity and with an incidence of 1 in 10,000
people.
Clinical Manifestations (Fig. 18.2.13)
The diagnosis of Marfan syndrome is made on the overall
pattern of malformations (typically skeletal, cardiovascular
and ocular; Table 18.2.12).
Figure 18.2.13: Marfan syndrome—arachnodactyly
For the proband, diagnosis requires the presence of
major criteria in at least two organ systems and
involvement of a third organ system. For a family member,
diagnosis requires the presence of one major criterion in
the family history and one major criterion in an organ
system and involvement of a second organ system.
Diagnosis
1. If the family and genetic history are not contributory,
then there should be a major criteria in at least 2
different organ systems and involvement of a third
organ system.
2. Diagnosis in the presence of an affected 1st degree
relative requires involvement of two systems with
preferably one major.
1004 IAP Textbook of Pediatrics

TABLE 18.2.12 : Features of Marfan syndrome

Major criteria Minor criteria

SKELETAL SYSTEM
Two components of the major
criterion or one component of
the major criterion+two of the
minor criteria must be present.
Pectus carinatum, Pectus excavatum requiring
surgery, Reduced upper-to-lower segment
ratio or arm span-to-height ratio >1.05,
Positive wrist and thumb sign
Scoliosis of >20° or Spondylolithesis
Reduced extension of the elbows
Medial displacement of the medial malleolus
causing pes planus.
Pectus excavatum of moderate severity,
Joint hyper mobility
Highly arched palate with dental crowding,
Facial appearance (dolichocephaly, malar
hypoplasia, enophthalmos, retrognathia, and
down slanting palpebral fissures.)

OCULAR SYSTEM Ectopia lentis Abnormally flat cornea

The major criterion or at least Increased axial length of globe
two of the minor criterion must Hypoplastic iris or Hypoplastic ciliary muscle
be present. causing decreased miosis.

PULMONARY SYSTEM
One of the minor criteria must None Spontaneous pneumothorax
be present Apical blebs (on CXR)

SKIN AND INTEGUMENT

The major criterion or one of Lumbosacral dural ectasia (by CT Scan or MRI) Stretch marks
the minor criteria must be Recurrent or incisional hernia.
present.

FAMILY HISTORY
One of the major criteria must Having a parent, child, or sibling with either:
be present. Presence of a mutation in FBN1 known to cause
Marfan’s syndrome or Presence of a haplotype
around FBN1, inherited by descent, known to
be associated with Marfan’s syndrome in the
family.

Etiology Children with Marfan syndrome should avoid com-

The basic defect in Marfan syndrome has now been traced
to a defective fibrillin in gene mapped to chromosome
15 (15q 21.1). Fibrillin is a recently discovered connective
tissue protein found in micro fibrils, a constituent of elastic
tissue and abundant in tissues affected in Marfan
syndrome, including the aorta, suspensory ligament of
the lens, and periosteum.
Treatment
Therapy for Marfan syndrome focuses on prevention of
complications and genetic counseling. The pediatrician
in consultation with the pediatric sub specialists should
coordinate and formulate rational approach to expectant
monitoring of potential complications. Use of blockers
reduce and postpone cardiac complications like aortic root
dissection and arrhythmias specially during pregnancies.
petitive sports.
Tuberous Sclerosis Complex (TSC) (Fig. 18.2.14)
(Syn: Epiloia or Bourneville’s Disease)
Tuberous sclerosis (TSC) is a type of neurocutaneous
syndrome, inherited as an autosomal dominant disorder
and involves multiple organs (brain, skin, kidney, eyes
and heart). The prevalence of TSC is 1:1000. The lesions in
this syndrome are caused by hamartomas and hamartias.
The major manifestation of this disorder includes skin
lesion (95%), mental retardation (50%), autism, seizures
(85%) (myoclonus in children), kidney diseases (60%) and
rarely cerebral giant cell astrocytoma. Mental retardation,
epilepsy and adenoma sebaceum were earlier considered
as triad of tuberous sclerosis.

Figure 18.2.14: Tuberous sclerosis—Note
adenoma sebaceum
The unique skin lesions and cranial MRI charac-
teristics are most helpful for confirming diagnosis. For
definite diagnosis of TSC patient should have 2 of 11 major
features. Genetic blood tests for the two genes TSC1 and
TSC2 which cause the disease are also available but in 30
percent of patients the test results are negative.
Major Criteria
1. Facial angiofibromas or forehead plaque. Facial
angiofibromas originally misnamed as adenoma
sebaceum distributed usually over malar area are the
classical lesions of TSC and occur in 50 percent of
cases. They make their appearance around 4 years of
age. Forehead plaques are darker than surrounding
skin and appear very early in infancy.
2. Nontraumatic ungal fibroma. They are flesh colored
angiofibromas.
3. There are many hypomelanotic macules. These are
present in nearly 90 percent of cases that occur over
face, trunk and extremities. The size varies from 0.5
to 2 cm and is pale and has ash leaf shape. They are
usually present at birth and are better appreciated
with ultraviolet woods light in fair skinned people.
4. Shagreen patch. These are usually present over lower
back often appearing after two years and are
characterized by flesh colored or slightly darker of
redder elevated lesions with surface of an orange peel.
Genetics 1005
5. Multiple retinal nodular hamartomas.
6. Cortical tubers (dysplasia plus migrating tracts count
as one features). These are seen both in cerebrum and
cerebellum. These are some times the source of seizure
activity and can be detected by MRI.
7. Subependymal nodules. They are present in more
than 80 percent of TSC patients and are commonly
calcified. MRI is superior to CT scan in detecting
cortical tubers, subependymal nodules and migration
tracts.
8. Subependymal giant cell astrocytoma.
9. Cardiac rhabdomyoma (single or multiple). These are
usually asymptomatic but may cause obstruction to
flow through the heart, CCF, arrhythmias including
WPW syndrome and sudden death. They are seen in
infancy.
10. Lymphangiomyomatosis usually in lungs.
11. Renal angiomyolipoma (when both lymphangio-
myomatiosis and renal angiomyolipomas are present,
they count as one feature). Renal involvement is seen
in 60 percent of TSC patients and includes renal cysts,
angiomyolipomas and rarely renal cell carcinoma.
Renal diseases leading cause of death in TSC.
Minor Diagnostic Features Include
1. Multiple dental pits.
2. Hamartomatous rectal polyp (histologic confirmation
is needed)
3. Bone cyst (radiographic diagnosis is sufficient)
4. Cerebral white matter radial migratory lines.
5. Gingival fibroma.
6. Non-renal hamartoma.
7. Retinal chromic patch.
8. “Confetti” skin lesions.
9. Multiple renal cyst.
Probable TSC include one major plus one minor feature
and possible TSC include one major or two or more minor
features.
The patients with TSC should be thoroughly evaluated
by careful history including family history, skin
examination, ophthalmic examination for a retinal
hamartoma, renal ultrasound for renal lesions and
echocardiography to detect rhabdomyoma below 2 years
(after that period they regress with age), neurodevelop-
ment testing for cortical tubers, subependymal giant cell
astrocytoma and hydrocephalus due to obstruction of
foramen of Monro due to tubers.
1006 IAP Textbook of Pediatrics
Management of TS comprises treatment of seizures,
educational programs for mental retardation and autism
and pharmacological treatment of seizures. Facial
angiogfibromas may require laser therapy. Surgical
treatment is indicated for giant cell astrocytoma and renal
angiomyolipoma.
Contrary to earlier understanding, the disorder is
caused by 2 distinct genes, TSC-1 and TSC-2. TSC-1 gene
is localized to chromosome 9 and produces a protein
hamartin. TSC-2 is localized to chromosome 16 and
produces a protein tuberin. Both hamartin from TSC-1 and
tuberin from TSC-2 are thought to function at least in part
as tumor suppressor gene by which they regulate cell
growth and development. The disease is inherited as
autosomal dominant trait and most cases occur as
sporadic mutations. Variability in expression is seen
between cases and even within family like in many other
autosomal dominant disorders. Clinical differences
between TSC-1 and TSC-2 are now being recognized but
they are typically differences of degree and not of character.
Neurofibromatosis
Neurofibromatosis is one of the commonest neuro-
cutaneous syndromes inherited as an autosomal
dominant disorder with variable expression. It is
historically associated with the name von Recklinghausen,
a German Pathologist who coined the term ‘neurofibroma’
in 1882. There are two main types of neurofibromatosis
known as NF-1 and NF-2. NF-1 has an incidence of
approximately 1 in 3000 and NF-2 has an incidence of 1
in 35,000.
The diagnostic suspicion of NF-1 is usually raised by
the presence of multiple cafe-au-lait spots, the hallmark of
NF-1. They are named as such because of its color, similar
to coffee with milk. Occasionally, facial malformation
caused by bone dysplasia and impaired vision from optic
nerve glioma brings the child to medical attention.
The diagnosis of NF-1 requires two or more of the
following diagnostic features.
1. Six or more cafe-au-lait spots 1.5 cm or larger in
postpubertal individuals and 0.5 cm or larger in
prepubertal children. These are macular lesions with
irregular border seen over trunk, face and body.
2. Two or more neurofibromas of any type or more
plexiform neurofibromas. Neurofibromas arise from
peripheral nerve sheath. They are rare in young
children but increase in number with advancing age.
They have no malignant potential. Plexiform
neurofibromas have ill defined borders and are diffuse
and highly vascular and do not follow tissue plane.
Skin over the lesions is pigmented and hairy. A small
percentage (1-4 percent) of plexiform neurofibromas
may turn malignant.
3. Freckling in the axillary or inguinal region. They
develop in early childhood and by 5 years 84 percent
have them.
4. Optic nerve glioma (optic pathway tumor). Decreased
visual acuity, optic pallor or atrophy, visual field
defects, proptosis, restricted eye movements,
hypothalamic dysfunction and headache are the
clinical manifestations of these slow growing low
grade astrocytomas of optic nerve.
5. Two or more Lisch nodules (iris hamartomas). These
are benign iris hamartomas visible usually by slit lamp
examination. They are uncommon in young children
but by 10 years, 70 percent of children and 95 percent
of adults will have them.
6. A distinctive osseous lesion, such as dysplasia of the
sphenoid bone and dysplasia or thinning of long bone
cortex (pseudoarthroses).
7. A first degree relative with NF-1 according to the
preceding criteria.
Absence of cafe-au-lait spots, axillary freckling,
cutaneous neurofibromas and Lisch nodules by 5 years,
for all practical purposes excludes the diagnosis of NF-1.
Genetic tests are available but have a high false negative
rate.
Epilepsy, macrocephaly, short stature, scoliosis,
glaucoma, stroke, mental retardation and cognitive
problems are other complications in NF-1. Neuro imaging
studies are not important in the diagnosis of NF-1 but are
used for monitoring complications.
There is only one gene that causes NF-1. Most NF-1
mutation causes premature truncation of the neurofi-
bromin protein. The NF-1 gene product, neurofibromin is
thought to function as a tumor suppressor.
The management of NF-1 mainly consists in evalu-
ation for complications like focal neurological dys-
function, abnormal puberty, optic pathway trauma,
scoliosis, cognitive/learning problems, hypertension and
surveillance of plexiform neurofibromas for malignant
transformation and their appropriate treatment.
In NF-2 both cafe au lait spots and neurofibromata
can occur but these are less common than in NF-1. The
most characteristic feature of NF-2 is the development in

early adult life of tumors involving 8th cranial nerves.
These used to be called acoustic neuromas and are now
known as vestibular schwannomas.
ACHONDROPLASIA
Achondroplasia occurs in about 1 in 25,000 births and is
inherited as an autosomal dominant trait. About 50 percent
of cases represent new mutations.
This disorder is due to a specific point mutation in
Fibroblast Growth Factor Receptor 3 (FGFR3) gene. The
mutations in the same gene produce two other short limb
dwarfs, viz. Thanatophoric Dwarf (a lethal severe short
limb dwarf with gross craniofacial abnormalities) and
Hypochondroplasia (a very mild benign short limb dwarf
with no craniofacial abnormalities).
Clinical Manifestations (Fig. 18.2.15)
The clinical manifestations include rhizomelic shortening
of the limbs, short stature, frontal bossing, depressed nasal
bridge, large head size, short and broad trident shaped
hands, spinal abnormalities like lumbar lordosis,
hypotonia, delayed motor development, mental develop-
ment is usually normal.
Complications include hydrocephalus, recurrent otitis
media, and chronic serous otitis media, leading to a high
incidence of conductive hearing loss in adulthood, lumbar
cord and nerve root compression syndromes.
Figure 18.2.15: Achondroplasia
Genetics 1007
Roentgenographic Manifestations
Short pelvis with broad iliac wings; horizontal acetabular
roofs; diminished vertebral interpedicular distance from
LI to L5; spinal canal is narrowed; anterior tonguing and
wedging of lower thoracic or upper lumbar vertebrae;
posterior scalloping of the lumbar vertebrae; the base of
the skull is shortened; foramen magnum is small and
irregular; the metaphyses have some flaring and may
appear V-shaped (circumflex sign); the short tubular bones
of the hands and feet are shorter and wider than normal;
the chest has a decreased anterioposterior diameter, with
anterior cupping of the ribs.
Health Supervision
The following table enumerates the guidelines for
supervision of children with achondroplasia, as stated
by the American Academy of Pediatrics (Table 18.2.13).
Treatment
i. Prompt recognition and appropriate treatment of
complications,
ii. Treatment of the psychological effects of severe short
stature and unusual appearance,
iii. Genetic counseling.
Rett Syndrome
Rett syndrome is characterized by a period of normal
development in the first few months after birth followed
by loss of developmental milestones, failure of head
growth, autistic behavior, seizures and dementia. This
syndrome affects female children only. It was first
described by Austrian Doctor, Andreas Rett in 1966. The
diagnosis is essentially clinical and the course of the illness
passes through four predictable stages.
Stage 1 (Birth to 18 months)
Acquired microcephaly
Disinterest in surroundings
Hypotonia
Stage 2 (1-2 year)
Loss of expressive language
Regression of gross motor milestones
Characteristic hand movements (Hand washing
movements)
 1008

TABLE 18.2.13: Achondroplasia guidelines for health supervision

Prenatal Infancy, 1 Month to 1 year Early childhood, 1 to 5 y Late Childhood, Adolescence

Neonatal 2 mo 4 mo 6 mo 9 mo 12 mo 15 mo 18 mo 24 mo 3y 4y 5 to 13 y 13 to 21 y
Annual Annual
Diagnosis
Radiography Whenever the diagnosis is suspected
Review phenotype Whenever the diagnosis is suspected
Review proportions Whenever the diagnosis is suspected
Molecular testing [FGFR3] See text When diagnosis is not certain
Genetic counseling
IAP Textbook of Pediatrics

Early intervention X
Recurrent risks X X X
Reproductive options X X X
Family support X X X X X
Support groups X X X X X
Long-term planning X X X X
Medical evaluation
Growth/weight/OPC X X X X X X X X X X X
Orthopedic consult
Neurology consult
Hearing XR XR XR XR
Social readiness S S S S
Orthodontics R R R
Speech S/O S/O S/O S/O O O
Medical evaluation
Radiology, only to make
diagnosis or II
complication
CT/MRT brain/cervical X
Spine X As indicated → → → → → → → → → → →
Social adjustment
Psychosocial S S S S S
Behavior and development S/O S/O S/O S/O S/O S/O S/O S/O S/O S/O
School O O O
Sexuality X

These guidelines ensure compliance with AAP recommendations for preventive health care. FGFR3 indicates fibroblast growth factor recepitro type 3;X to be performed;
S subjects; b history; O objective, by a standard testing method; R diseases referral to a specialist; — continue to monitor.

Seizures (50%)
Irritability
Insomnia
Stage 3 (2-10 year)
Severe mental retardation
Stereotypic hand movements (wringing, patting,
clapping, tapping and mouthing)
Ataxia
Tremulousness
Breath holding spells
Stage 4 (> 10 years)
Scoliosis
Muscle wasting
Death in late adolescence from infection or cardiac
arrhythmia
Atypical presentations include onset from birth, late
onset, preservation of speech and hand skills and rare
occurrence in males.
The inheritance is X-linked dominant with lethality in
hemizygous males. The mutation is on MECP2 gene on
the long arm of X-chromosome. This mutation results in
shortage of MECP2 protein, which is required to recruit
other genes during early brain development. This results
in brain remaining developmentally immature in sensory,
motor, emotional and autonomic functions. Most
mutations are sporadic in nature. There are more than
100 mutations known in MECP2 gene. MECP2 mutation
can be detected by DNA test in more than 80 percent of
cases with clinical symptoms.
L-dopa has been tried for rigidity during motor
regression stage. Naltrexone, an opiate antagonist may
benefit irregular breathing, seizures and screaming spells.
Bromocriptine has shown some help in improving
communication and reducing agitation and hand
movements. L-carnitine tried in some patients showed
benefit in language skills. Dextromethorphan is being
studied because of its role in neurotransmitter mechanism.
POLYGENIC DISORDERS
Congenital Malformations
An anatomical defect that is present at birth is called as
congenital malformation.
Genetics 1009
A malformation is a morphologic defect of an organ,
part of an organ, or larger region of the body resulting
from an intrinsically abnormal developmental process;
Intrinsic means the developmental potential of the organ.
From fertilization the organ never had a chance to develop
normal form or structure.
When the congenital malformation has a major impact
on health, function, survival and cosmetic aspects it is
called as congenital malformation major (e.g. Neural tube
defects, congenital heart disease, cleft lip and palate) and
when it has no impact on health function, survival and
cosmetic aspects it is called congenital malformation
minor (e.g. epicanthic fold, single palmar crease,
clinodactyly). When multiple anomalies which are
pathogenetically related, occur in a single baby it is said
to be a malformation syndrome (e.g. Down syndrome,
Nail-patella syndrome, Marfan syndrome).
A disruption is a morphologic defect of an organ, part
of an organ, or a larger region of the body resulting from
the extrinsic breakdown or an interference with an
originally normal developmental process (e.g. Amniotic
band syndrome). In contrast to a malformation, the
developmental potential of the involved organ was
originally normal. Secondly, an extrinsic factor such as
an infection, teratogen, or trauma interfered with the
development which thereafter proceeded abnormally. By
definition, a disruption cannot be inherited. However,
inherited factors can predispose to and influence the
development of a disruption, e.g. Amniotic band syndrome.
A deformation is an abnormal form, shape, or position
of a part of the body caused by mechanical forces. The use
of the term deformation is restricted to aberrations of form
considered a normal response of the affected tissue to
unusual mechanical forces. These forces may be extrinsic
to the fetus (e.g. as a result of intrauterine constraint) or
intrinsic (such as fetal hypomobility caused by a nervous
system defect). An example of a prenatal deformation is
an equinovarus foot, which may result from extrinsic
compression of the fetus caused by oligohydramnios.
A dysplasia is an abnormal organization of cells into
tissue(s) and its morphologic result(s). In other words, a
dysplasia is the process and the consequence of
dyshistogenesis. Osteogenesis imperfecta and Marfan
syndrome are dysplasias because the abnormalities in
each condition can be reduced to a defect in connective
tissue. In contrast to malformations, disruptions and
deformities, dysplastic lesions are frequently not confined
to single organs.
1010 IAP Textbook of Pediatrics

Multiple anomalies in a given patient may be causally TABLE 18.2.14: Summary of human teratogens
or pathogenetically related, or occur together on a
Agents Most common major defects
statistical basis or by chance alone.
A polytopic field defect is a pattern of anomalies I Drugs
1. Thalidomide Limb reduction defects
derived from the disturbance of a single development field. Girdle hypoplasia
Dysmorphogenetically polytopic field defects represent Ear Anomalies
disturbances of long-distance inductive relationship as 2. Alcohol Growth retardation
between limb buds and meso and metanephros, gonads Reduced palpebral fissures
Microcephaly, mental retardation
and genitalia, circulation and cardiac morphogenesis, etc.
3. Diethystilbesterol Vaginal Adenosis
A sequence is a pattern of multiple anomalies derived Cervical erosion and ridges
from a single known or presumed prior anomaly or Adenocarcinoma of the vagina (rare)
mechanical factor. A malformation, a disruption, or a 4. Warfarin Hypoplasia of nasal cartilage
Various CNS defects
mechanical factor may give rise to a cascade of secondary
Stippled epiphyses
problems in subsequent morphogenesis. Thus, a myelo- 5. Hydantoin Growth retardation
meningocele may lead to lower limb paralysis, muscle (Dilantin) Dysmorphic craniofacial features
wasting, club-feet, incontinence, urinary tract infection Microcephaly, mental retardation
and renal damage, constipation and dilatation of the 6. Trimethadione Developmental delay
V-shaped eyebrows, low ears
bowel, etc. The pattern is called the myelomeningocele Cleft lip or palate
sequence. Other examples are Potter sequence, due to 7. Aminopterin and Abortion
oligohydramnios and Pierre Robin sequence due to methotrexate Hydrocephalus
maldevelopment of mandible. (Folic acid Growth retardation, mental
deficiency) retardation
An association is a nonrandom occurrence in two or
8. Antituberculous Hearing loss
more individuals of multiple anomalies not known to be a drugs (streptomycin)
polytopic field defect, sequence, or syndrome. It refers 9. Tetracycline Stained teeth
solely to statistically, not pathogenetically or causally Hypoplasias of enamel
related anomalies, e.g. VATER association (Vertebral 10. Valproic acid Neural tube defects
11. Retinoic acid Abortion
anomaly, anal atresia, tracheoesophageal fistula (TEF), (Vitamin A) Craniofacial dysmorphism
radial/renal dysplasia). 12. Lithium Neural tube defects
Ebstein heart anomaly
Incidence Other cardiac defects
13. Antithyroid drugs Hypothyroidism
Approximately 3 percent of newborn babies have Goiter
congenital malformations. The figure doubles at 5 years if II. Infections
these children are followed up. 1. Rubella Deafness, cataracts, heart defects
2. Cytomegalovirus Growth retardation, mental
retardation,
Etiology Hearing loss
3. Toxoplasmosis Hydrocephalus, blindness,
Etiological agents could be broadly divided into
mental retardation
4 categories-specific teratogenic agents (8-10%), mono- 4. Varicella Skin scarring, muscle atrophy,
genic (15-25%), chromosomal (15-28%) and unknown Mental retardation
(including multifactorial) (40-65%). A teratogen is an 5. Venezuelan Brain destruction, cataracts, death,
agent, when applied during prenatal life, produces a equine encephalitis
6. Syphilis Abnormal teeth and bones
permanent postnatal damage, change in morphology, or Mental retardation
functions. Such agents can be chemicals, drugs, virus or III. Chemicals
physical or deficiency states. Majority of the malformations 1. Mehylmercury Cerebral atrophy, Spasticity,
are due to complex involvement of genetic and environ- Seizures, Mental retardation,
2. PCP Growth retardation
mental factors. The summary of human teratogens is given
Skin discoloration
in Table 18.2.14.
Contd.
 Genetics 1011

Contd. DYSMORPHIC CHILD

IV. Physical, nutritional and other factors Approximately 1 percent of newborn infants have multiple
1. Smoking Abortion, Intrauterine growth anomalies or syndromes. Only 40 percent of these have
retardation
recognized syndromes and the remaining need to be
2. Ionizing radiation (Dependent on stage of pregnancy)
(exposures above Abortion further delineated. A syndrome literally means “running
the diagnostic Major organ malformations together” (a Greek word) and clinically indicates a
range) (18-36 d) constellation of malformations thought to be patho-
Microcephaly and mental genitically related.
retardation (8-15 weeks) Different systems of nomenclature are employed (Table
3. Diabetes Congenital heart defects
18.2.13), a single syndrome may be known by several
Caudal dysgenesis
4. Iodine deficiency Goiter, mental retardation, terms, thus causing confusion. For example, in past,
growth retardation William’s syndrome has also been known as William-
5. Maternal Abortion, microcephaly, Beuren syndrome, idiopathic hypercalcemia, supra-
phenylketonuria Mental retardation valvular aortic stenosis syndrome, and elfin facies
syndrome. In general, a syndrome may be denoted by (1)
The common life-threatening congenital anomalies are an eponym, (2) one or more striking features, (3) an
acronym, (4) a numeral, (5) a geographic term, or (6) some
listed in Table 18.2.15.
combination of the above. Examples are given in Table
Some simple procedures can be done to diagnose the
18.2.16.
common congenital anomalies in the neonatal period:
A proper approach begins with a careful history
• Not able to pass nasal catheter: suspect choanal atresia including personal, family and pregnancy history. A
• Not able to pass gastric catheter: suspect esophageal summary of important points in history is presented in
atresia Table 18.2.17.
• If not able to pass anal catheter, suspect anal atresia The physical recognition of genetic syndromes is done
• Positive Ortoloni’s test should clinch the diagnosis of either by (i) gestalt recognition, or by (ii) identifying suitable
congenital dislocation of hip handles.
• In case of absence of femoral arterial pulsation, suspect
coarctation of aorta. Gestalt Recognition
• In case of presence of single umbilical artery, one Individual malformation can be easily organized into a
should suspect GIT anomalies. meaningful problem without consciously analyzing the
• Presence of a tuft of hair in the lumbosacral region individual abnormalities. Recognition is immediate. For
indicates spina bifida occulta. instance, the diagnosis of Down syndrome is often
• Auscultate the heart for murmurs which suggests possible from the examination of craniofacial features
congenital heart disease. alone.

TABLE 18.2.15: Common life-threatening congenital anomalies

1. Choanal atresia Respiratory distress in labor room, inability to pass nasal tube. Suspect CHARGE syndrome
(coloboma, heart defect, atresia choane, retarded growth, genital abnormality, ear anomaly)
2. Tracheo-esophageal fistula Polyhydramnios, aspiration pneumonia, excessive salivation, inability to pass NG tube, suspect
VATER syndrome
3. Diaphragmatic hernia Scaphoid abdomen, bowels in chest, respiratory distress, cyanosis, apparent dextrocardia
4. Pierre Robin syndrome Micrognathia, cleft palate, airway obstruction
5. Intestinal obstruction Polyhydramnios
6. Duodenal atresia Bile stained vomiting, suspect Down’s syndrome
7. Ileal atresia Abdominal ditension
8. Omphalocele Polyhydramnios, intestinal obstruction
9. Neural tube defects Polyhydramnios
1012 IAP Textbook of Pediatrics

TABLE 18.2.16: Syndrome nomenclature

Basis of nomenclature Examples
Etiology α-L-iduronidase deficiency, 47, XXY syndrome, abused child syndrome
Pathogenesis Dumping syndrome
Striking feature Scalded skin syndrome, whistling face syndrome
Anatomic location Nail-patella syndrome, trichorhinophalangeal syndrome
Eponym Good pasture syndrome, Peutz Jeghers syndrome, Klippel-Trenaunay-Weber syndrome
Acronym Leopard syndrome, CREST syndrome
Patient’s name Cowden syndrome, BBB syndrome
Geographic location Typus Amstelodamensis
Numerical nomenclature MPS IV, type II achondrogenesis
Compound designations Hurler syndrome (α-L-iduro-nidase deficiency), Taybi oto-palato-digital syndrome
Mythical nomenclature Gargoyle syndrome, elfin facies syndrome
Animal nomenclature Cat-cry syndrome, bird-headed dwarf syndrome

TABLE 18.2.17: Important points in history taking

Questions Relevance
Personal/family history
1. Elderly mother ? chromosomal aneuploidy
2. Elderly father ? New autosomal dominant mutation
3. Maternal disease (e.g. diabetes) Known associated fetal abnormalities (e.g. sacral agenesis with maternal
diabetes)
4. Poor social history Possible alcohol/drug ingestion
5. Racial origin of parents Known genes of high frequency in certain racial groups (e.g. Ellis-van Creveld
syndrome in the Amish)
6. Parental consanguinity Autosomal recessive disorders
7. Other affected family members or multiple Single gene or chromosomal disorder. Possible maternal uterine abnormalities
malformations
Pregnancy history
8. Maternal drug or alcohol ingestion Teratogenic effects
9. Exposure to radiation (especially therapeutic) Possible mutagenic or teratogenic effects
10. Early rupture of membranes membranes Possible fetal compression leading to deformation
11. Oligohydramnios Renal agenesis or outflow obstruction
12. Polyhydramnios Esophageal atresia, neuro-muscular disorders
13. Poor fetal movements Fetal compression, neuro-muscular disorders
14. Breech presentation Neuromuscular disorders

Identification of Suitable Handles malformations). The Murdoch Institute, Royal Children

When immediate recognition is not possible, it is necessary
to identify one or more features (handles) which might
lead to syndrome diagnosis. Useful handles for the
diagnosis are given in Table 18.2.18.
Features like mental retardation, simian crease,
clinodactyly are nonspecific and act as poor handles for
syndrome delineation.
If one handle does not lead to a diagnosis then other
combinations should be tried. Once a suitable handle is
identified, reference should be made to standard mono-
grams on syndromology (e.g. Smith’s recognizable
patterns of human malformation edited by KL Jones, 1988,
WB Saunders, Philadelphia) or computer databases (i)
possum (pictures of standard syndromes and unusual
Hospital, Flemington Road, Parkville Victoria 3053,
Australia, (ii) London medical database, Institute of child
health, Great Ormond street hospital, London.
BIBLIOGRAPHY
1. American Academy of Pediatrics. Committee on Genetics.
American Academy of Pediatrics: Health supervision for
children with Down syndrome. Pediatrics. 2001
Feb;107(2):442-9.
2. Bhasin S, Ma K, Sinha I, Limbo M, Taylor WE, Salehian B.
Genetic basis of male infertility. Endocrine Metab Clin
North Am 1998;27:345-48.
3. Chiurazzi P, Neri G, Oostra BA.Understanding the
biological underpinning of Fragile X syndrome. Curr
Opin Pediatr 2003;15:559-66.
 Genetics 1013

TABLE 18.2.18: Useful handles in diagnosis of a syndrome 4. Conclusion of the 6th World Congress on Down
syndrome. In Rondal JA, (Ed): Down syndrome a review
Head Mouth Nails of current knowledge. (1st edn). Philadelphia. WB
Abnormal hair Cleft lip/palate Dystrophic Saunders 1998.
Scalp defects Absent or abnormal 5. Hersh JH; American Academy of Pediatrics Committee
Craniosynostosis teeth on Genetics. Health supervision for children with
Encephalocele neurofibromatosis. Pediatrics. 2008 Mar;121(3):633-42.
Microcephaly 6. HO NC, Tran JR, Bektas A. Marfan’s syndrome.Lancet.
Eyes Limbs Genitalia 2005 Dec 3;366(9501):1978-81.
7. Kandt RS. Tuberous sclerosis complex and NF typel: The
Coloboma Partial or total absence Micropenis
two most common neurocutaneous syndrome. Neur Clin
Small/absent eyes
Cataract Joint webbing N Am 2003;20:983-1004.
Short limbed dwarf 8. Sybert VP. Turner syndrome. N Eng J Med 2004;351:
1227-38.
Ears Digits Skin
9. Trotter TL, Hall JG; American Academy of Pediatrics
Deafness Syndactyly White pathches Committee on Genetics. Health supervision for children
Malformed pinna Polydactyly Pigmented with achondroplasia. Pediatrics. 2005 Sep;116(3):771-83.
patches 10. Visootsak J, Graham JM Jr. Klinefelter syndrome and
Preauricular tags Arachnodactyly
other sex chromosomal aneuploidies. Orphanet J Rare
Brachydactyly
Dis 2006 Oct 24;1:42.

18.3 New Genetics and Advances in Genetics

ML Kulkarni

INTRODUCTION Basics of DNA

The contribution of genetics to the understanding of
pediatric disease has increased dramatically over recent
years. The identification of disease genes and the
understanding of disease process at the molecular level,
have implications for screening, diagnosis and therapeutic
manipulation. Inevitably, complex ethical issues have
arisen from such a rapid rate of scientific progress and
society may not be prepared for the consequences of such
advances.
The term ‘New genetics’ was coined by Dr Coming DE
in the year 1980 shortly after, Dr Southern discovered the
method of detecting different sizes of fragments of DNA
produced by a technique known after his name “Southern
blot”.
Three important aspects of the subject are discussed
here: (i) Basics of DNA structure and function, (ii) Tools of
molecular genetics, (iii) Clinical application of molecular
genetics for the study of inherited diseases.
All genetic material (DNA) contained in a single germ cell
(sperm and ovum) is known as human genome, that
contains all the information of life. Therefore, each body
cell or somatic cell contains 2 sets of human genome. The
human genome contains about 3 billion base pairs which
is roughly the number of people on earth.
The noncoding stretch of DNA constitutes 95 percent
of the total DNA stretch of human genome and is often
referred to as ‘junk’, ‘redundant’ or ‘selfish’ DNA. (Fig.
18.3.1). The exact function of this large stretch of DNA is
still not known. The coding region of human genome is
called gene. The size of human genes varies considerably.
The Structure of DNA (Fig. 18.3.2)
DNA exists as a double stranded helix. The analogy of
‘rope ladder’ can be given for the structure of DNA. Each
side of the ladder is made up of chains of sugar(s) and
phosphates (P). The ‘step’ of the ladder is made up of
1014 IAP Textbook of Pediatrics

Figure 18.3.1: ABCDE = Genes (form only 5% of human genome, remaining is junk DNA, X = Pseudo-genes (structurally
similar to gene but does not code for protein

Figure 18.3.2: DNA structure


2 nitrogenous bases from 2 poles projecting inward and
the two bases are joined by hydrogen bond. The
nitrogenous bases consists of the purines (adenine A,
guanine-G), pyrimidines (cytosine-C, thymine-T). A
always pairs with T and G with C (complementary
pairing). The ‘rope ladder’ is twisted around its vertical
axis (helix formation).
Each pair of complementary nitrogenous base is
termed ‘a base pair’ (bp), e.g. AT, GC, TA, CG. The length
of DNA is expressed as base pairs. One thousand base
pairs make one kilobase (kb). A nucleotide is defined as a
unit consisting of phosphate, sugar and nitrogenous pair
(Fig. 18.3.2). The order of base on one single strand is
known as DNA sequence. The DNA is packaged in
chromosomes (Fig. 18.3.3).
Figure 18.3.3: DNA structure
Genetics 1015
Gene Structure
Genes are segments of DNA stretches and are transcribed
into RNA and later translated into proteins. The genes are
composed of exons (the coding region) and introns
(noncoding regions) in between exons (Fig. 18.3.4). At both
ends of the gene are some sequences which are important
in gene regulation. At the 5' end (in untranslated part), are
promoter regions like ‘TATA BOX’, CCAT BOX, enhancer,
sequences which are important in transcription, tissue
specific transcription, controlling quantity of RNA and
determining the start site for transcription and add ‘Cap’
to the 5' end of the RNA.
At the 3' end, the sequence AATTAA provides a signal
for polyadenylation of RNA (poly ‘A’ tail). Poly ‘A’ tail is
1016 IAP Textbook of Pediatrics

Figure 18.3.4: Structure of a gene

essential for the RNA to exit from the nucleus to cytoplasm

for translation.

How Genes Act?

One strand of structural gene DNA forms a template for
the synthesis of a form of RNA known as messenger RNA
(mRNA). This process is called transcription. In the nucleus,
introns are excised and exons are joined together and the
AATAAA sequences signal the addition of a series of A’s
(poly A tail) producing the processed mRNA that leaves
the nucleus to cytoplasm for translation (protein
synthesis). A triplet of bases called codon, codes for
synthesis of a particular amino acid. mRNA becomes the
template in the ribosome for translation. The initiation site
AUG is recognized and translation begins (Fig. 18.3.5). A
tRNA contains a codon (anticodon) complementary to
mRNA codon for the specific amino acid that the tRNA
carries. When tRNA finds a complementary codon on the
mRNA, the particular amino acid is added to the growing
peptide chain. The ribosome then moves to the next codon
in a 5" to 3" direction adding amino acids until a stop
codon is reached. Then, protein is released from the
ribosome and is used by the cell.

Mutations (Fig. 18.3.6)

Mutations are structural changes in a DNA sequence.
Types
Large Scale Mutations
They occur in chromosomes Figure 18.3.5: Gene action

For example: Gain/loss of chromosomal regions.
Translocations (switching of parts between two
chromosomes).
Small Scale Mutations
They include nucleotide base changes: For example:
Substitution,deletions and insertions.
There are different types of single base mutations that
can occur in coding regions of a DNA sequence.
Missense mutation: Mutation results in coding of a new
amino acid in place of the original (substitution) resulting
in an abnormal protein product.
Silent mutation: Mutation results in an abnormal codon
but the amino acid coded is the same as that of the original
codon.
Nonsense mutation: Mutation results in introduction of
a stop codon causing premature termination of protein
synthesis resulting in a truncated protein.
Frame shift mutations: Mutation causing single base
insertion or deletions resulting in a shift of the translational
reading frame which leads to production of a completely
different sequence of amino acids.
Figure 18.3.6: Example of different single base mutations
Genetics 1017
Mutations in non coding regions like promoter region
and introns in genes result in abnormal production, i.e. in
excess or in less. Mutations in intron/exon boundary may
lead to differently spliced mRNAs.
Causes of Mutations
Mutations may be generated spontaneously by rare errors
that occur during DNA replications. More frequently
mutations are produced by exposure to the so called
mutagens like high energy radiation (e.g. X-rays, UV rays)
and certain chemicals that can damage the DNA.
DNA Repair
There is a complex system of DNA repair enzymes called
proof reading polymerases that repair errors occurring
during DNA replication which prevents against deadly
accumulation of changes in the DNA sequence.
Somatic and Germ Line Mutations
Somatic mutations occur in all cells of the body except the
germ cells. They are transmitted to all daughter cells, but
are not carried on to the next generations. Some somatic
1018 IAP Textbook of Pediatrics

mutations may cause suppression of the tumor suppressor
genes resulting in cancer.
Germ line mutations occur in the germ cells of the body
and these mutations can be inherited from the parents
and can be transmitted to the offspring. Some germ line
mutations occur in frequency of more than 1 percent in
the population. These are called polymorphisms and they
are responsible for the normal genetic variation. Most
polymorphisms have no relevance in health or disease
but some can have medical importance. Polymorphisms
may help in the process of evolution by making necessary
arrangements for the survival. Non-polymorphism
mutations are the causes for the genetic disorders. Some
mutations manifest only in pairs; one of the pair inherited
from each parent, the so called recessive traits. Others
manifest even in single; inherited from either of the parents,
the so called dominant traits.
even from mouth washings. The cells are dissolved in
detergent solutions and treated with Protein and RNA
degrading enzymes to purify the DNA. Alcohol is then
added to precipitate the genomic DNA as a fibrous thread.
The DNA fibre is then suspended in a mildly alkaline
buffer for storage. Purified DNA can be stored for long
periods in liquid nitrogen or at -80°C.
II. Restriction Enzymes: (Fig. 18.3.7)
Certain bacterial enzymes known as restriction
endonucleases have the capacity to cut the double
stranded DNA at specific sequences. They are named after
the bacteria from which they have been obtained. The size
of the fragments produced is constant in an individual
subject but varies among subjects because of differences
in noncoding DNA sequences. This is the basis of many
DNA predictive tests.

RECOMBINANT DNA TECHNOLOGY

The process of manipulating genetic material, in which
DNA is artificially cut, joined and synthesized is termed
as Recombinant DNA technology or genetic engineering.
This technology has made it possible to analyze and
change the functions of genes and hence finding its many
applications in medicine (Table 18.3.1)

TABLE 18.3.1: Uses of recombinant DNA technology

I. Gene structure/Mapping/Function
II. Clinical Genetics
• Preimplantation genetic diagnosis
• Prenatal diag.
• Presymptomatic diag.
• Carrier detection
III. Diagnosis and pathogenesis of disease
• Genetic
• Infective
• Malignant
IV. Biosynthesis
• Recombinant products
• Vaccines
V. Treatment of genetic diseases
VI. Gene therapy
Figure 18.3.7: DNA structure

Tools of Genetic Engineering

I. DNA Isolation
The first step in Recombinant DNA technology is to isolate
DNA in its pure form.DNA can be isolated from peripheral
leukocytes, skin fibroblasts, solid tissues, tumour cells or
III. Probes (Fig.18.3.8)
A probe is a piece of single stranded DNA that is tagged
either with a radioactive isotope P32 or by fluorophores
(Fluoroscein or rhodamine).The single stranded DNA
detects the presence of its complementary sequence. These

Figure 18.3.8: Probes
probes are used to detect the gene of interest or a region of
DNA which is nearer to the gene of interest or to more
distant DNA sequences. There are four types of probes –
Gene specific probe, Complementary DNA probe (C-DNA
probe), Oligonucleotide probe and Randomly generated
probe.
IV. Vectors
This refers to a carrier DNA molecule which contains the
DNA segment of interest. When a vector containg the target
DNA is introduced into the host cell, it replicates with the
DNA of the host cell resulting in production of multiple
copies of the target DNA. Commonly used vectors are
Plasmids and Bacteriophages
V. Plasmids
They are circular, double stranded DNA molecules that
occur naturally in bacteria and replicate extrachro-
mosomally in bacteria or yeast. They usually carry
antibiotic resistance genes and can easily pass from one
bacterium to another; they are also distributed to daughter
cells during cell division. During cloning the DNA of
interest is incorporated into the plasmid DNA with the
help of restriction endonucleases and then introduced into
the bacteria, which multiply giving high yield of the DNA
of interest. Knowledge of the specific antibiotic to which
resistance is carried by the plasmid will help in allowing
the multiplication of only selected bacterium when grown
with that antibiotic.
VI. Bacteriophages
These are viruses that infect bacteria. A DNA fragment
can be introduced into a virus which then infects a
bacterium and multiplies. During replication, the inserted
DNA fragment also multiplies and gets incorporated into
the daughter cells.
Genetics 1019
VII. DNA Ampilification
Cloning
DNA cloning is the selective amplification of a specific
DNA segment or sequence, so that it can be produced in
relatively large amounts, permitting the analysis or
manipulation of its structure and investigation of its
functions.
The DNA of interest is incorporated into a plasmid by
cutting both of them with the same restriction
endonucleases, the cut ends are then joined together
generating a recombinant molecule. The recombinant
plasmid is then introduced into a bacterial cell. The
bacterial cell is then cultured in broth or agar plates. As
the bacteria multiply the plasmid and inserted DNA
fragment will also replicate and a large amount of the
target DNA will be available.
Polymerase Chain Reaction (PCR): (Fig. 18.3.9)
PCR is a powerful technology that is used to amplify the
DNA segment of interest. To put it in lay man’s language
it is “molecular photocopying”. The process runs as a
series of physicochemical cycles in a special device called
PCR chamber.
The steps involved include
1. The target DNA is denatured by heat, which makes
double stranded DNA to separate into 2 single strands.
These 2 ends can grow in 2 direction, 3’ and 5’ end of
DNA segments.
2. The primers are added to the chamber which contains
the DNA strands. These primers hybridize (bind) to
the complementary fragments of the now single
stranded target DNA.
3. Then bases (deoxynucleotide) and tag polymerase are
added while temperature increases. The bases are used
as building blocks for synthesis of DNA strands and
the polymerase begins to assemble them.
4. The primer extends in 3’ direction as well as in 5’
direction to produce new DNA.
5. Such cycles are repeated several times automatically
and in few hours the target DNA segment or sequence
can be amplified to one million fold.
6. The produced DNA (i.e. PCR product) can be analysed
using labelled probes, sequencing or by direct vision
with UV light after adding ethedium bromide to the
electrophoretic gel.
1020 IAP Textbook of Pediatrics
Figure 18.3.9: Steps of PCR
Applications of PCR
1. Genetic disorder caused by single base pair changes,
small deletion or insertions. This helps in diagnosis,
carrier detection and for prenatal diagnosis. (E.g.
Thalassemia with base pair changes, DMD with DNA
deletions.)
2. Diagnosis of infectious diseases (E.g. HIV infection)
3. Diagnosis and follow up of cancers.
4. Study of bone marrow engraftment.
5. DNA fingerprinting for paternity cases and forensic
purposes.
6. HLA typing for Bone marrow transplant and Kidney
transplantation
7. Study of Gene linkage and gene mapping .
8. Study of Single Nucleotide Polymorphism (SNP) for
noting the susceptibility of a person to a disease or a
particular response of a drug to this disease
(PharmacoGenetics).
9. Study of evolution.
Limitations of PCR
1. At least part of the sequence of the target DNA must be
known for meaningful interpretation.
2. It can amplify few hundred base pairs sized segments.
Larger segments cannot be amplified, for which
cloning may be used.
3. There can be errors due to the inclusion of wrong bases,
since polymerase has no capacity to read the proof.
Multiplex PCR
In chromosomal disorders, deletion of a part of a gene can
be easily detected by the absence of the band due to non-
amplification of the part of the gene corresponding to the
deleted region. This principle is used in Multiplex PCR
and groups of 6 or 9 exons are amplified simultaneously
in a tube. The products are separated by gel electrophoresis.
Each band in the gel represents an exon. In the presence of
a deletion in an exon, the corresponding band will be
absent.
However when the need to identify carrier females in
X-Linked disorders arises then a different technique called,
Quantitative PCR is used. In which the band corres-
ponding to the deleted exons will have a decreased density
in carrier females when compared to those of non-deleted
exons of normal individuals.

TECHNIQUES FOR DNA ANALYSIS
Southern Blot Hybridization (Fig. 18.3.10)
In this technique, first the DNA is cut into fragments by
the use of bacterial restriction enzymes. These millions of
pieces of DNA fragments are subjected to electrophoresis
in an agarose gel. The smaller fragments move faster than
the larger ones producing a track of DNA fragments. The
agarose gel with DNA tracks is fragile and needs to be
transferred for a permanent record, this is done by placing
a nitrocellulose paper on top of the agarose gel, over which
Figure 18.3.10: Southern blot
Genetics 1021
dry paper towels are put. The fluid in the electrophoretic
tank then rises through the gel transferring the DNA on
the nitrocellulose paper, retaining the alignment of the
fragments (Blotting). The DNA bound to the nitrocellulose
membrane is a stable record. The record is then washed in
a solution containing radiolabelled DNA probe with
phosphorous 32. The probe, if it finds its complementary
fragments of DNA, unites with it (Hybridization). This
hybridized fragment then can be identified as a visible
band on an X-ray film, placed on the membrane and this
technique is known as autoradiography.
1022 IAP Textbook of Pediatrics

Applications
1. To find the presence of a particular gene or a part of
the DNA fragment in the sample DNA
2. To know whether the size of the DNA fragment carrying
the gene is normal, increased or decreased.
3. To identify presence of large deletions, duplications
or large gene rearrangements.

AUTOMATED SEQUENCING
Sequencing means knowing the orderly arrangement of
bases (A,T,G,C) along the DNA ladder. This technique
uses primers or nucleotides labeled with fluorescent dyes,
which can be detected by a computerized laser detection
system, allowing rapid, accurate and automated sequen-
cing. Since different fluorescent dyes are used in each of
the four base- specific reactions, all the four reactions can
be loaded in single lane. The output is in the form of
intensity profiles for each of the differently coloured
flurochromes. This technique is used in human genome
sequencing, detection of mutations in single gene disorders
and in mutationally heterogeneous disorder.

FLUOROSCENCE IN SITU HYBRIDIZATION (FISH)

(FIG.18.3.11)
The DNA being compactly arranged in chromosomes the
smallest visible deletion or duplication by routine
cytogenetics consist of 4 megabases i.e. 4x106 basepairs.
Thus, routine cytogenetics cannot resolve genetic
abnormalities smaller than this. This limitation of
cytogenetics has been overcome by a technical
advancement called Fluorescence in situ hybridization
(FISH).
The DNA of the subject is first denatured i.e. made into
2 separate single strands by heating. The fluorescent probe
of interest is added to the denatured DNA sample, which
then hybridizes (unites) with the complementary segment
if present and then reforms into a double helix (Reanneals).
The recombinant DNA is then seen through a fluorescent
microscope, which detects the presence or absence of the
fluorescent signal from the probe.
The following classes of DNA probes are used in FISH
technique for specific applications.
Total genome probes – Chromosomes hybridized
with these probes show an evenly distributed signal along
their length.
Figure 18.3.11: Diagrammatic representation of FISH
technique
Chromosome specific painting probes – In this the
probe consists of an entire chromosome e.g. Chromosome
1 probe will paint the whole chromosome 1 from one end
to other and also parts of chromosome 1, if it is attached to
some other chromosome. These probes cannot identify
intrachromosomal rearrangements like inversion and
areas containing repetitive elements like centromeres and
telomeres are not painted.
Chromosome specific Centromeric probes – These
are mainly used in the determination of chromosome copy
number in interphase nuclei. These are used in aneuploidy
detection in uncultured amniotic fluid cells, for pre-
implantation diagnosis from a single cell from a blastocyst
and for analysis of nondisjunctional abnormalities in
sperm.
 Genetics 1023

Locus specific DNA probes – These are probes from Spectral Karyotyping (SKY) (Fig. 18.3.12)
small regions of a particular chromosome. These probes
SKY is a multicolour genome wide FISH. It used probes
can be used for diagnosis of microdeletion syndromes like
for all chromosomes simultaneously. Each chromosome
Prader Willi syndrome, William’s syndrome, retino-
is labeled with a different coloured probe and hence
blastoma etc., where deletion may not be visible cyto-
emitting a different fluorescence spectrum. This technique
genetically. They can also be used to delineate exact break
combines the resolution and power of FISH with the
points of a chromosomal rearrangement and to identify
advantages of conventional cytogenetics methods to scan
known chromosomal rearrangements in cancer.
simultaneously all human chromosomes in a single image.
Applications
1. Preimplantation chromosomal analysis. In this since
only one or two cells are available, the techniques
comes in handy.
2. Post natal and prenatal diagnosis for conditions
associated with aneuploidy (Downs Syndrome) and
translocations (Philadelphia chromosome).
3. Chromosomal microdeletion syndromes. Williams
syndrome ( Chr 7q), Prader-Willi and Angelman
syndrome (Chr. 15q), Digeorge syndrome (Chr. 22q)
4. Age related disorders. In which telomeric probes are
used to assess the length of the telomerese which is
decreased. (E.g. Cancer, Reproductive losses)
5. Oncology. (E.g. Philadelphia chromosome) In which
it is used for drug tailoring, staging and for prognos-
tication.
6. Chromosomal structure study. In which multiple
probes for one chromosome are used which is called
chromosome painting. Figure 18.3.12: Image of a normal karyotype obtained by SKY
7. Specific probe preparation. Probes are prepared for
specific areas of the chromosome. (E.g. Chromosome Fiber FISH
specific probes for Downs syndrome and Locus specific
This is used in contiguous gene syndromes (E.g. William’s
probes for Williams syndrome )
Syndrome). Probes hybridized to same chromosome can
only be differentiated if they are more than 2 to 3 bases
MODIFICATIONS OF FISH
apart, so in order to identify multiple probes in a small
Comparative Genomic Hybridization (CGH) area ( as in contiguous gene syndromes) we need to stretch
This method is found to be a very important tool in cancer the chromatin fiber. This is done by doing the process
research and mapping of various genes involved in during interphase when chromatin fibers are less
tumourogenesis. CGH uses Fluroescein labeled tumour condensed and by further stretching the chromatin with
DNA (Green) and Texas red labeled normal genomic DNA the help of melting agarose.
(Red) in mixed forms, which is hybridized to normal
DNA Microarray Technique (Fig. 18.3.13)
metaphases. The relative amount of tumour and normal
DNA that anneals to a particular region of chromosomes This technique is used to study the expression of many
depends on the number of copies of DNA complementary genes at a time and that too, on a single slide known as a
to that region in the test sample. The abnormalities, thus DNA CHIP.DNA CHIP is a glass slide in which several
detected in tumour genome are used for identifying cancer miniature wells are arranged in an order i.e. microarray.
related genes. In these wells are placed oligonucleotide probes.
1024 IAP Textbook of Pediatrics
Figure 18.3.13: Showing the use of microarray in the evaluation of a tumour “Courtesy: National Human
Genome Research Institute”
The messenger RNA(mRNA) is extracted from the
sample to be tested. The mRNA indicates that the DNA
has set into function, as we know the DNA forms the
mRNA and the mRNA form the proteins. This mRNA is
converted to cDNA(Coding DNA, i.e. has exons but not
introns ) which is then labeled with a fluorescent dye. The
mRNA from a normal cell is also extracted and from this
CDNA is prepared and tagged with a different fluorescent
dye. Both labeled cDNA are then mixed with the
oligonucleotide probes that are placed in the wells
(Microarray). Laser beams are then used to excite the
fluorochromes. The exciting pattern will depend on the
relative amount of normal and abnormal CDNA. Analysis
of the color pattern of the microarray after hybridization
is done by capturing the digital image and then with the
help of a computer analyzing the images. This is a gene
expression study (FUNCTIONAL GENOMICS).
This technique is important in drug designing,
pharmacogenetics, cancer research, analyzing several
mutations in a single go and in several others. This
technique is so powerful that hundreds of mutations can
be analyzed in a single test.
Linkage Analysis
If the disease causing mutation cannot be identified in a
patient or is difficult to test, DNA markers situated in or
near the gene can be used to trace the mutated gene in the
family. This method, known as linkage analysis, can be
used for prenatal diagnosis and carrier detection. The use
of linked markers is based on the fact that closely related
genes or DNA segments are transmitted together to the
next generation. This method is also useful for the
detection of carriers of X-Linked disorders such as DMD
and hemophilia.
Restriction Fragment Length Polymorphism (RFLP)
To understand this concept an example is taken. In Figure
18.3.14, ‘G’ is the disease gene on X chromosome, which
has not been isolated, and therefore no gene probe is
available.

Figure 18.3.14: Gene tracking
By studying a large number of family members by
linkage studies, a gene probe ‘P’ has been identified which
hybridizes to X-chromosome very close to the disease gene
locus ‘G’. They are so close that they segregate together
(Inherited together) during meiosis; in other words they
show close genetic linkage. Closer the marker probe to the
disease gene, more accurate is the prediction of the genetic
pattern.
The markers (probes) that show less than 5 percent
recombination with a disease gene are useful in detecting
carrier status and in prenatal diagnosis. As 1 percent
recombination occurs between loci that are separated by
around 1 million base pairs, these probes may be up to 5
million bases away from the gene of interest.
A polymorphic restriction enzyme cutting site ‘B’ is
identified very close to the disease gene ‘G’. (Polymorphic
means it may be present or absent in a particular
individual. This is because of variation in noncoding
region of DNA that effects restriction endonuclease cutting
sites, resulting in DNA fragments of different sizes). If it is
present, the probe ‘P’ will hybridize to a 2 Kb fragment
and if absent, the probe will hybridize to a 5 Kb fragment.
The portions or segments produced using probe
enzyme combination which identifies a polymorphic
cleavage site are known as restriction fragment length
polymorphisms (RFLP). RFLPs are used in carrier
detection and prenatal diagnosis of conditions such as
DMD and BMD. Before prediction is possible , a family
must have DNA analysis performed to see if there is a
variation in the size of the fragments detected by an
appropriate probes that gives an informative pattern in
the family. After identifying the fragment associated with
the disease, the gene can be identified in carrier or in the
pregnancy being tested.
DNA BASED DIAGNOSIS OF GENETIC DISORDERS
Beta-Thallasemia
It is a heterogeneous hematological disorder due to many
mutations in the Beta-globin gene. Most gene defects are
Genetics 1025
due to point mutations, deletions or insertions. Despite
marked heterogeneity at the molecular level, a set of
mutations are commonly prevalent in a given population.
In the Indian population the five commonest mutations –
“IVS1 -5{G!C}, 619bp deletion, IVS1-1{G!T}, Codon 8/9,
and Codon 41/42{-CTTT}” account for 91.8% of all
mutations. Though an infant with marked microcytic
anemia with splenomegaly and raised fetal hemoglobin
level is diagnostic of Beta-Thallasemia, the following are
the techniques used for disease confirmation, prenatal
diagnosis and carrier detection.
Multiplex PCR – [Described above]
Dot blot method – Beta Globin genomic DNA adjacent to
the different mutations is amplified by PCR. The products
are immobilized onto 2 separate membranes and
hybridized with labeled Allele Specific Oligonucleotide
(ASO) probes complementary to the wild (Normal) and
mutant sequences. A person homozygous for the mutation
will show hybridization with the mutant probe, normal
individual’s DNA hybridizes with the wild type probe
and heterozygote(Carrier) have hybridization with both
probes.
Reverse dot blot method – It is the reverse of above
procedure, with membrane bound normal and mutant ASO
probes serving as hybridization targets for PCR amplified
DNA.
Amplification refractory mutation system (ARMS) - The
DNA to be tested is amplified by PCR technique using 2
sets of primers in 2 separate tubes. One primer is common
to both, while the other primer, in one tube has a sequence
specific for a mutation(Mutant type) and that in the other
tube has a normal sequence(Wild type) at the site of the
mutation. Genomic DNA will be amplified only in the
presence of complementary pairing of the primer and
genomic DNA. Electrophoresis will demonstrate a band
in the reaction of a homozygote for the wild type allele
and primer; a homozygous mutant for the mutant allele
and mutant primer; a heterozygote for both the alleles and
primers.
DUCHENNE AND BECKER MUSCULAR
DYSTROPHIES (DMD AND BMD)
These are X-Linked neuromuscular diseases resulting
from mutations of the Dystrophin gene which codes for a
muscular cytoskeleton protein, Dystrophin. 65% of the
mutations are deletions occurring predominantly in
1026 IAP Textbook of Pediatrics
2 hotspots around the first 20 exons and around exons
45-55. Mutations that result in the failure of production of
a stable protein will result in DMD (severe phenotype),
mutations that result in production of a stable and partially
functional protein results in BMD (Milder phenotype).
Clinical presentation cannot give any clue to the type or
site of mutation; hence it is necessary to identify the
mutation of the proband prior to offering carrier detection
and prenatal diagnosis. The following are the techniques
used for confirmation, prenatal diagnosis and carrier
detection.
multiplex pcr – Explained earlier. Cannot identify
duplication, insertions and point mutations which are
sometimes responsible for the condition.
linkage analysis – Explained earlier. This technique
is limited by the fact that some individuals with muscular
dystrophy may have new mutations and cannot be
determined definitely. Hence there are possibilities of false
negative or false positive results which should be kept in
mind during prenatal diagnosis.
Spinal Muscular Atrophy
The spinal muscular atrophies represent a heterogeneous
group of diseases with predominantly AR inheritance and
characterized by degeneration of the motor neurons in the
anterior horn cells of the spinal cord and brainstem. There
are 4 types, of which 3 are of childhood onset, with SMA
Type I having the worst prognosis. Majority of them are
associated with homozygous deletion in the survival motor
neuron (SMN1) gene on chromosome 5q13 (Exon 7).
There is no non-cytogenetic diagnostic test for SMA
other than the supportive evidence of neurogenic changes
on EMG. Detection of the deletion in the SMN1 gene
confirms the diagnosis of SMA. This is done by PCR
followed by Restriction enzyme digestion, which confirms
the presence or absence of the Exon 7.
Carrier detection is done by Quantitative PCR based
assay. Prenatal diagnosis is straightforward once the
mutation in the SMN1 gene is identified in the carrier.
Preimplantation diagnosis in families at risk has also been
reported.
Fragile X Syndrome
Fragile X syndrome is an X-Linked condition which is
most common cause for inherited mental retardation. It is
due to the presence of a fragile site at the Xq27.3 locus in
which there is an abnormally large number of trinucleotide
(CGG) repeats. This can be detected by PCR technique.
Clinical features of the condition are subtle, and
characteristics such as facial dysmorphism and macro-
orchidism appear as the child grows. Hence, it is
necessary to conduct DNA tests for the diagnosis of this
condition in all males and females with idiopathic mental
retardation.
ADVANCES IN GENETICS
Human Genome Project
Genome refers to all the genetic material contained in a
cell, i.e. the DNA. The order of arrangement of the base
pairs (AT,GC) along the DNA molecule is called as its
sequence.
In 1990, the National Institutes of Health (NIH) and
the Department of Energy joined with international
partners in a quest to sequence all 3 billion base pairs in
the human genome. This concerted, public effort was the
Human Genome Project (HGP). In April 2003, researchers
successfully completed the HGP, under budget and more
than two years ahead of schedule.
Objectives
• To know the arrangements of all the 3 billion base
pairs in the human genome.
• To identify the roughly 30,000 genes in the human
genome and know their exact location on the different
chromosomes.
• To develop new DNA technology, especially for
automated DNA sequencing.
• To make all the data generated by the HGP, freely and
rapidly available on the internet, serving to accelerate
the pace of medical discovery around the globe
(Bioinformatics).
• To study some model organisms like fruitfly,
earthworm, E.coli etc. for comparison.
• To study and support the ethical, legal and social
implications that might arise from this science.
Outcomes
• The human genome sequence was found to be almost
the same (99.9%) in all human beings, with only 0.1%
variations being responsible for the phenotype and
diseases susceptibility.
• Single Nucleotide Polymorphisms (SNP), which have
been discovered in the genome are frequently occurring

variation in individuals and are being studied for their
association with disease susceptibility to common
disorders and drug idiosyncrasy.
• Human genome is very much similar to many other
organisms, for example the genome of the fruitfly
shares 40% of its genes with the humans, and the
chimpanzee’s DNA sequence is 96% similar to
humans; making man humble.
• More than 1800 disease genes have been identified.
• More than 1000 genetic tests have been devised for
diagnosis.
• At least 350 biotechnology based products resulting
from the HGP are currently in clinical trials.
• The study of mitochondrial DNA has revealed that
the origin of the human race is from central Africa, in
other words mankind took origin from an African
woman.
• The study of the human genome has shed light on the
migration of the human race around the globe.
Functional Genomics
Genomics is the study of the entire genome of an organism.
Functional genomics is the study of the functions of the
genes in normal development and physiology and their
dysfunction in disease states. The main tool of functional
genomics is the DNA microarray technique which has
been explained earlier. Proteomics, an important
component of functional genomics is the identification of
proteins and elucidation of their involvement in the
biological pathways, as well as their interaction in
development, differentiation, health and disease.
Phenomics is a field of study concerned with the
characterization of phenotypes, which are characteristics
of organisms that arise via the interaction of the genome
with the environment. Metabolomics is the “systematic
study of the unique chemical fingerprints that specific
cellular processes leave behind” - specifically, the study
of their small-molecule metabolite profiles. The meta-
bolome represents the collection of all metabolites in a
biological organism, which are the end products of its
gene expression
RNA Interference
RNA interference (RNAi) is a mechanism that inhibits or
silences gene expression at the stage of translation or by
hindering the transcription of specific genes. RNAi targets
include RNA from viruses and transposons (significant
Genetics 1027
for some forms of innate immune response), and also plays
a role in regulating development and genome maintenance.
In 2006, Andrew Fire and Craig C. Mello shared the Nobel
Prize in Physiology or Medicine for their work on RNA
interference in the nematode worm C. elegans, which they
published in 1998. It is unusual for the Nobel committee
to award a prize in medicine so soon after the relevant
discovery. But then, hardly ever has such a discovery given
rise so quickly to such a broad range of promising medical
applications such as in diseases (amyotrophic lateral
sclerosis, spinocerebellar ataxia, hepatitis viral infections
etc.) in drug designing, in cancer genetics and in
biotechnology. It is also the principal behind the “knockout
mice” in which the consequences of the silencing of the
function of a particular gene is studied, to understand the
gene’s function.
Bioinformatics and Databases
Bioinformatics is the field of science in which biology,
computer science, and information technology merge to
form a single discipline. The ultimate goal of the field is to
enable the discovery of new biological insights as well as
to create a global perspective from which unifying
principles in biology can be discerned. The actual process
of analyzing and interpreting data is referred to as
computational biology.
A biological database is a large, organized body of
persistent data, usually associated with computerized
software designed to update, query, and retrieve compo-
nents of the data stored within the system. A simple
database might be a single file containing many records,
each of which includes the same set of information. For
example, a record associated with a nucleotide sequence
database typically contains information such as contact
name, the input sequence with a description of the type of
molecule, the scientific name of the source organism from
which it was isolated, and often, literature citations
associated with the sequence.
• NIH genetic sequence database – GENBANK
www.ncbi.nlm.nih.gov/sites/entrez?db=nucleotide
• European Molecular Biology Laboratory Nucleotide
sequence database – EMBL www.ebi.ac.uk/embl
• GDB human genome database - The Official World-
Wide Database for the Annotation of the Human
Genome. www.gdb.org
• Online mendelian Inheritance in man – OMIM –
Catalogue of inherited diseases in humans.
www.ncbi.nlm.nih.gov/omim
1028 IAP Textbook of Pediatrics
Cancer Genetics
The aetiology of cancer is multifactorial, with genetic,
environmental, medical, and lifestyle factors interacting
to produce a given malignancy. Knowledge of cancer
genetics is rapidly improving our understanding of cancer
biology, helping to identify at-risk individuals, furthering
the ability to characterize malignancies, establishing
treatment tailored to the molecular fingerprint of the
disease, and leading to the development of new therapeutic
modalities. As a consequence, this expanding knowledge
base has implications for all aspects of cancer manage-
ment, including prevention, screening, and treatment.
Following are some of the examples of the inherited
family cancer syndromes.
• Breast cancer – BRCA 1 (17q21), BRCA 2 (13q21)
• Familial adenomatous polyposis – APC (5q21)
• Juvenile polyposis – SMAD4/DPC4 (18q21.1),
BMPR1A(10q22)
• Peutz-Jeghers – STK11 (19p13.3)
• Familial retinoblastoma – RB1(13q14)
• Multiple endocrine neoplasia(MEN) Type 1 – MEN1
(11q13)
• MEN Type 2 – RET (10q11.2)
Patient Support Groups and Non Profit Organization
A patient support group is a gathering of people with the
same illness or condition who meet either physically or
online to share information, experiences, problems and
solutions. Run by members for members, the groups help
foster a sense of self-esteem and courage to help face the
social, financial, emotional difficulties that may lie ahead.
A strong body of literature shows that belonging to such a
group can optimise the outcome of the patient.
Support groups in India for common genetic conditions:
• Downs Syndrome - www.downsyndrome.in
• Thalassemia - www.thalassemicsindia.org
• Haemophilia - www.hfindia.org
Enzyme Replacement Therapy
Though replacement of deficient substrates such as insulin
and factor VIII have been in use for a long time, certain
lysosomal storage disorders which are genetically
transmitted are currently amendable for treatment. This is
done by replacing the deficient enzyme; though the disease
itself is not cured, the morbidity and mortality are brought
down drastically.
1. Gaucher’s disease - Approved 1991 Imiglucerase®
(Cerezyme)
2. Fabry disease Approved 2001 Agalsidase®
(Fabrazyme)
3. Mucopolysaccharidosis I Approved 2003 Aldurazyme®
(laronidase)
4. Mucopolysaccharidosis VI Approved 2005 Galsulfase®
(Naglazyme)
5. Mucopolysaccharidosis II Approved 2006 Idursulfase®
(Elaprase)
6. Pompe Disease Approved 2006 Myozyme®
(Alglucosidase alfa)
7. Niemann-Pick B Disease Phase 1 Trial
Stem Cell Therapy
Stem cells are unspecialized cells that are defined by their
capacity for self renewal and their ability to differentiate
into specialized cells along many lineages. Somatic stem
cells can differentiate into the cell types found in the
tissues from which they are derived. They are usually
described by reference to the organ of origin (E.g.
Hematopoietic stem cell)
Bone marrow transplantation is one form of somatic stem
cell therapy, and is being successfully used in genetic
conditions such as hemoglobinopthies, Adenosine
Deaminase deficiency, Severe combined Immuno-
deficiency, lysosomal storage disorders, fanconi anemia
etc.
Embryonic stem cell therapy is a newer form of stem cell
therapy in which the inner cell mass of the growing
embryo is isolated and disrupted to form embryonic cell
line. Under special culture conditions, the cells of the
embryonic lines can be coaxed to form certain kind of cell
type (e.g. Heart myocytes). In theory these different cells
could be used to replace deficient or injured cells or tissues.
This is being tried in conditions like myocardial infarction
and spinal cord damage.
Umbilical cord blood banking is a controversial area of
stem cell therapy. Umbilical cord blood, which contains a
rich source of hematopoietic stem and progenitor cells,
has been used successfully as an alternative allogeneic
donor source to treat a variety of pediatric genetic,
hematologic, immunologic, and oncologic disorders.
Because there is diminished risk of graft-versus-host
disease after transplantation of cord stem cells using
matched related donors, the use of less-than-completely
matched HLA cord blood stem cells may incur less risk of
graft-versus-host disease than mismatched cells from

either a related or unrelated “walking” donor, although
this remains to be proven. As yet the American academy
of pediatrics states, “Because there are no scientific data
at the present time to support autologous cord blood
banking and given the difficulty of making an accurate
estimate of the need for autologous transplantation and
the ready availability of allogeneic transplantation, private
storage of cord blood as “biological insurance” should be
discouraged.”
BIBLIOGRAPHY
1. American Academy of Pediatrics Section on Hematology/
Oncology; American Academy of Pediatrics Section on
Allergy/Immunology, Lubin BH, Shearer W:Cord blood
banking for potential future transplantation. Pediatrics.
2007 Jan; 119(1):165-70.
2. Bernards R: Exploring the uses of RNAi—gene knockdown
and the Nobel Prize. N Engl J Med. 2006 Dec 7;
355(23):2391-3.
18.4 Inborn Errors of Metabolism
INTRODUCTION
Inborn errors of metabolism result from mutations in DNA
that code for a specific protein, which may act as an
enzyme, receptor, transport vehicle, membrane pump or
structural element. In these disorders, biochemically one
observes accumulation of compounds proximal to the
enzymatic block and deficiency of product distal to it. Some
genetic changes may be clinically inconsequential
whereas others produce disease states which range from
very mild to lethal. Most disorders present in neonatal
period with nonspecific manifestations that include
lethargy, vomiting, jaundice, convulsions, coma, hurried
respiration, unusual body odor, hypoglycemia, acidosis
and hyperammonemia, elevated blood/urine levels of a
particular metabolite, for example an amino acid or
ammonia. In older children metabolic disorder should be
suspected in the following situations:
1. Unexplained mental retardation, developmental delay,
motor deficits or convulsions.
2. Unusual odor particularly during an acute illness.
3. Intermittent episodes of unexplained vomiting,
acidosis, mental deterioration or coma.
Genetics 1029
3. Hessner MJ, Liang M, Kwitek AE: The application of
microarray analysis to pediatric diseases. Pediatr Clin
North Am. 2006 Aug; 53(4):579-90.
4. Morrison C: Fluorescent in situ hybridization and array
comparative genomic hybridization: complementary
techniques for genomic evaluation. Arch Pathol Lab Med.
2006 Jul;130(7):967-74.
5. National Institute of Health: Fact sheet Available at: http:/
/www.nih.gov/about/researchresultsforthepublic/
HumanGenomeProject.pdf.
6. National Library of Medicine. MEDLINE Fact Sheet
Available at www.ncbi.nlm.nih.gov/About/primer/
bioinformatics.html.
7. Rohrbach M, Clarke JT: Treatment of lysosomal storage
disorders: progress with enzyme replacement therapy.
Drugs. 2007;67(18):2697-716.
8. Turnpenny P, Ellard S. Emery’s elements of medical
genetics. 13th ed. China. Churchill livingstone elsevier;
2007.
ML Kulkarni
4. Hepatomegaly.
5. Dislocation of lens, cataract or corneal opacity.
6. Renal stones.
The common inborn errors of metabolism are discussed
here.
Phenylketonuria
Phenylketonuria (PKU) is the most common inborn error
of amino acid metabolism, characterized by diminished
activity of the enzyme phenylalanine hydroxylase and
thus an elevation of plasma phenylalanine. The symptoms
of hyperphenylalaninemia are usually absent in the
newborn, but ultimately result in light colored hair, blue-
eyed child with light complexion, eczema and mental
retardation. Seizures and behavioral problems frequently
result. The urine and sweat of these children have a
“mousy” odor, which is caused by phenylacetic acid in
the urine and sweat. There are four clinically and
biochemically distinct forms of hyperphenylalaninemia,
out of which classic phenylketonuria is the most common.
All defects of persistent hyperphenylalaninemia and PKU
are inherited as autosomal recessive traits. They have a
collective prevalence of 1:10,000 to 1:20,000 live births.
1030 IAP Textbook of Pediatrics

Classic Phenylketonuria (PKU) tyrosine and tryptophan hydroxylases, which are

essential for biosynthesis of the neurotransmitters
This form is caused by the complete or near-complete
dopamine and serotonin.
deficiency of phenylalanine hydroxylase. The affected
The clinical manifestations of this disorder are similar
infant is normal at birth. The clinical manifestations of
and usually indistinguishable from those of classic PKU,
classic PKU are rarely seen in those countries in which
but neurologic manifestations such as loss of head control,
neonatal screening programs for detection of PKU are in
hypertonia, drooling, swallowing difficulties and
effect. The bacterial inhibition assay method of Guthrie is
myoclonic seizures develop after 3 months of age, despite
widely used in the newborn period to screen for PKU.
adequate dietary therapy. Diagnosis of BH4 deficiency and
This test requires a few drops of capillary blood, which
the responsible enzyme defect may be established by
are placed on a filter paper and mailed to the laboratory
performing one of the following tests: (1) Measurement of
for assay. Blood for screening should be obtained after 72
neopterin and biopterin in body fluids (neopterin
hours of life and preferably after feeding proteins, in order
biopterin ratio is low) (2) BH4 loading test (3) Enzyme
to reduce the possibility of false-negative results. The
assay.
criteria for diagnosis of classic PKU are: (i) a plasma
The treatment includes: (i) low phenylalanine diet; (ii)
phenylalanine level above 20 mg/dl, (ii) a normal plasma
administration of neurotransmitter precusors; L-dopa and
tyrosine level, (iii) increased urinary levels of metabolites
5-hydroxytryptophan seems to be most effective and may
of phenylalanine (phenylpyruvic and hydroxypheny-
prevent neurologic damage if started early in life; (iii) oral
lacetic acids), (iv) a normal concentration of the cofactor
administration of the BH4 cofactor in small daily doses
tetrahydrobiopterin.
normalizes serum levels of phenylalanine. This should
The goal of therapy is to reduce phenylalanine and its
be given in high doses of 20 to 40 mg/kg/day to cross the
metabolites in body fluids in order to prevent or minimize
blood brain barrier and stop the progression of neuro-
brain damage. This can be achieved by instituting a diet
logical damage.
low in phenylalanine; formulas low in this essential amino
acid are now available; it should be started soon after
Benign Hyperphenylalaninemia
birth as soon as the diagnosis is established. Dietary
management is almost always complicated by emotional These infants have been detected by screening tests in the
problems especially in the adolescent period; therefore, neonatal period; they are asymptomatic and may develop
parents and children need continuous skillful and normally without special dietary treatment. These patients
empathetic support and guidance. have a deficiency of the phenylalanine hydroxylase enzyme
but with some residual enzyme activity. These children
Pregnancy in Mothers with PKU should be systematically monitored with repeated
determinations of plasma phenylalanine and develop-
Pregnant women with PKU who are not on a low
mental evaluation.
phenylalanine diet have a higher risk of spontaneous
abortion than the general population. Infants born to such
Transient Hyperphenylalaninemia
mothers have mental retardation, microcephaly and/or a
congenital heart disease. These complications are related Moderately elevated levels of phenylalanine occur in
to high levels of blood phenylalanine. Prospective mothers, transient tyrosinemia of the newborn infant. When the
who have PKU, should be started on a low phenylalanine infant’s ability to oxidize tyrosine matures, the elevated
diet before conception, and every effort should be made to levels of tyrosine and phenylalanine return to normal.
keep blood phenylalanine levels below 10 mg/dl,
throughout pregnancy. ALKAPTONURIA
It is the first inborn error of metabolism identified and
Hyperphenylalaninemia due to Deficiency of
was reported by Sir A Garrod in the year 1908.
Cofactor Tetrahydrobiopterin (BH4)
It is a rare autosomal recessive disorder caused by a
In about 2 percent of infants with hyperphenylalaninemia, deficiency of the enzyme homogentisic acid oxidase. This
the defect resides in one of the enzymes necessary for enzyme deficiency results in defective tyrosine metabolism
production or recycling of BH4 which is a cofactor for and the accumulation of homogentisic acid in tissues and

urine. The elevated levels of homogentisic acid in the urine
with oxidation results in a dark brown-black color, and
the initial diagnosis may result from observation of
discolored urine. Visible pigmentary deposition may occur
in the face, nose, ears and eyes and is referred to as
ochronosis.
To aid in the diagnosis, one should consider the clinical
triad of: (1) black urine with increased levels of homo-
gentisic acid, (2) ochronosis, and (3) degenerative arthritis.
Most of these patients have arthritis involving the
intervertebral disks, knees, shoulders, and hips, which
can be visualized radiographically. The urine gives a
positive Benedict’s test and a purple black color with ferric
chloride test. The condition is generally benign and there
is no specific treatment available for this disorder.
ALBINISM
Albinism describes a group of genetically inherited
conditions caused by defective melanin production. The
biosynthesis of melanin by melanocytes requires the
oxidative enzyme tyrosinase. In albinism, the tyro-sinase
system appears to be defective. The disorder may be
generalized, affecting the skin, eyes and hair (oculo-
cutaneous albinism), or localized, affecting primarily the
eyes (ocular albinism). Oculocutaneous albinism may be
tyrosinase-negative or tyrosinase positive depending on
the ability of a hair-bulb plucked from the patient and
incubated in tyrosine solution to synthesize melanin. This
test may not prove accurate until a child is 3 to 5 years of
age; thus, ascertaining the type of albinism when the
patient is younger than age 3 may be difficult.
Witkep recognized 10 different types of oculocutaneous
albinism (OCA) and 4 types of ocular albinism. Of these,
tyrosinase positive OCA is the most common form of
albinism with normal tyrosinase activity.
Albinism (all types) has a worldwide prevalence of 1
in 20,000. Oculocutaneous albinism is inherited as an
autosomal recessive trait except for a rare type that is
dominantly inherited; ocular albinism is inherited as an
X-linked or autosomal recessive trait; and partial albinism
(piebaldism) is inherited as an autosomal dominant trait.
Clinical manifestations common to almost all forms of
albinism include depigmentation of skin, iris, and retina.
Nystagmus, strabismus, photophobia, decreased visual
acuity, and presence of red reflex are common eye findings.
Blindness and skin cancer are the two major late sequelae
of albinism, in its severe form. It is important to make the
diagnosis of albinism as early as possible and to offer
Genetics 1031
genetic counseling to the patient and parents. The family
should be informed that there is no cure but individuals
with this disorder can live a fairly normal life with
appropriate support. An ophthalmologist should provide
lenses to relieve glare intolerance and various low vision
aids, in conjunction with the patient’s best visual
correction, to allow sufficient vision for daily activities. A
dermatologist can provide instructions on skin protection
and regular examinations for cutaneous disorders and
malignancies. Support groups are essential to provide
social and psychological support to these patients.
HOMOCYSTINURIA
Homocystinuria is an autosomal recessive disorder and
is the second most common inborn error of metabolism.
Homocystinuria is due to deficiency in cystathionine P-
synthetase resulting in an increased concentration of
homocystine and its dietary precursor, methionine, in
blood and other body fluids. The patient with untreated
homocystinuria is asymptomatic in infancy, but subse-
quently, develops mental retardation, skeletal disorders,
and thromboembolism in addition to numerous ocular
complications. Ectopia lentis is the most notable eye finding.
Other ocular features of this disorder include microcystic
peripheral retinal degeneration, secondary pupillary
block, glaucoma, retinal detachment, myopia, cataract,
strabismus, optic atrophy, spherophakia, iris atrophy,
uveitis and keratitis.
The skeletal abnormalities include scoliosis, arachno-
dactyly, and pectus excavatum.
Patients with homocystinuria are also susceptible to
thromboembolic episodes involving both arteries and
veins. Consequently, these patients are subjected to
premature deaths from myocardial infarctions, pulmonary
emboli, and cerebrovascular accidents. Surgeons must be
aware that affected patients experience a greater incidence
of postoperative thromboembolism with general anes-
thesia and surgical procedures and therefore, are best
performed under local anesthesia, if possible.
Elevations of both methionine and homocystine in
body fluids are the diagnostic laboratory findings. Freshly
voided urine should be tested, since homocystine is
unstable and may disappear as the urine is stored. The
diagnosis may be confirmed by assay of the enzyme in
liver biopsy specimens, cultured fibroblasts, or phyto-
hemaglutinin stimulated lymphocytes. Prenatal diagnosis
is feasible by an enzyme assay of cultured amniotic cells
or chorionic villi.
1032 IAP Textbook of Pediatrics
Homocystinuria is one of the few metabolic disorders
which are treatable. Pyridoxine (vitamin B6) combined
with dietary restriction of methionine benefits nearly 40
percent of these patients (Table 18.4.1).
TABLE 18.4.1: Diet for Homocystinuria patients
List A - Forbidden foods
(a) Meat, chicken, fish, eggs.
(b) Milk, cheese, curd, ice-cream, chocolates, horlicks,
oval-tine.
(c) Wheat flour, bajra, maize, barley, jowar, oat meal, bread,
cakes, biscuits and pasteries.
(d) Rice and pulses.
(e) Nuts and dried fruits.
(f) Maggi and other soup cubes.
(g) Peas.
(h) Methi, arvileaves.
List B - Foods to be consumed in moderate amounts
(a) Beans, beet root, cauliflower, bathua, cabbage, carrot,
onion, potatoes, radish, sweet potatoes, lowki, brinjal,
cucumber, bhindi, pumpkin, tomatoes.
(b) Banana, grapes, guava, mango, papaya, apple.
List C - Unrestricted foods
(a) Arrowroot, cornflour, sago, custard powder.
(b) Sugars, honey, jam, marmalade, jellies.
(c) Butter, cooking fat and oil.
(d) Tea, coffee, squash.
(e) Salt, pepper, vinegar, spices, curry powder.
(f) Lowki, tori, tinda.
MAPLE SYRUP URINE DISEASE (MSUD)
Decarboxylation of leucine, isoleucine and valine
(branched chain amino acids) is carried out by a complex
enzyme system (branched chain ketoacid dehydrogenase)
using thiamine pyrophosphate as a coenzyme. Deficiency
of this enzyme system causes MSUD, named after the sweet
odor of maple syrup, found in body fluids, especially urine.
Several forms of this condition have been reported.
The classic form presents in the neonatal period with
lethargy, poor feeding, hypertonicity, convulsions,
resistant hypoglycemia, metabolic acidosis and coma.
Death occurs in few weeks to few months in untreated
cases. Diagnosis is established by noting the peculiar odor
of urine, by noting elevated levels of branched chain amino
acids in urine and plasma.
Management in acute stage consists of provision of
high calories intravenously and doing peritoneal dialysis,
to remove excess amounts of branched chain amino acids
from circulation. The diet should be low in these amino
acids and synthetic formulas are; available. The long-term
outcome is guarded. Some forms of MSUD respond to
thiamine.
HARTNUP DISEASE
This rare autosomal recessive disorder is characterized
by a transport failure of tryptophan in the gut and in the
renal tubules with subsequent breaking down of this
amino acid by the intestinal flora, reabsorption of indols
and indicans, thus formed and their elimination into
urine. Plasma levels of all amino acids and even of
tryptophan are normal as absorption of small peptides
containing the latter, takes place in the usual manner.
The major degradative pathway of tryptophan leads
normally to formation of nicotinic acid, which is the main
component of NAD and NADP. Thus, the deficiency of
this amino acid or precisely of coenzyme I and II will give
a picture resembling pellagra, characterized by photo-
sensitive dermatitis, tremor, headache, ataxia, diplopia,
psychiatric disturbances. The symptoms are usually
intermittent and precipitated by stress, infection, poor
nutrition and sulphonamide therapy.
Classical clinical picture and excretion of large
amounts of indoles and indicans in urine establish the
diagnosis. Avoidance of undue exposure to sun and daily
intake of 50 to 300 mg of nicotinamide helps these patients.
TYROSINEMIA
Tyrosine is used for protein synthesis and is a precursor
of dopamine, norepinephrine, epinephrine, melanin, and
thyroxine. At least two distinct clinical entities are
associated with increase in plasma concentrations of
tyrosine, but only in tyrosinemia II are signs and symptoms
attributed to high levels of tyrosine in body fluids. A
transient form of tyrosinemia is seen in newborn infants.
Tyrosinemia Type-I (Tyrosinosis,
Hereditary Tyrosinemia)
Tyrosinemia type-I is an autosomal recessive trait. This
condition is caused by a deficiency of an enzyme
fumarylacetoacetate hydrolase, which results in a
moderate elevation of serum tyrosine which in turn causes
severe involvement of the liver, kidney and central nervous
system. There are two main forms of the disease: the
neonatal or acute form and the chronic or latent form.
Infants having the acute form, become symptomatic
within the first 6 months of life. The common findings are
failure to thrive, developmental delay, irritability, vomiting,
diarrhea, fever, hepatomegaly, jaundice, hypoglycemia,

bleeding tendencies, cabbage like odor and death from
hepatic failure usually occurs before the second year of life.
In the chronic form, clinical manifestations may not
appear until after the first year of age. It is characterized
by failure to thrive, developmental delay, progressive
cirrhosis, renal tubular dysfunction (Fanconi’s syndrome),
Genetics 1033
motor activity. Tyrosinemia usually resolves
spontaneously during the 1st month of life. The condition
is presumably due to delayed maturation of p-
hydroxyphenyl pyruvic acid oxidase. The condition can
be corrected by reducing the amount of protein in the diet
and